TW202515903A - Anti-pd-1-based treatment before and after surgery - Google Patents

Abstract

The disclosure relates to treatment of solid cancers, such as breast, colon and lung cancer (in particular, non-small cell lung cancer (NSCLC)) in human subjects with an anti-PD-1 antibody and, optionally, chemotherapy. In some embodiments, the cancer is an early-to-moderate ( e.g., resectable) stage ( e.g., stage I, stage IIA, stage IIB, or stage IIIA) breast, colon or NSCLC. In some embodiments, the treatment is Tislelizumab in combination with chemotherapy prior to surgery, with a different dose of Tislelizumab in the adjuvant phase following surgery. In some embodiments, the administration regimen comprises administration of 200 mg of an anti-PD-1 antibody ( e.g., tislelizumab) ( e.g., every three weeks), followed by tumor resection, and administration of 400 mg of the anti-PD-1 antibody ( e.g., every six weeks). In some embodiments, the chemotherapy is platinum-based ( e.g., carboplatin and/or cisplatin), and optionally further comprises pemetrexed ( e.g., for non-squamous carcinoma) or paclitaxel ( e.g., for squamous carcinoma). In some embodiments, the treatment is first-line treatment for patients with untreated solid cancer ( e.g., NSCLC). In some embodiments, the claimed therapy is effective in the treatment of NSCLC, and the human subject is a responder to treatment by at least one measure of response to treatment.

Description

Anti-PD-1 based treatment before and after surgery

Disclosed herein are methods for preventing, delaying progression, or treating solid tumors (such as breast cancer, colon cancer, and lung cancer (e.g., non-small cell lung cancer)) in an individual in need thereof, the methods comprising administering an antibody or fragment thereof that binds to anti-PD-1 as described herein (particularly using the administration doses and schedules described herein), optionally in combination with chemotherapy.

Programmed death ligand 1 (PD-L1; also known as CD274 and B7-H1) is believed to play an important role in immune regulation and maintenance of peripheral tolerance. Immune checkpoint therapy targeting PD-L1 or its receptor PD-1 has achieved breakthrough improvements in clinical responses in a variety of human cancer types (e.g., see Brahmer et al., N Engl J Med , 366: 2455-2465 (2012); Robert et al., N Engl J Med , 372: 320-330 (2015); Topalian et al., N Engl J Med , 366: 2443-2454 (2012); Wolchok et al., N Engl J Med , 369: 122-133 (2013)).

Tislelizumab (also known as BGB A317) is a humanized immunoglobulin G4 (IgG4) variant monoclonal antibody against PD-1 that is being developed for the treatment of human malignancies in multiple organs and tissues. Tislelizumab binds to the extracellular domain of human PD-1 with high specificity and affinity, and competitively blocks the binding of PD-L1 and programmed death ligand-2 (PD-L2). Unlike other PD-1 inhibitors, tislelizumab is specifically engineered to remove the Fc and hinge regions in order to minimize binding of Fcγ receptors on macrophages, which can reduce potential negative interactions.

The management of early and advanced solid tumors is a major challenge and typically consists of a combination of surgical, radiotherapy, and systemic therapy approaches. However, upfront surgical treatment, with or without adjuvant therapy, carries significant risks of morbidity and potential complications. For example, in the case of non-small cell lung cancer (NSCLC), although surgery is considered a first-line option, only 25%-30% of NSCLC are amenable to potentially curative resection. Furthermore, despite optimal surgical management, the 5-year survival rate of resected NSCLC ranges from 73% for pathological stage Ia to 25% for pathological stage IIIa (Le Chevalier, T., 2010. Annals of Oncology , 21, pp. vii196-vii198). As a result, only a small percentage of patients with newly diagnosed lung tumors are eligible for curative surgery, and many of these patients are at increased risk for recurrence after surgery.

Treatment with chemotherapy and/or immunotherapy in the form of checkpoint inhibitors targeting the PD-1/PD-L1 axis before surgery (neoadjuvant) can be incorporated into the care of patients with early-stage solid tumors. The optimal timing of neoadjuvant and adjuvant immunotherapy treatment remains unclear. (Owen D. et al. J Thorac Dis . 2018 Feb;10(Suppl 3):S404-S411). For NSCLC, the disease-free survival (DFS) benefit of targeted immunotherapy does not translate into an overall survival (OS) benefit for patients with cancer driver gene mutations. For patients without lung cancer driver gene mutations, chemotherapy has reached a plateau in terms of improving efficacy and survival. (Bai, R. et al., 2020. Frontiers in Oncology , 10, pp. 575472).

Therefore, there is a long-standing unmet need in the industry for effective treatments for solid tumors, such as breast cancer, colon cancer, and non-small cell lung cancer. In particular, there is a need to improve the life expectancy, survival rate, and response to treatment of patients with early-stage, operable disease.

In some aspects, the present disclosure provides a method for treating cancer in an individual in need thereof, wherein the cancer is a solid cancer that is surgically resectable, the method comprising: (i) during a first treatment period, parenterally administering to the individual a first dose of an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the first dose of the anti-PD-1 antibody is 200 mg (e.g., once every three weeks); (ii) after (i), surgically resecting the cancer in the individual; and (iii) during a second treatment period after (ii), parenterally administering to the individual a second dose of the anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the second dose of the anti-PD-1 antibody is 400 mg (e.g., once every 6 weeks).

In some embodiments, tumor lesions are measured by CT scan or X-ray before treatment, and then measured at the time of surgery after 200 mg. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: VH CDR1, VH CDR2 and VH CDR3, which comprise the amino acid sequences shown in SEQ ID Nos: 31, 32 and 33, and VL CDR1, VL CDR2 and VL CDR3, which comprise the amino acid sequences shown in SEQ ID Nos: 34, 35 and 36.

In some aspects, the cancer is an early stage cancer. In some aspects, the cancer is a stage II or stage IIIA cancer. In some aspects, the cancer is a stage I cancer. In some aspects, the cancer is a stage IIA cancer. In some aspects, the cancer is a stage IIB cancer. In some aspects, the cancer is an intermediate stage cancer. In some aspects, the cancer is an advanced or metastatic cancer (e.g., a resectable advanced or metastatic cancer). In some aspects, the cancer is breast cancer, colon cancer, or lung cancer. In some aspects, the cancer is non-small cell lung cancer (NSCLC). In some aspects, the cancer is squamous cell carcinoma. In some aspects, the cancer is non-squamous cell carcinoma. In some aspects, the cancer is stage II or stage IIIA NSCLC. In some aspects, the cancer is not locally advanced or metastatic (e.g., not locally advanced or metastatic NSCLC).

In some aspects, the heavy chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID NO: 24, and the light chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID NO: 26. In some aspects, the anti-PD-1 antibody comprises an IgG constant region comprising the amino acid sequence of SEQ ID NO: 88. In some aspects, the anti-PD-1 antibody is administered intravenously, optionally wherein the administration is performed by IV infusion.

In some aspects, the individual has not previously received cancer treatment or the treatment is a first line treatment. In some aspects, the individual has not previously received chemotherapy, radiation therapy, and/or immunotherapy. In some aspects, the treatment is a second line treatment.

In some aspects, the first treatment period comprises 3 or 4 cycles, each of which is three weeks. In some aspects, the second treatment period comprises less than or equal to 8 cycles, each of which is six weeks. In some aspects, the second treatment period comprises at least 8 cycles, each of which is six weeks. In some aspects, the second treatment period begins within 8 weeks of surgical resection.

In some embodiments, radiation therapy is administered after surgical resection before the start of the second treatment period. In some embodiments, radiation therapy is administered 30 to 60 days after surgical resection, and the second treatment period begins between 7 to 30 days after radiation therapy. In some embodiments, radiation therapy is not administered after surgical resection. In some embodiments, the second treatment period begins between 2 to 8 weeks after surgical resection.

In some embodiments, the first treatment period further comprises administering a therapeutically effective amount of one or more chemotherapeutic drugs. In some embodiments, the one or more chemotherapeutic drugs comprise a platinum chemotherapeutic drug. In some embodiments, the one or more chemotherapeutic drugs are carboplatin or cisplatin. In some embodiments, cisplatin is administered intravenously at about 75 mg/m2, or at an area under the plasma or serum concentration-time curve of about 5 (AUC5), optionally wherein the administration is once every three weeks (Q3W), optionally wherein the administration is performed by IV infusion.

In some embodiments, the one or more chemotherapeutic agents further comprise pemetrexed or paclitaxel, optionally wherein pemetrexed is used when the NSCLC is non-squamous and paclitaxel is used when the NSCLC is squamous. In some embodiments, pemetrexed is administered intravenously at about 500 mg/m2, optionally wherein the administration is once every three weeks (Q3W), optionally wherein the administration is performed by IV infusion. In some embodiments, paclitaxel is administered intravenously at about 175 mg/m2, optionally wherein the administration is once every three weeks (Q3W), optionally wherein the administration is performed by IV infusion.

In some aspects, the treatment is clinically effective, or the individual is a responder to the treatment according to at least one measure of response to the treatment. In some aspects, the response to the treatment is measured by overall survival, progression-free or event-free survival, major pathological response ("MPR"), pathological complete response ("pCR"), overall response, partial response, duration of response, and/or tumor volume, diameter or size. A major pathological response (MPR) is defined as less than 10% of the residual viable tumor after the lead therapy. In some aspects, the treatment produces an MPR in the individual. In some aspects, the MPR is at least twice the MPR observed in a control group not treated with an anti-PD-1 antibody. In some aspects, the subject has a probability of MPR of at least 25%, 35%, 40%, 45%, or 50%. In some aspects, treatment is effective as evidenced by an MPR of at least 25%, 35%, 40%, 45%, or 50% in a patient population. In some aspects, response to treatment is measured by tumor volume, size, or diameter, and wherein treatment reduces tumor volume, size, or diameter in the subject by at least or more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%. In some aspects, treatment results in pCR in the subject. In some aspects, the subject has a probability of pCR of at least 15%, 20%, 25%, 30%, 35%, or 40%, or treatment is effective as evidenced by a pCR of at least 15%, 20%, 25%, 30%, 35%, or 40% in the patient population.

In some aspects, the individual does not have an EGFR mutation, a ROS1 mutation, or an ALK gene translocation. In some aspects, the individual is negative for EGFR genomic tumor aberrations. In some aspects, the individual is negative for ALK genomic tumor aberrations.

In some aspects, the subject is a human. In some aspects, the human is an adult. In some aspects, the subject does not have locally advanced cancer and/or metastatic cancer. In some aspects, the subject has liver, lung, lymph node, bone and/or adrenal metastasis, as appropriate, wherein the subject has liver, lung and/or lymph node metastasis.

References to Electronic Sequence Listings

The contents of the electronic sequence listing (BEIG_109_00US_SeqList_ST26.xml; size: 130,386 bytes; and creation date: August 11, 2023) are incorporated herein by reference in their entirety.

In some aspects, provided herein are methods for treating or delaying progression of solid cancers (e.g., lung cancer, such as non-small cell lung cancer) in individuals (e.g., humans) by administering an anti-PD-1 antibody or antigen-binding fragment thereof (e.g., tislelizumab or an anti-PD-1 antibody having the CDRs of tislelizumab) and, optionally, chemotherapy (carboplatin, cisplatin, paclitaxel, and/or pemetrexed). In some embodiments, the chemotherapy is carboplatin and/or cisplatin, and, optionally, paclitaxel and/or pemetrexed (e.g., paclitaxel if the cancer is squamous cell carcinoma, and pemetrexed if the cancer is non-squamous cell carcinoma).

In some embodiments, provided herein are methods for treating or delaying progression of a resectable solid cancer (e.g., lung cancer, such as non-small cell lung cancer) in an individual (e.g., a human) by administering an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., tislelizumab or an anti-PD-1 antibody having the CDRs of tislelizumab) and, if appropriate, chemotherapy (carboplatin, cisplatin, paclitaxel and/or pemetrexed), followed by resection or surgical removal of the cancer.

In some embodiments, provided herein are methods for treating or delaying progression of a resectable solid cancer (e.g., lung cancer, such as non-small cell lung cancer) in an individual (e.g., a human) by administering a first dose of an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., tislelizumab or an anti-PD-1 antibody having the CDRs of tislelizumab) and, if appropriate, chemotherapy (carboplatin, cisplatin, paclitaxel and/or pemetrexed), followed by resection of the cancer, and then administering a second dose of the anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the first dose of the anti-PD-1 antibody or fragment thereof is 200 mg, and the second dose of the anti-PD-1 antibody or fragment thereof is 400 mg. In some embodiments, the first dose is administered every 3 weeks (e.g., for 2, 3, or 4 cycles). In some embodiments, the second dose is administered every 6 weeks (e.g., for 6, 7, 8, 9, or 10 cycles or more).

In some embodiments, the solid cancer treated according to the methods described herein is an early to mid-stage solid cancer, such as lung cancer (e.g., non-small cell lung cancer).

In some embodiments, the solid cancer is squamous cell carcinoma. In some embodiments, the solid cancer is non-squamous cell carcinoma.

In some embodiments, the non-small cell lung cancer is squamous cell carcinoma. In some embodiments, the non-small cell lung cancer is non-squamous cell carcinoma.

In some embodiments, the therapy is a first-line therapy, i.e., the individual has not received treatment (e.g., chemotherapy and/or immunotherapy) for the cancer (e.g., lung cancer).

In some embodiments, the individual has progressed after, or is intolerant to, prior chemotherapy.

In some embodiments, the human subject is a responder to treatment according to at least one measure of response to treatment. In some embodiments, the claimed treatment is effective in treating a solid cancer (e.g., a stage I, stage IIA, stage II, or stage IIIA solid cancer, such as breast cancer, colon cancer, or lung cancer). In some embodiments, the claimed treatment is effective in treating non-small cell lung cancer (e.g., stage I, stage IIA, stage II, or stage IIIA non-small cell lung cancer).

The inventors of this application have discovered unexpected clinical benefits of the treatment regimen described herein for a specified group of human patients suffering from solid tumor types, such as non-small cell lung cancer. Definition

To make this disclosure easier to understand, some terms are first defined below. Other definitions of the following terms and other terms are set forth throughout this specification.

Although various embodiments and aspects of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that these embodiments and aspects are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the disclosure herein. It should be understood that various alternatives to the embodiments disclosed or described herein may be employed in practicing the present disclosure.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents or portions of documents cited in this application (including but not limited to patents, patent applications, articles, books, manuals, and theses) are expressly incorporated herein by reference in their entirety for any purpose.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure relates. For example, Juo, The Concise Dictionary of Biomedicine and Molecular Biology, 2nd edition, (2001), CRC Press; The Dictionary of Cell & Molecular Biology, 5th edition, (2013), Academic Press; and "The Oxford Dictionary of Biochemistry and Molecular Biology", Cammack et al., eds., 2nd edition, (2006), Oxford University Press provide general dictionaries of many of the terms used in this disclosure for those skilled in the art. Additional definitions of commonly used terms in molecular biology may be found in Benjamin Lewin, Genes V, published by Oxford University Press, 1994 (ISBN 0-19 854287-9); Kendrew et al. (eds.), The Encyclopedia of Molecular Biology, published by Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: A Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8).

Unless the context clearly indicates otherwise, as used herein (including the attached claims), the singular form of words (such as "a, an", and "the") include their corresponding plural referents. Unless the context clearly indicates otherwise, the term "or" is used to mean the term "and/or" and can be used interchangeably with the term "and/or". The term "and/or", when used herein, should be regarded as specifically disclosing the situation where each of the two specified features or components is with or without the other. Therefore, the term "and/or" used in phrases such as "A and/or B" herein is intended to include "A and B", "A or B", "A" (alone) and "B" (alone). Similarly, the term "and/or" used in phrases such as "A, B and/or C" is intended to cover each of the following: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

As used herein, the terms "such as" and "ie" are used for illustration only and are not intended to be limiting, and should not be construed as referring to only those items explicitly listed in this specification.

Unless expressly stated or obvious from the context, the term "about" as used herein means that a value or composition is within an acceptable error range for the particular value or composition as determined by one skilled in the art, which error range will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about" or "substantially comprising" can mean within one or more standard deviations according to practice in the art. "About" or "substantially comprising" can mean a range of up to 10% (i.e., ±10%). Thus, "about" can be understood to mean greater than or less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, 0.01%, or 0.001% of the stated value. For example, about 5 mg may include any amount between 4.5 mg and 5.5 mg. In addition, particularly with respect to biological systems or processes, the term may mean within an order of magnitude of a value or within 5 times of a value. When specific values or compositions are provided in the present disclosure, unless otherwise stated, the meaning of "about" or "substantially comprising" should be assumed to be within an acceptable error range for that specific value or composition.

Ranges may be expressed herein as from "about" one particular value and/or to "about" another particular value. When such a range is expressed, an alternative scenario includes from one particular value and/or to another particular value. Similarly, when a value is expressed as an approximation by using the antecedent "about," it is understood that the particular value forms an alternative scenario. It should be further understood that the endpoints of each range have meaning both in relation to the other endpoint and in relation to the other endpoint. As described herein, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value and, where appropriate, its fractional portion (such as one-tenth and one-hundredth of an integer) within the listed range.

The units, suffixes and symbols used herein are provided in their International System of Units (SI) recognized forms. Numerical ranges are inclusive of the values defining the range.

The terms “at least”, “more than”, “or more” and the like, for example, “at least one”, should be understood to include (but not limited to) at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 8, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88 ,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,1 29, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 or 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000 or more than the stated values. Any greater value or fraction therebetween is also included. Conversely, the term "not more than" includes every value that is less than the stated value. For example, "no more than 100 nucleotides" includes 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 7, 6, 5, 4, 3, 2, 1, and 0 nucleotides. Any smaller number or fraction therebetween is also included. The terms "plurality", "at least two", "two or more", "at least a second" and the like should be understood to include, but are not limited to, at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86 ,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149 or 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000 or more, including any greater number or fraction therebetween.

"Administering" as applied to animals, humans, experimental subjects, cells, tissues, organs or biological fluids means contacting an exogenous drug, therapeutic, diagnostic agent or composition with an animal, human, subject, cell, tissue, organ or biological fluid. Treating a cell encompasses contacting a reagent with the cell, as well as contacting a reagent with a fluid, wherein the fluid is in contact with the cell. The term "subject" or "patient" refers to any single individual desired to be treated or to participate in a clinical trial, epidemiological study or used as a control, and includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, horse, cow), and most preferably a human.

As used herein, the term "anticancer agent" refers to any agent useful in treating a cell proliferative disorder such as cancer, including but not limited to cytotoxic agents, chemotherapeutic agents, radiation therapy and radiotherapeutic agents, targeted anticancer agents, and immunotherapeutic agents, including cellular therapy.

Antibodies are large, complex molecules (molecular weight of about 150,000 or about 1320 amino acids) with a complex internal structure. The term "antibody" (Ab) includes, but is not limited to, glycoprotein immunoglobulins that specifically bind to an antigen. Generally speaking, antibodies are large, complex molecules (molecular weight of about 150,000 or about 1320 amino acids) with a complex internal structure. Antibodies may comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or antigen-binding molecules thereof. Each H chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH or Vh) and a heavy chain constant region. The heavy chain constant region comprises three constant domains, namely CH1, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL or Vl) and a light chain constant region. As used herein, the term "antibody" refers to a polypeptide in the immunoglobulin family that can non-covalently, reversibly and specifically bind to the corresponding antigen.

The light and heavy chain variable regions combine in 3-dimensional space to form variable regions that bind antigens (e.g., receptors on the surface of cells). The variable regions of each light/heavy chain (Vl/Vh) pair form an antibody binding site. In general, a complete antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are usually identical in primary sequence.

As will be presented in more detail below, within each light or heavy chain variable region, there are three short segments (average length of 10 amino acids) called complementation determining regions ("CDRs"). The six CDRs (three from the light chain and three from the heavy chain) in the antibody variable domain fold together in 3-dimensional space to form the actual antibody binding site that attaches to the target antigen. As provided herein, the terms "CDR-L1", "CDR-L2" and "CDR-L3" refer to the complementation determining regions (CDRs) 1, 2 and 3 of the antibody variable light (L) chain. In an embodiment, the variable light chain provided herein includes CDR-L1, CDR-L2 and CDR-L3 in the N-terminal to C-terminal direction. Likewise, the terms "CDR-H1", "CDR-H2", and "CDR-H3" as provided herein refer to the complementarity determining regions (CDRs) 1, 2, and 3 of the variable heavy (H) chain of an antibody. In certain embodiments, the variable heavy chain provided herein includes CDR-H1, CDR-H2, and CDR-H3 in the N-terminal to C-terminal direction. As further described below, the position and length of the CDRs have been precisely defined by Kabat, E. et al., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1983, 1987. Naturally produced antibodies are also glycosylated, for example, on the CH2 domain.

The portion of the variable region not contained in the CDR is called the framework ("FR"), which forms the environment of the CDR. Therefore, the complementation determining regions (CDRs) are interspersed with more conserved regions (i.e., framework regions). Therefore, each VH and VL contains three CDRs and four FRs, which are arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Although the variable regions of the heavy and light chains contain binding domains that interact with antigens, the constant regions of antibodies can mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. Table 1 : CDR number : Ring Kabat AbM Chothia Contact L1 L24--L34 L24--L34 L24--L34 L30--L36 L2 L50--L56 L50--L56 L50--L56 L46--L55 L3 L89--L97 L89--L97 L89--L97 L89--L96 H1 H31--H35B H26--H35B H26--H32...34 H30--H35B (Kabat number) H1 H31--H35 H26--H35 H26--H32 H30--H35 (Chothia Number) H2 H50--H65 H50--H58 H52--H56 H47--H58 H3 H95--H102 H95--H102 H95--H102 H93--H101

A number of definitions of CDRs are commonly used: Kabat numbering, Chothia numbering, AbM numbering, or contact numbering. The AbM definition is a compromise between the two definitions used by Oxford Molecular's AbM antibody modeling software. The contact definition is based on analysis of the complex crystal structures available.

The positions of CDRs and framework regions can be determined using various definitions well known in the art, such as Kabat, Chothia, AbM, and IMGT (see, e.g., Johnson et al., Nucleic Acids Res., 29:205-206 (2001); Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987); Chothia et al., Nature, 342:877-883 (1989); Chothia et al., J. Mol. Biol., 227:799-817 (1992); Al-Lazikani et al., J. Mol. Biol., 273:927-748 (1997); ImMunoGenTics (IMGT) numbers (Lefranc, M.-P., The Immunologist, 7, 132-136). (1999); Lefranc, M.P. et al., Dev. Comp. Immunol., 27, 55-77 (2003) ("IMGT" numbering scheme). The definition of antigenic binding sites is also described in the following references: Ruiz et al., Nucleic Acids Res., 28:219-221 (2000); and Lefranc, M.P., Nucleic Acids Res., 29:207-209 (2001); MacCallum et al., J. Mol. Biol., 262:732-745 (1996); and Martin et al., Proc. Natl. Acad. Sci. USA, 86:9268-9272 (1989); Martin et al., Methods Enzymol., 203:121-153 (1991); and Rees et al., In Sternberg M. J. E. (eds.), Protein Structure Prediction, Oxford University Press, Oxford, 141-172 (1996).

For example, according to Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3). According to Chothia, the CDR amino acid residues in VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3). By combining the CDR definitions of Kabat and Chothia, CDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in human VL. According to IMGT, the CDR amino acid residues in VH are numbered approximately 26-35 (HCDR1), 51-57 (HCDR2), and 93-102 (HCDR3), and the CDR amino acid residues in VL are numbered approximately 27-32 (LCDR1), 50-52 (LCDR2), and 89-97 (LCDR3) (according to Kabat numbering). According to IMGT, the CDR regions of the antibody can be determined using the program IMGT/DomainGapAlign.

In certain aspects, the CDRs of an antibody may be identified according to the Chothia numbering scheme, which refers to the locations of immunoglobulin structural loops (e.g., see Chothia C. and Lesk A.M., (1987), J Mol Biol 196: 901-917; Al-Lazikani B. et al., (1997) J Mol Biol 273: 927-948; Chothia C. et al., (1992) J Mol Biol 227: 799-817; Tramontano A. et al., (1990) J Mol Biol 215(1): 175-82; and U.S. Patent No. 7,709,226). Typically, when the Kabat numbering convention is used, the Chothia CDR-H1 loop is present at heavy chain amino acids 26 to 32, 33, or 34, the Chothia CDR-H2 loop is present at heavy chain amino acids 52 to 56, and the Chothia CDR-H3 loop is present at heavy chain amino acids 95 to 102, while the Chothia CDR-L1 loop is present at light chain amino acids 24 to 34, the Chothia CDR-L2 loop is present at light chain amino acids 50 to 56, and the Chothia CDR-L3 loop is present at light chain amino acids 89 to 97. The ends of the Chothia CDR-H1 loop vary in length between H32 and H34 when numbering using the Kabat numbering convention (this is because the Kabat numbering scheme places insertions at H35A and H35B; if both 35A and 35B are absent, the loop ends at 32; if only 35A is present, the loop ends at 33; if both 35A and 35B are present, the loop ends at 34). In specific embodiments, the CDRs of the antibodies described herein have been identified according to the Chothia numbering scheme.

When an antibody is said to contain CDRs according to a certain definition of CDRs (e.g., Kabat), that definition specifies the minimum number of CDR residues present in the antibody (i.e., Kabat CDRs). This does not exclude the fact that there are also other residues that fall within another customary CDR definition but are outside the specified definition. For example, an antibody containing CDRs defined by Kabat includes other possibilities: an antibody whose CDRs contain Kabat CDR residues but not other CDR residues, and an antibody whose HCDR1 is a composite Chothia-Kabat HCDR1 and whose other CDRs contain Kabat CDR residues but not other CDR residues based on other definitions.

In some cases, the CDR is substantially identical to that found in a reference antibody (e.g., an antibody of the present disclosure) and/or a CDR sequence provided in the present disclosure. In some embodiments, the CDR is substantially identical to a reference CDR (e.g., a CDR provided in the present disclosure) in that it is identical in sequence or contains 1, 2, 3, 4, or 5 (e.g., 1-5) amino acid substitutions compared to the reference CDR. In some embodiments, a CDR is substantially identical to a reference CDR in that it exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity (e.g., 85%-90%, 85%-95%, 85%-100%, 90%-95%, 90%-100%, or 95%-100%) with the reference CDR. In some embodiments, a CDR is substantially identical to a reference CDR in that it exhibits at least 96%, 96%, 97%, 98%, 99%, or 100% sequence identity with the reference CDR. In some embodiments, a CDR is substantially identical to a reference CDR in that one amino acid in the CDR is deleted, added, or substituted compared to the reference CDR, and the CDR has an amino acid sequence that is otherwise identical to the sequence of the reference CDR. In some embodiments, a CDR is substantially identical to a reference CDR in that 2, 3, 4, or 5 (e.g., 2-5) amino acids in the CDR are deleted, added, or substituted compared to the reference CDR, and the CDR has an amino acid sequence that is otherwise identical to the sequence of the reference CDR. In various embodiments, the antigen-binding fragment binds to the same antigen as the reference antibody.

The term "antibody" further includes, but is not limited to, monoclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, and anti-idiotypic (anti-Id) antibodies. Antibodies may include, for example, monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, engineered antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, endoantibodies, antibody fusions (sometimes referred to herein as "antibody conjugates"), heterologous binding antibodies, single domain antibodies, monovalent antibodies, single chain antibodies, or single chain Fv (scFv), camelized antibodies, affibodies, Fab fragments, F(ab')2 fragments, disulfide-linked Fv (sdFv), anti-idiotypic (anti-Id) antibodies (including, for example, anti-anti-Id antibodies), minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as "antibody mimetics"), and antigen-binding fragments of any of the above. In certain embodiments, the antibodies described herein refer to a polyclonal antibody population. The antibody may also comprise, for example, a Fab' fragment, a Fd' fragment, a Fd fragment, an isolated CDR, a single chain Fv, a polypeptide-Fc fusion, a single domain antibody (e.g., a shark single domain antibody such as an IgNAR or a fragment thereof), a camel antibody, a single chain or tandem bivalent antibody (TandAb®), Anticalins®, Nanobodies®, BiTE®, ankyrin repeat sequence proteins or DARPINs®, Avimers®, DARTs, TCR-like antibodies, Adnectins®, Affilins®, Trans-Bodies®, Affibodies®, TrimerX®, MicroProteins, Fynomers®, Centyrins®, and KALBITOR®.

Immunoglobulins may be derived from any of the commonly known isotypes, including, but not limited to, IgA, secretory IgA, IgG, IgE, IgM, IgD, IgA, and IgY. IgG subclasses are also well known to those skilled in the art, and include, but are not limited to, human IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The terms "antibody" and "immunoglobulin" or "Ig" are used interchangeably herein.

The term "antibody" includes intact antibodies and binding fragments thereof. Typically, a fragment competes with the intact antibody from which it is derived for specific binding to a target. Fragments include individual heavy chain, light chain Fab, Fab', F(ab')2, Fv fragments and single domain antibodies. Single (variable) domain antibodies include VH regions separated from VL partners in conventional antibodies (or vice versa) (Ward et al., 1989, Nature 341: 544-546), as well as VH regions (sometimes referred to as VHH) from species such as Camelidae or cartilaginous fish (e.g., arthropod sharks), where the VH region is not associated with the VL region (e.g., see WO 9404678). For example, a natural single variable region antibody from Camelidae includes a VHH variable region, and CH2 and CH3 constant regions. Single domain antibodies can be humanized by methods similar to conventional antibodies. Dab-type antibodies are usually obtained from antibodies of human origin. Nanobody-type antibodies have camel or shark origin and can be humanized. Fragments can be produced by recombinant DNA technology, or by enzymatic or chemical separation of intact immunoglobulins. The term "antibody" also includes bispecific, trispecific and multispecific antibodies. For example, bispecific or bifunctional antibodies are artificial hybrid antibodies with two different heavy chain/light chain pairs and two different binding sites (see, e.g., Songsivilai and Lachmann, Clin. Exp. Immunol., 79:315-321 (1990); Kostelny et al., J. Immunol., 148:1547-53 (1992)).

Antibodies can exist, for example, as intact immunoglobulins or as a number of well-characterized fragments produced by digestion with various peptidases. For example, pepsin digests the antibody below the disulfide bonds in the hinge region to produce F(ab)'2, which is a dimer of Fab, which itself is a light chain joined to VH-CH1 by a disulfide bond. F(ab)'2 can be reduced under mild conditions to cleave the disulfide bonds in the hinge region, thereby converting the F(ab)'2 dimer into a Fab' monomer. The Fab' monomer is essentially a Fab with a portion of the hinge region (see Fundamental Immunology (Paul ed., 3rd edition, 1993). Although various antibody fragments are defined with respect to the digestion of intact antibodies, those skilled in the art will appreciate that these fragments can be synthesized de novo chemically or by using recombinant DNA methods. Therefore, the term antibody as used herein also includes antibody fragments produced by modifying whole antibodies, or those antibody fragments (e.g., single-chain Fv) synthesized de novo using recombinant DNA methods, or those antibody fragments identified using phage display libraries (e.g., see McCafferty et al. (1990)).

"Antigen binding molecule", "antigen binding portion" or "antibody fragment" refers to any molecule that comprises the antigen binding portion (e.g., CDR) of the antibody from which the molecule is derived. Examples of antibody fragments include (but are not limited to) Fab, Fab', F(ab')2 and Fv fragments, dAb, linear antibodies, scFv antibodies, and multispecific antibodies formed from antigen binding molecules. Peptibodies (i.e., Fc fusion molecules comprising a peptide binding domain) are another example of suitable antigen binding molecules. In some embodiments, the antigen binding molecule binds to an antigen on a tumor cell. In certain embodiments, the antigen binding molecule binds to PD-1. In other embodiments, the antigen binding molecule is an antibody fragment that specifically binds to an antigen, including one or more complementary determining regions (CDRs) thereof. In other embodiments, the antigen binding molecule is a single-chain variable fragment (scFv).

Unless otherwise indicated, "antigen-binding fragment" means an antigen-binding fragment of an antibody, i.e., an antibody fragment that retains the ability to specifically bind to an antigen bound by a full-length antibody, such as a fragment that retains one or more CDR regions. Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; bivalent antibodies; linear antibodies; single-chain antibody molecules, such as single-chain Fv (ScFv); nanobodies and multispecific antibodies formed from antibody fragments. In some embodiments, the antigen-binding molecule binds to an antigen on a tumor cell. In certain embodiments, the antigen-binding molecule binds to PD-1.

The antigen binding fragment can be produced by any means. For example, in some embodiments, the antigen binding fragment can be produced enzymatically or chemically by fragmentation of a complete antibody. In some embodiments, the antigen binding fragment can be recombinantly produced (i.e., by expressing an engineered nucleic acid sequence). In some embodiments, the antigen binding fragment can be synthesized in whole or in part. In some embodiments, the length of the antigen binding fragment can be at least about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 amino acids or more; in some embodiments, at least about 200 amino acids (e.g., 50-100, 50-150, 50-200, or 100-200 amino acids).

As used herein, "anti-tumor effect" refers to a biological effect that may be manifested by a reduction in tumor size, a reduction in the number of tumor cells, a reduction in tumor cell proliferation, a reduction in the number of metastases, a prolongation of overall or progression-free survival, a prolongation of life expectancy, or an improvement in various physiological symptoms associated with tumors.

When referring to a cancer patient treated with a treatment regimen (such as the treatment described herein), "anti-tumor response" means at least one positive treatment effect, such as a decrease in the number of cancer cells, a decrease in tumor size, a decrease in the rate of cancer cell infiltration in peripheral organs, a decrease in the rate of tumor metastasis or tumor growth, or progression-free survival. Positive treatment effects in cancer can be measured in a variety of ways (e.g., see Weber, W.A. "Assessing tumor response to therapy." Journal of nuclear medicine 50. Suppl 1 (2009): 1S-10S); Eisenhauer et al., supra). In some embodiments, the anti-tumor response to the treatment described herein is evaluated using RECIST 1.1 criteria, bidirectional irRC or unidirectional irRC. In some embodiments, the anti-tumor response is any one of SD, PR, CR, PFS or DFS.

With respect to amino acid sequences, those skilled in the art will recognize that individual substitutions, deletions or additions of nucleic acid, peptide, polypeptide or protein sequences that alter, add or delete a single amino acid or a small percentage of amino acids in the encoded sequence are "conservatively modified variants," wherein the alteration results in the substitution of an amino acid with a chemically similar amino acid. Such conservatively modified variants are distinct from and do not exclude polymorphic variants, interspecies homologs and alleles.

The most common exchanges are isoleucine/valine, tyrosine/phenylalanine, aspartate/glutamine, lysine/arginine, methionine/leucine, aspartate/asparagine, glutamine/glutamine, leucine/isoleucine, methionine/isoleucine, threonine/serine, tryptophan/phenylalanine, tyrosine/histidine, Tyrosine/tryptophan, glutamine/arginine, histidine/asparagine, histidine/glutamine, lysine/asparagine, lysine/glutamine, lysine/glutamine, lysine/glutamine, phenylalanine/leucine, phenylalanine/methionine, serine/alanine, serine/asparagine, valine/leucine, and valine/methionine. Each of the following eight groups contains exemplary amino acids that can be considered conservative substitutions for one another (e.g., see Creighton, Proteins (1984)). 1) Alanine (A), glycine (G); 2) Aspartic acid (D), glutamine (E); 3) Asparagine (N), glutamine (Q); 4) Arginine (R), lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M) Individual exemplary conservative amino acid substitutions: Table 2 Original Residue Conservative substitution Ala (A) Gly; Ser Arg (R) Lys、His Asn(N) Gln; His Asp (D) Glu; Asn Cys (C) Ser; Ala Gln (Q) Asn Glu (E) Asp; Gln Gly (G) Ala His (H) Asn; Gln Ile (I) Leu; Val Leu (L) Ile; Val Lys (K) Arg; His Met (M) Leu; Ile; Tyr Phe (F) Tyr；Met；Leu Pro (P) Ala Ser (S) Thr Thr (T) Ser Trp (W) Tyr; Phe Tyr (Y) Trp; Phe Val (V) Ile; Leu

In some embodiments, there may be at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, or at least 40 conservative substitutions. In some embodiments, there may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 conservative substitutions. Thus, "conservative amino acid substitutions" refer to substitutions of amino acids in a protein with other amino acids having similar properties (e.g., charge, side chain size, hydrophobicity/hydrophilicity, main chain conformation and rigidity, etc.), such that changes can be made frequently without altering the biological activity or other desired properties of the protein, such as antigen affinity and/or specificity. Those skilled in the art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide will not substantially alter biological activity (e.g., see Watson et al. (1987) Molecular Biology of the Gene, The Benjamin/Cummings Pub. Co., p. 224 (4th ed.)). In addition, substitutions of structurally or functionally similar amino acids are less likely to destroy biological activity.

The term "buffer" encompasses those agents that maintain the solution pH of the compositions of the present disclosure within an acceptable range.

"Chemotherapeutic agents" are chemical or biological substances that can induce cancer cell death or interfere with cancer cell growth, differentiation, repair and/or function. Classes of chemotherapeutic agents include, but are not limited to: microtubule inhibitors, such as taxanes (paclitaxel, docetaxel) and vinca alkaloids (vincristine, vinblastine, vinorelbine); anti-metabolites (5-fluorouracil, capecitabine, gemcitabine) and antifolates (methotrexate, pemetrexed); kinase inhibitors (crizotinib, erlotinib, sunitinib); topoisomerase inhibitors (deruxtecan, topotecan, irinotecan); otecan, anthracycline, etoposide); Cytotoxic/antitumor antibiotics (bleomycin, m Ithramycin), mitomycin), photosensitizers, antiestrogens and selective estrogen receptor modulators (SERMs), antiprogestins, estrogen receptor downregulators (ERDs), estrogen receptor antagonists, luteinizing hormone-releasing hormone agonists, antiandrogens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, and antisense oligonucleotides that inhibit abnormal cell proliferation or tumor growth-related gene expression. Current standard of care (SOC) treatment for certain cancers (e.g., colorectal cancer) in the early-line setting includes chemotherapy based on fluoropyrimidines, oxaliplatin, and irinotecan, either in combination or sequentially, with monoclonal antibodies targeting vascular endothelial growth factor (VEGF) (e.g., bevacizumab, ziv-aflibercept) or VEGF receptors (e.g., ramucirumab), as appropriate, and, in patients with Ras wild-type tumors, monoclonal antibodies targeting epidermal growth factor (EGF) receptors (e.g., cetuximab, panitumumab). For patients who have been heavily pretreated beyond a second-line setting, treatment options are particularly limited, and associated toxicities can be severe.

As used herein with respect to agents such as the disclosed anti-PD-1 antibodies (e.g., tislelizumab) and chemotherapeutic agents, "co-administration" means administering the agents to have overlapping therapeutic activities, without necessarily administering the agents to a subject at the same time. The agents may or may not be in physical combination prior to administration. In one embodiment, the agents are administered to a subject at the same time or about the same time. For example, the agents may be contained in separate vials, when in liquid solution, may be mixed into the same intravenous infusion bag or injection device, and administered to a patient at the same time.

"Combination therapy" refers to those situations in which an individual is exposed to two or more therapeutic regimens (e.g., two or more therapeutic moieties) simultaneously. In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, the regimens may be administered sequentially (e.g., all "doses" of the first regimen are administered before any doses of the second regimen are administered); in some embodiments, the doses are administered in overlapping dosing schedules. In some embodiments, "administration" of a combination therapy may involve administering one or more agents or dosing regimens to an individual receiving the other agents or dosing regimens in the combination. For clarity, combination therapy does not require that the individual agents be administered together in a single composition (or even necessarily at the same time), but in some embodiments, two or more agents or their active portions may be administered together in a combined composition or even in a combined compound (e.g., as part of a single chemical complex or covalent entity). This administration also encompasses co-administration of each active ingredient in multiple or separate containers (e.g., capsules, powders, and liquids). Powders and/or liquids may be reconstituted or diluted to the desired dose prior to administration. Thus, the phrase "in combination with" means administering an anti-PD-1 antibody to an individual at the same time, immediately before, or immediately after the administration of another therapeutic agent. In certain embodiments, an anti-PD-1 antibody is administered as a co-formulation with another therapeutic agent.

Throughout the specification, the word "comprising" or variations such as "comprises" or "comprising" should be understood to imply the inclusion of the stated elements, integers or steps or groups of elements, integers or steps, but not the exclusion of any other elements, integers or steps or groups of elements, integers or steps. It should be understood that wherever the word "comprising" is used herein to describe an aspect, other similar aspects described by "consisting of" and/or "consisting essentially of" are also provided.

The terms "constant region" and "constant domain" are used interchangeably and have the meanings commonly used in the art. The constant region is the portion of the antibody, such as the carboxyl terminal portion of the light chain and/or heavy chain, which is not directly involved in the binding of the antibody to the antigen, but can exhibit various effector functions, such as interaction with Fc receptors. The constant region of an immunoglobulin molecule generally has a more conserved amino acid sequence than the immunoglobulin variable domain.

"Conservatively modified variants" or "conservative substitutions" refer to the substitution of an amino acid in a protein with another amino acid having similar properties (e.g., charge, side chain size, hydrophobicity/hydrophilicity, main chain conformation and rigidity, etc.), so that changes can be made frequently without changing the biological activity or other desirable properties of the protein, such as antigen affinity and/or specificity. Those skilled in the art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide will not substantially alter biological activity (e.g., see Watson et al. (1987) Molecular Biology of the Gene, The Benjamin/Cummings Pub. Co., p. 224 (4th ed.)). In addition, substitutions of amino acids that are similar in structure or function are less likely to destroy biological activity. Exemplary conservative substitutions are set forth herein.

The term "dosage form" may be used to refer to a physically discrete unit of an active agent (e.g., an antigen binding system or an antibody) for administration to an individual. Typically, each such unit contains a predetermined amount of active agent. In some embodiments, this amount is an amount (or an integral portion thereof) of a unit dose suitable for administration according to a dosing regimen, which is determined to be associated with a desired or beneficial outcome when administered to a relevant population. The total amount of the therapeutic composition or dose administered to an individual is determined by one or more medical practitioners and may involve administration of more than one dosage form.

The term "dosage regimen" may be used to refer to a group of one or more unit doses that are individually administered to an individual. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, the dosing regimen comprises a plurality of doses, each dose being separated in time from the other doses. In some embodiments, the dosing regimen comprises a plurality of doses, and consecutive doses are separated from each other by equal time periods; in some embodiments, the dosing regimen comprises a plurality of doses, and consecutive doses are separated from each other by time periods of at least two different lengths. In some embodiments, all doses within a dosing regimen have the same unit dose amount. In some embodiments, different doses within a dosing regimen have different amounts. In some embodiments, the dosing regimen comprises a first dose in a first dosage amount, followed by one or more additional doses in a second dosage amount different from the first dosage amount. In some embodiments, the dosing regimen is adjusted periodically to achieve a desired or beneficial result.

"Persistent stable disease rate" means stable disease (SD) lasting about 23 weeks, where SD is cancer that is neither decreasing nor increasing in size or severity.

"Effector cells" refer to cells of the immune system that express one or more Fc receptors and mediate one or more effector functions. In some embodiments, effector cells may include (but are not limited to) one or more of the following: monocytes, macrophages, neutrophils, dendritic cells, eosinophils, fat cells, platelets, large granulocytes, Langerhans' cells, natural killer (NK) cells, T lymphocytes and B lymphocytes. Effector cells can be cells of any organism, including (but not limited to) humans, mice, rats, rabbits and monkeys.

"Effector function" refers to the biological consequence of the interaction of the Fc region of an antibody with an Fc receptor or ligand. Effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and complement-mediated cytotoxicity (CMC). Effector functions may be antigen binding-dependent, antigen binding-independent, or both. ADCC refers to the lysis of antibody-bound target cells by immune effector cells. Without wishing to be bound by any theory, ADCC is generally understood to involve effector cells bearing Fc receptors (FcRs) (e.g., cells that display the antibody-bound antigen on their surface) that recognize and subsequently kill antibody-coated target cells. Effector cells that mediate ADCC may include immune cells, including but not limited to one or more of natural killer (NK) cells, macrophages, neutrophils, and eosinophils.

The term "excipient" refers to an agent that can be included in the composition, for example, to provide or contribute to a desired consistency or stabilizing effect. In some embodiments, suitable excipients can include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene, ethylene glycol, water, ethanol, or the like.

The term "heavy chain" when used in reference to antibodies may refer to any of the different types of amino acid sequences based on constant domains, such as alpha (α), delta (δ), epsilon (ε), gamma (γ), and muon (μ), which give rise to IgA, IgD, IgE, IgG, and IgM classes of antibodies, respectively, including subclasses of IgG, such as IgG1, IgG2, IgG3, and IgG4.

As used herein, "host cell" refers to any cell of any organism used for the purpose of producing a recombinant protein encoded by an expression vector or amplifying an expression vector introduced into a host cell. "Mammalian recombinant host cell" refers to a mammalian host cell that contains a heterologous expression vector, which may or may not be integrated into a host cell chromosome. "Bacterial recombinant host cell" refers to a bacterial host cell that contains a heterologous expression vector, which may or may not be integrated into a host cell chromosome.

The term "human antibody" herein means an antibody that contains only human immunoglobulin protein sequences. The variable and constant domain sequences generated may be assembled, or derived from human immunoglobulin sequences, or sequences that are indistinguishable therefrom. Human antibodies may contain murine carbohydrate chains if produced in mice, in mouse cells, or in hybridomas derived from mouse cells. Similarly, "mouse antibodies" or "rat antibodies" mean antibodies that contain only mouse or rat immunoglobulin protein sequences, respectively.

In some embodiments, an antibody (or antibody component) may be considered "human" even if its amino acid sequence contains residues or elements that are not encoded by human germline immunoglobulin sequences (e.g., variations introduced by random or site-directed mutagenesis in vitro or by in vivo somatic mutagenesis).

The term "humanized" or "humanized antibody" refers to a form of an antibody that contains sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequences derived from non-human immunoglobulins. In general, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin, and all or substantially all of the FR regions are those of a human immunoglobulin sequence. Humanized antibodies will also optionally comprise at least a portion of an immunoglobulin constant region (Fc), typically at least a portion of a human immunoglobulin. Where necessary, the prefix "hum", "hu", "Hu" or "h" is added to the antibody homologous name to distinguish the humanized antibody from the parent rodent antibody. Humanized forms of doxycycline antibodies will generally include the same CDR sequences of the parent doxycycline antibody, but may include certain amino acid substitutions to increase affinity, increase the stability of the humanized antibody, remove post-translational modifications, or other reasons. In some embodiments, a "humanized" antibody comprises one or more framework domains having substantially the amino acid sequence of a human framework domain, and one or more complementary determining regions having substantially the amino acid sequence of a non-human antibody. In some embodiments, a humanized antibody comprises at least a portion of an immunoglobulin constant region (Fc) (typically a human immunoglobulin constant domain). In some embodiments, a humanized antibody may comprise CH1, hinge, CH2, CH3, and optionally a CH4 region of a human heavy chain constant domain.

Monoclonal antibody-producing "hybridomas" can be cultured in vitro or in vivo. High titers of monoclonal antibodies can be obtained in vivo production, where cells from individual hybridomas are injected intraperitoneally into mice (e.g., pristine-primed Balb/c mice) to produce ascites fluid containing high concentrations of the desired antibody. Monoclonal antibodies of the IgM or IgG isotype can be purified from such ascites fluid or from culture supernatants using column chromatography methods well known to those skilled in the art.

The term "hypervariable region" refers to the amino acid residues in an antibody that are responsible for antigen binding. The hypervariable region includes amino acid residues from the "complementary determining regions" or "CDRs" (i.e., CDR-L1, CDR-L2, and CDR-L3 in the light chain variable domain and CDR-H1, CDR-H2, and CDR-H3 in the heavy chain variable domain). See Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md. (defining the CDR regions of antibodies by sequence); see also Chothia and Lesk (1987) J. Mol. Biol. 196: 901-917 (defining the CDR regions of antibodies by structure). The term "framework" or "FR" refers to those variable domain residues other than the hypervariable region residues defined herein as CDR residues.

Typically, the variable domains of the heavy and light chains contain three hypervariable regions, also called "complementary determining regions (CDRs)", which are located between relatively conserved framework regions (FRs). The CDRs are usually aligned by the framework regions, enabling binding to specific antigenic determinants. In general, from N-terminus to C-terminus, the variable domains of the light and heavy chains contain FR-1 (or FR1), CDR-1 (or CDR1), FR-2 (FR2), CDR-2 (CDR2), FR-3 (or FR3), CDR-3 (CDR3) and FR-4 (or FR4). The amino acid assignments for each domain are generally based on the definitions of Kabat et al., Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md.; 5th edition; NIH Publication No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32: 1-75; Kabat et al. (1977) J. Biol. Chem. 252:6609-6616; Chothia et al. (1987) J Mol. Biol. 196:901-917 or Chothia et al. (1989) Nature 342:878-883.

The term "identity" refers to the overall relatedness between polymeric molecules, such as nucleic acid molecules (such as DNA molecules and/or RNA molecules) and/or polypeptide molecules. The term "identity" or "percent identity" is a numerical score determined for a pair of aligned amino acid or nucleic acid sequences. The percent identity measures the number of identical residues between two sequences ("identity"), which is related to the length of the alignment over a "comparison window". The numbers show the % of amino acid residues or nucleotides that are identical between the two sequences and indicate the degree of primary structural similarity.

Methods for calculating the percent identity between two provided polypeptide sequences are known. The percent identity of two nucleic acid or polypeptide sequences can be calculated by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced into one or both of the first and second sequences to achieve optimal alignment, and non-identical sequences can be ignored for comparison purposes). The nucleotides or amino acids at corresponding positions are then compared. When a position in the first sequence is occupied by the same residue (e.g., nucleotide or amino acid) as at the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences varies with the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap that need to be introduced to achieve optimal alignment of the two sequences. The comparison or alignment of sequences and the determination of the percent identity between two sequences can be accomplished using a mathematical algorithm, such as BLAST (Basic Local Alignment Search Tool). In some embodiments, polymeric molecules are considered "homologous" to each other if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical (e.g., 85%-90%, 85%-95%, 85%-100%, 90%-95%, 90%-100%, or 95%-100%).

To calculate percent identity, the compared sequences are typically aligned in a manner that produces the largest match between the sequences. For sequence comparison, typically one sequence serves as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, the test and reference sequences can be input into a computer, subsequence coordinates can be specified if necessary, and sequence algorithm program parameters can be specified. A polypeptide can be considered identical or substantially identical to a second polypeptide, for example, where the two peptides differ only in conservative substitutions. Methods of sequence alignment for comparison are well known in the art.

One example of a computer program that can be used to determine percent identity is the GCG program package, which includes GAP (Devereux et al., 1984, Nucl. Acid Res. 12:387; Genetics Computer Group, University of Wisconsin, Madison, Wis.). The computer algorithm GAP is used to align two polypeptides or polynucleotides for which percent sequence identity is to be determined. The sequences are aligned so that the best match (the "match span," as determined by the algorithm) is obtained for their individual amino acids or nucleotides. In certain embodiments, the algorithm also uses a standard comparison matrix (for the PAM 250 comparison matrix, see Dayhoff et al., 1978, Atlas of Protein Sequence and Structure 5:345-352; for the BLOSUM 62 comparison matrix, see Henikoff et al., 1992, Proc. Natl. Acad. Sci. U.S.A. 89:10915-10919). Other algorithms can also be used to compare amino acid or nucleic acid sequences, including those available in commercially available computer programs, such as BLASTN for nucleotide sequences and BLASTP, Gapped BLAST, and PSI-BLAST for amino acid sequences. Exemplary such programs are described in Altschul et al., "Basic local alignment search tool", J. Mol. Biol., 215(3): 403-410, 1990; Altschul et al., Methods in Enzymology; Altschul et al., "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs", Nucleic Acids Res. 25:3389-3402, 1997; Baxevanis et al., Bioinformatics: A Practical Guide to the Analysis of Genes and Proteins, Wiley, 1998; and Misener et al. (eds.), Bioinformatics Methods and Protocols (Methods in Molecular Biology, Vol. 132), Humana Press, 1999.

In addition to identifying similar sequences, the above-mentioned programs also generally provide an indication of the degree of similarity. In some embodiments, if at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more of the corresponding residues of the two sequences are similar and/or consistent (e.g., 85%-90%, 85%-95%, 85%-100%, 90%-95%, 90%-100% or 95%-100%) on the relevant residue segments, then the two sequences are considered to be substantially similar. In some embodiments, the relevant segment is a complete sequence. In some embodiments, the relevant segment is at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, at least 250, at least 275, at least 300, at least 325, at least 350, at least 375, at least 400, at least 425, at least 450, at least 475, at least 500 or more residues. Sequences with substantial sequence similarity can be homologs of each other.

Active treatment effects on cancer can be measured in a variety of ways (see W. A Weber, J Nucl. Med. 50: IS-10S (2009)). One common efficacy measure is the T/C ratio, which is the ratio of tumor volume in control subjects relative to treated subjects at a given time, where T/C (%) = median tumor volume of treatment/median tumor volume of control × 100. Regarding tumor growth inhibition, according to NCI standards, T/C ≤ 42% is the lowest level of anti-tumor activity. T/C < 10% is considered a high level of anti-tumor activity. In some embodiments, the treatment achieved by administering the compositions of the present disclosure is any of progression-free survival (PFS), disease-free survival (DFS), or overall survival (OS). PFS, also known as "tumor progression time," indicates the length of time that the cancer does not grow again during and after treatment, and includes the amount of time a patient has experienced a complete response or a partial response, and the amount of time a patient has experienced stable disease. DFS refers to the length of time an individual remains disease-free during and after treatment. OS refers to the extension of expected lifespan compared to an initially or untreated individual or patient.

The term "major pathological response"("MPR") is defined as less than 10% of residual viable tumor after lead therapy. The 10% cutoff was established based on previous studies evaluating pathology of resected lungs after lead chemoradiation (Junker K et al., J Cancer Res Clin Oncol . 1997; Pataer A et al., JTO 2012). MPR is observed more frequently than pathological complete response ("pCR"), which is defined as no viable residual tumor.

Although the embodiments of the compositions, methods of treatment, and uses of the present disclosure may not be effective in achieving a positive therapeutic effect in every patient, they should be achieved in a statistically significant number of individuals as determined by any statistical test known in the art, such as Student's t-test, chi-square test, U test according to Mann and Whitney, Kruskal-Wallis test (H test), Cochran-Mantel-Haenszel chi-square test method, Jonckheere-Terpstra test, or Wilcoxon test.

"Immune response" refers to the actions of cells of the immune system (e.g., T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, leukocytes, dendritic cells, or neutrophils) and soluble macromolecules (including Abs, interleukins, and complements) produced by any of these cells or the liver, which results in the selective targeting, binding, damage, destruction, and/or elimination from the vertebrate body of invading pathogens, cells or tissues infected with pathogens, cancerous or other abnormal cells, or, in the case of autoimmunity or pathological inflammation, normal human cells or tissues.

The terms "immunospecific binding", "immunospecific recognition", "specific binding" and "specific recognition" are similar terms in the context of antibodies and refer to the binding of a molecule to an antigen (e.g., an antigenic determinant or an immunocomplex) as understood by those skilled in the art. For example, a molecule that specifically binds to an antigen may typically bind to other peptides or polypeptides with lower affinity as determined by, for example, an immunoassay, BIACORE®, KinExA 3000 instrument (Sapidyne Instruments, Boise, Id.) or other assays known in the art. Thus, under certain specified immunoassay conditions, the antibody or antigen-binding fragment thereof specifically binds to a particular antigen at least two (2) times more than background levels, and does not specifically bind to other antigens present in the sample in significant amounts. In another aspect, under specified immunoassay conditions, the antibody or antigen-binding fragment thereof specifically binds to a particular antigen at least ten (10) times more than background binding levels, and does not specifically bind to other antigens present in the sample in significant amounts.

An antibody that "specifically binds to" a specified target protein is one that exhibits preferential binding to that target as compared to other proteins, but such specificity does not require absolute binding specificity. An antibody is considered "specific" for its intended target if binding of the antibody determines the presence of the target protein in a sample without, for example , producing undesirable results (such as false positives). Antibodies or binding fragments thereof that can be used in the present invention will bind to the target protein with an affinity that is at least two times, at least ten times, at least 20 times, or at least 100 times greater than that of non-target proteins. If an antibody herein binds to a polypeptide comprising a given amino acid sequence (e.g., the amino acid sequence of a mature human PD-1 molecule), but does not bind to a protein lacking that sequence, the antibody is said to specifically bind to a polypeptide comprising that sequence.

The term "immunotherapy" refers to the treatment of an individual suffering from a disease or at risk of disease recurrence by methods including inducing, enhancing, suppressing or otherwise modifying an immune response. Examples of immunotherapy include, but are not limited to, T cell and NK cell therapy. T cell and NK cell therapy may include donor cell therapy, tumor infiltrating lymphocyte (TIL) immunotherapy, autologous cell therapy, engineered autologous cell therapy (eACT™), and allogeneic T cell and NK cell transplantation.

The terms "improve," "increase," "inhibit," and "decrease" indicate values relative to a baseline or other reference measurement. In some embodiments, an appropriate reference measurement may include a measurement in a system (e.g., a single subject) in the absence of an agent or treatment (e.g., before and/or after) or in the presence of an appropriate comparable reference agent under otherwise equivalent conditions. In some embodiments, an appropriate reference measurement may include a measurement in a comparable system that is known or expected to react in a comparable manner in the presence of the agent or treatment of interest.

The term "isolated" refers to a substance that: (1) has been separated from at least some components that were or would have been associated with the substance at an earlier time, and/or (2) is present in a composition that contains limited or defined amounts or concentrations of one or more known or unknown contaminants. In some embodiments, the separated substance can be separated from about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more (e.g., 85%-90%, 85%-95%, 85%-100%, 90%-95%, 90%-100% or 95%-100%) of other non-substance components that were associated with the substance at an earlier time, such as other components or contaminants that were previously or would have been associated with the substance. In some cases, a substance is separated if it is present in a composition that contains a limited or reduced amount or concentration of the same or similar type of molecule. For example, in some cases, a nucleic acid, DNA or RNA substance is isolated if it is present in a composition that includes a limited or reduced amount or concentration of a non-substance nucleic acid, DNA or RNA molecule. For example, in some cases, a polypeptide substance is isolated if it is present in a composition that includes a limited or reduced amount or concentration of a non-substance polypeptide molecule. In some embodiments, an amount can be, for example, an amount measured relative to the amount of a desired substance present in a composition. In some embodiments, the limited amount may be an amount that is no more than 100% of the amount of the substance in the composition, such as no more than 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% (e.g., 85%-90%, 85%-95%, 85%-100%, 90%-95%, 90%-100% or 95%-100%) of the amount of the substance in the composition. In some cases, the composition is pure or substantially pure with respect to the selected substance. In some embodiments, the isolated material is about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure (e.g., 85%-90%, 85%-95%, 85%-100%, 90%-95%, 90%-100%, or 95%-100%).

"Isotype" refers to the antibody class or subclass (e.g., IgM or IgG1) encoded by the heavy chain constant region gene. Therefore, the term "antibody" includes, for example, natural and non-natural antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human or non-human antibodies; fully synthetic antibodies; and single-chain antibodies. Non-human Abs can be humanized by recombinant methods to reduce their immunogenicity in humans. In the absence of explicit statements, and unless the context indicates otherwise, the term "antibody" also includes antigen-binding fragments or antigen-binding portions of any of the above-mentioned immunoglobulins, and includes monovalent and bivalent fragments or portions, as well as single-chain Abs.

The term "Kabat numbering" and similar terms are well known in the art and refer to a system for numbering amino acid residues in the heavy and light chain variable regions of an antibody or antigen-binding molecule thereof. In certain aspects, the CDRs of an antibody may be identified according to the Kabat numbering system (e.g., see Kabat EA and Wu TT (1971) Ann NY Acad Sci 190: 382-391 and Kabat EA et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242). Using the Kabat numbering system, the CDRs within an antibody heavy chain molecule are typically present at amino acid positions 31 to 35, which may include one or two additional amino acids after 35 (referred to as 35A and 35B in the Kabat numbering scheme) (CDR1); amino acid positions 50 to 65 (CDR2); and amino acid positions 95 to 102 (CDR3). Using the Kabat numbering system, the CDRs within an antibody light chain molecule are typically present at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2), and amino acid positions 89 to 97 (CDR3). In specific embodiments, the CDRs of the antibodies described herein have been determined according to the Kabat numbering scheme.

The term "light chain" when used in relation to an antibody can refer to any of the different types of amino acid sequences based on a constant structural domain, such as kappa (κ) or lambda (λ). Light chain amino acid sequences are well known in the art. In a specific embodiment, the light chain is a human light chain.

As used herein, the term "monoclonal antibody" or "mAb" or "Mab" refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules contained in the population are identical except for the presence of very few possible natural mutations. In contrast, conventional (polyclonal) antibody preparations typically include a plurality of different antibodies that contain different amino acid sequences in their variable domains, specifically their complementary determining regions (CDRs), which are typically specific for different antigenic determinants. The modifier "monoclonal" indicates the character of the antibody as being obtained from a population of substantially homogeneous antibodies, and should not be construed as requiring the antibody to be produced by any particular method. Monoclonal antibodies (mAbs) can be obtained by methods known to those skilled in the art (see, for example, Kohler et al., Nature 1975 256:495-497; U.S. Pat. No. 4,376,110; Ausubel et al., Current Protocols in Molecular Biology 1992; Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory 1988; and Colligan et al., Current Protocols in Immunology 1993).

"PD-L1 expression positivity" refers to a tumor proportion score, mononuclear inflammation density score, or a combined positive score of at least 1%; or an increased level of PD-L1 expression (protein and/or mRNA) in malignant cells and/or infiltrating immune cells in the tumor compared with appropriate controls.

The term "pharmaceutical composition" refers to a preparation in a pharmaceutically acceptable formulation in a form that renders the active ingredient effective and does not contain additional components that are toxic to the subject to which the composition is administered. In some embodiments, the pharmaceutical composition may be formulated for administration in solid or liquid form, including but not limited to forms suitable for: oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., intended for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; parenteral administration, such as by Subcutaneous, intramuscular, intravenous or epidural injection, for example as a sterile solution or suspension, or a sustained release formulation; topical application, for example as a cream, ointment or controlled release patch or spray applied to the skin, lungs or mouth; intravaginal or rectal, for example as a pessary, cream or foam; sublingual; ocular; transdermal; or nasal, pulmonary and to other mucosal surfaces. In some aspects, the present disclosure provides a composition, for example a pharmaceutically acceptable composition, comprising an anti-PD-1 antibody described herein formulated with at least one pharmaceutically acceptable excipient. In some aspects, the present disclosure provides compositions, such as pharmaceutically acceptable compositions, comprising a chemotherapeutic agent as described herein formulated together with at least one pharmaceutically acceptable excipient.

The term "pharmaceutically acceptable" refers to a molecule or composition that, when administered to a recipient, is not harmful to the recipient or that the benefits to the recipient outweigh any harmful effects.

Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as rosehip oil; crude oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic water; Ringer’s solution; ethanol; pH buffering solutions; polyesters, polycarbonates and/or polyanhydrides; and other nontoxic compatible substances used in pharmaceutical formulations.

"Pharmaceutically acceptable formulations" include any and all solvents, dispersion media, isotonic agents, and absorption delaying agents, and the like, that are physiologically compatible. Formulations may be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g., by injection or infusion).

The compositions disclosed herein may be in a variety of forms. Such forms include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., injectable solutions and infusible solutions), dispersions or suspensions, liposomes and suppositories. The appropriate form depends on the intended mode of administration and therapeutic application. Typical suitable compositions are in the form of injectable solutions or infusible solutions. One suitable mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In some embodiments, the antibody is administered by intravenous infusion or injection. In certain embodiments, the antibody is administered by intramuscular or subcutaneous injection. In some embodiments, the antibody is administered by means of a syringe infusion system.

As used herein, "purification" with respect to an antibody or antigen-binding fragment or a "purified composition" refers to increasing the purity of the antibody or antigen-binding fragment in a composition by removing (completely or partially) at least one impurity from the composition. Impurities may be host cell components such as serum, proteins or nucleic acids, cell debris, growth media, or antibody aggregates. The term is not intended to imply the complete absence of such biomolecules, or the absence of water, buffers or salts, or components of a pharmaceutical composition comprising an antibody or antigen-binding fragment.

As used herein, "RECIST 1.1 response criteria" means the definitions set forth by Eisenhauer et al., Eur. J Cancer 45:228-247 (2009) for target lesions or non-target lesions, as appropriate, based on the context of the response being measured.

The terms "reduced" and "reduced" are used interchangeably herein and refer to any change from an initial value. "Reduced" and "reduced" are relative terms, requiring a comparison between before and after the measurement. "Reduced" and "reduced" include complete depletion.

The term "reference" describes a standard or comparison relative to which a comparison is made. For example, in some embodiments, an agent, animal, individual, group, sample, sequence, or value of interest is compared to a reference or comparison that serves as an agent, animal, individual, group, sample, sequence, or value. In some embodiments, the reference or comparison is tested, measured, and/or determined substantially simultaneously with the test, measurement, or determination of interest. In some embodiments, the reference or comparison is a historical reference or comparison, as appropriate, embodied in a tangible medium. Typically, a reference or comparison is measured or characterized under conditions or circumstances comparable to those being evaluated. When there is sufficient similarity to justify reliance on and/or comparison to the selected reference or comparison.

When referring to a specific anti-tumor response to treatment with a therapy as described herein, a "responding patient" means a patient who exhibits an anti-tumor response.

The term "cancer stage" refers to a qualitative or quantitative assessment of the level of progression of a cancer. In some embodiments, the criteria used to determine the stage of a cancer may include, but are not limited to, one or more of the following: the location of the cancer in the body, the size of the tumor, whether the cancer has spread to the lymph nodes, whether the cancer has spread to one or more different parts of the body, etc. In some embodiments, cancer may be staged using the so-called TNM system, according to which T refers to the size and extent of the main tumor, usually called the primary tumor; N refers to the number of nearby cancerous lymph nodes; and M refers to whether the cancer has metastasized. In some embodiments, cancer may be referred to as stage 0 (abnormal cells are present, but have not spread to nearby tissues, also called carcinoma in situ or CIS; CIS is not cancer, but can become cancer), stage I-III (cancer is present; the higher the number, the larger the tumor and the more it has spread into nearby tissues), or stage IV (cancer has spread to internal organs and/or distant parts of the body). In some embodiments, cancer may be assigned to a stage selected from the group consisting of: in situ; localized (cancer is confined to where it started, with no signs of spread); regional (cancer has spread to nearby lymph nodes, tissues, or organs); distant (cancer has spread to distant parts of the body); and unknown (not enough information to determine the stage).

The term "subject" in the context of this disclosure is a mammal, such as a primate, preferably a higher primate, such as a human (eg, a patient suffering from or at risk of suffering from a disorder described herein).

In general, two sequences are considered "substantially similar" if they contain conservative amino acid substitutions at corresponding positions. For example, certain amino acids are often classified as "hydrophobic" or "hydrophilic" amino acids, and/or as having "polar" or "non-polar" side chains. Substituting one amino acid for another of the same type is considered a conservative substitution.

In general, an "effective amount" refers to an amount effective for treating a disease or condition in an individual, and the amount will induce a biological or medical response in the tissue, system, animal or human being sought to a large extent, such as when administered, sufficient to prevent the development of one or more symptoms of the disease or condition being treated or to alleviate one or more symptoms to some extent. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated. More specifically, a "therapeutically effective amount," "effective dose," "effective amount," or "therapeutically effective dose" of a therapeutic agent (e.g., an antibody) is any amount that, when used alone or in combination with another therapeutic agent, protects a subject from disease onset or promotes disease regression as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or prevention of damage or disability due to susceptibility. The ability of a therapeutic agent to promote disease regression can be assessed using a variety of methods known to skilled practitioners, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by analyzing the activity of the agent in an in vitro assay. A "therapeutically effective amount" may vary depending on the antibody; the disease, disorder and/or symptoms of the disease or disorder; the severity of the disease, disorder and/or symptoms of the disease or disorder; the age of the individual to be treated; and/or the weight of the individual to be treated. The appropriate amount for any given situation will be apparent to one skilled in the art or can be determined by routine experimentation. In the context of combination therapy, a "therapeutically effective amount" refers to the total amount of the combination subject that is effective to treat the disease, disorder or condition.

The terms "treatment regimen", "dosing protocol" and "dosing regimen" are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in the combination of the invention.

"Tumor" as applied to an individual diagnosed with or suspected of having cancer refers to a malignant or potentially malignant tumor or mass of tissue of any size and includes primary tumors and secondary tumors. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or areas of fluid. The different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and 30 types of lymphomas.

"Tumor burden," also called "tumor load," refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of tumors throughout the body, including lymph nodes and bone marrow. Tumor burden can be determined by a variety of methods known in the art, such as by measuring the size of the tumor after removal from the individual, for example, using a caliper, or while in vivo using imaging techniques, such as ultrasound, bone scan, computed tomography (CT), or magnetic resonance imaging (MRI) scans.

The term "tumor size" refers to the overall size of the tumor, which can be measured as the length and width of the tumor. Tumor size can be determined by a variety of methods known in the art, such as by measuring the dimensions of the tumor after removal from the individual, for example using a caliper, or while in vivo using imaging techniques, such as bone scans, ultrasound, CT or MRI scans.

"Unidimensional irRC" refers to the set of criteria described in Nishino et al., Developing a Common Language for Tumor Response to Immunotherapy: Immune-related Response Criteria using Unidimensional measurements. Clin Cancer Res. 2013;19(14):3936-3943. These criteria utilize the longest diameter (cm) of each lesion. The term "tumor size" refers to the overall size of the tumor, which can be measured as the length and width of the tumor. Tumor size can be determined by a variety of methods known in the art, such as by measuring the size of the tumor after removal from the individual, such as using a caliper, or while in vivo using imaging techniques, such as bone scans, ultrasound, CT, or MRI scans.

The "tumor proportion score (TPS)" refers to the percentage of tumor cells that express PD-L1 or another tumor antigen on the cell membrane at any intensity (weak, moderate, or strong). Linear partial or complete cell membrane staining is interpreted as positive for PD-L1 or another antigen of interest.

As used herein, the term "variable region" or "variable domain" means a segment of the IgG chain whose sequence is variable between different antibodies. Typically, it extends to Kabat residue 109 in the light chain and 113 in the heavy chain. The variability of the sequence is concentrated in those regions called complementation determining regions (CDRs), while the more highly conserved regions in the variable domains are called framework regions (FRs). Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction and specificity of the antibody with the antigen. In certain embodiments, the variable region is a human variable region. In certain embodiments, the variable region comprises rodent or murine CDRs and human framework regions (FRs). In specific embodiments, the variable region is a primate (e.g., non-human primate) variable region. In certain embodiments, the variable region comprises a rodent or mouse CDR and a primate (e.g., non-human primate) framework region (FR).

The terms "VH", "VL", "LCVR" and "VL domain" are used interchangeably to refer to the light chain variable region of an antibody.

The terms "VH", "Vh", "HCVR" and "Vh domain" are used interchangeably to refer to the heavy chain variable region of an antibody.

The variable regions of each light chain/heavy chain (Vl/Vh) pair form an antibody binding site. Therefore, in general, a complete antibody has two binding sites. Except in bifunctional or bispecific antibodies, the two binding sites are usually the same.

In certain embodiments, a HCVR sequence having at least 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 24 contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-PD-1 antibody or antigen-binding fragment thereof comprising the sequence retains the ability to specifically bind to PD-1. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 24 are substituted, inserted and/or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 24 are substituted, inserted and/or deleted. In certain embodiments, the substitutions, insertions or deletions occur in regions outside of CDRs (i.e., in FRs).

In certain embodiments, a LCVR sequence having at least 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% amino acid sequence identity to the amino acid sequence of SEQ ID NO: 26 contains substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence, but the anti-PD-1 antibody or antigen-binding fragment thereof comprising the sequence retains the ability to specifically bind to PD-1. In certain embodiments, a total of 1 to 10 amino acids in SEQ ID NO: 26 are substituted, inserted and/or deleted. In certain embodiments, a total of 1 to 5 amino acids in SEQ ID NO: 26 are substituted, inserted and/or deleted. In certain embodiments, the substitution, insertion or deletion occurs in a region outside of the CDR (i.e., in the FR). PD-1

Programmed death-1 (PD-1, also known as programmed death-1, PD1, Pdcd-1 and CD279) is a 55 KD receptor protein that is related to the CD28/CTLA4 co-stimulatory/inhibitory receptor family (Blank et al., 2005 Cancer Immunol Immunother 54:307-314). The gene and cDNA encoding PD-1 were cloned and characterized in mice and humans (Ishida et al., 1992 EMBO J 11:3887-3395; Shinohara et al., 1994 Genomics 23:704-706). The full-length PD-1 contains 288 amino acid residues (NCBI Accession No.: NP_005009). Its extracellular domain consists of amino acid residues 1-167 and the cytoplasmic C-terminal tail contains residues 191-288, which has two putative immune regulatory motifs, the immunoreceptor tyrosine-based inhibitory motif (ITIM; Vivier et al., 1997 Immunol Today 18:286-291) and the immunoreceptor tyrosine switch motif (ITSM; Chemnitz et al., 2004 J Immunol 173:945-954).

To date, two sequence-related ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), have been identified that specifically interact with PD-1, thereby inducing intracellular signal transduction that inhibits CD3- and CD28-mediated T cell activation (Riley, 2009 Immunol Rev 229:114-125), which in turn attenuates T cell activity, such as reduced cell proliferation, IL-2 and IFN-γ secretion, and other growth factors and cytokines secretion.

The expression of PD-1 is frequently found in immune cells, such as T cells, B cells, monocytes, and natural killer (NK) cells. It is rarely expressed in other human tissues, such as muscle, epithelium, and neural tissue. In addition, high levels of PD-1 expression are often associated with the activation of immune cells. For example, when the human T cell line Jurkat is activated by phytohemagglutinin (PHA) or phorbol ester (12-O-tetradecanoylphorbol-13-acetate, or TPA), the expression of PD-1 can be seen upregulated in Western Blot (Vibharka et al., 1997 Exp Cell Res 232:25-28). The same phenomenon was observed in stimulated mouse T and B lymphocytes and primary human CD4+ T cells after stimulation with anti-CD3 antibodies (Agata et al., 1996 Int Immunol 8:765-772; Bennett et al., 2003 J Immunol 170:711-118). The increase in PD-1 expression after stimulation of T effector cells redirects activated T effector cells to exhaustion and reduced immune activity. Therefore, PD-1-mediated inhibitory signals play an important role in immune tolerance (Bour-Jordan et al., 2011 Immunol Rev 241:180-205).

Increased expression of PD-1 in tumor infiltrating lymphocytes (TILs) and PD-1 ligands in tumor cells have been reported in a variety of cancers involving different types of tissues and organs, such as lung (Konishi et al., 2004 Clin Cancer Res 10:5094-5100), liver (Shi et al., 2008 Int J Cancer 128:887-896; Gao et al., 2009 Clin Cancer Res 15:971-979), stomach (Wu et al., 2006 Acta Histochem 108:19-24), kidney (Thompson et al., 2004 Proc Natl Acad Sci 101:17174-17179; Thompson et al., 2007 Clin Cancer Res 15:971-979), and pancreatic cancer (Wu et al., 2006 Acta Histochem 108:19-24). 13:1757-1761), breast (Ghebeh et al., 2006 Neoplasia 8:190-198), ovary (Hamanishi et al., 2007 Proc Natl Acad Sci 104:3360-3365), pancreas (Nomi et al., 2007 Clin Cancer Res 13:2151-2157), melanocytes (Hino et al., 2010 Cancer 116:1757-1766) and esophagus (Ohigashi et al., 2005 Clin Cancer Res 11:2947-2953). More generally, increased expression of PD-1 and PD-L1 in these cancers is associated with poor prognosis for patient survival outcomes. Transgenic mice with PD-1 knockout that inhibit xenograft cancer cell growth further demonstrate the importance of PD-1 signaling in regulating the immune system to achieve cancer eradication or tolerance (Zhang et al., 2009 Blood 114:1545-1552).

PD-1 blockade can be achieved through a variety of mechanisms, including antibodies that bind to PD-1 or its ligands. Examples of PD-1 and PD-L1 blockers (also referred to as PD-1 and PD-L1 inhibitors) are described in US7488802; US7943743; US8008449; US8,168,757; US8217149 and WO03042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, WO2011161699 and WO2015035606, the entire contents of each of which are incorporated herein by reference. Anti -PD-1 Antibodies

In some embodiments, the methods described herein include administering an anti-PD-1 antibody or an antigen-binding fragment thereof. Any antibody or antigen-binding fragment thereof that specifically binds to PD-1, in particular human PD-1, as described herein, can be used in the compositions, combinations, uses and methods described herein.

In some embodiments, the anti-PD-1 antibody is any antibody known in the art or described herein. In some embodiments, the anti-PD-1 antibody is any antibody that specifically binds to PD-1. In some embodiments, the anti-PD-1 antibody inhibits PD-1-mediated cell signaling and activity in immune cells. In some embodiments, the anti-PD-1 antibody binds to an amino acid residue that requires its ligand to bind and/or inhibits ligand binding.

In some embodiments, the antibodies and fragments described herein are isolated and purified.

In some embodiments, the disclosure relates to an antibody or an antigen-binding fragment thereof, wherein the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a human engineered antibody, a single chain antibody (scFv), a Fab fragment, a Fab' fragment or a F(ab')2 fragment.

In some embodiments, the anti-PD-1 antibody is a monoclonal antibody. In some embodiments, the anti-PD-1 antibody is a humanized antibody. In some embodiments, the anti-PD-1 antibody is a human antibody. In some embodiments, the anti-PD-1 antibody is a chimeric antibody.

In some embodiments, anti-PD-1 antibodies are described herein, wherein the antibody is an immunoglobulin comprising any VH and VL regions described herein. The immunoglobulin molecules that can be used are of any type (e.g., IgG, IgE, IgM, IgD, IgY, IgA). The immunoglobulin molecules that can be used are of any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, IgA2). The immunoglobulin molecules that can be used are of any subclass.

In some embodiments, the anti-PD-1 antibody is an IgG4 antibody. In some embodiments, the disclosure relates to an antibody or an antigen-binding fragment thereof, wherein the Fc domain is the Fc domain of IgG4.

In some embodiments, the anti-PD-1 antibody is an IgG1 antibody. In some embodiments, the disclosure relates to an antibody or an antigen-binding fragment thereof, wherein the Fc domain is an IgG1 Fc domain.

In some embodiments, the anti-PD-1 antibody is a monoclonal humanized IgG1 antibody.

In some embodiments, the anti-PD-1 antibody is a monoclonal humanized IgG4 antibody.

In some embodiments, the anti-PD-1 antibodies and fragments contemplated comprise any of the CDRs described herein. In some embodiments, the anti-PD-1 antibodies and fragments contemplated comprise the CDRs of any of the antibodies described herein. Complementarity determining regions (CDRs) are defined in a variety of ways in this art, including Kabat, Chothia, AbM, Contact, and IMGT. In some embodiments, the CDRs of an antibody are defined according to the Kabat system.

In some embodiments, the anti-PD-1 antibodies and fragments contemplated include any light chain variable region described herein and/or any heavy chain variable region described herein. In some embodiments, the anti-PD-1 antibodies and fragments described herein include a light chain variable region having a sequence that is at least 85%, 90%, or 95% identical to any light chain variable region described herein; and/or a heavy chain variable region having a sequence that is at least 85%, 90%, or 95% identical to any heavy chain variable region described herein. In some embodiments, the anti-PD-1 antibodies and fragments described herein comprise a light chain variable region having a sequence that is at least 85%, 90% or 95% identical to any light chain variable region described herein (at least 90%, 95%, 97%, 99% or 100% identical in the CDR region, e.g., six CDRs); and/or a heavy chain variable region having a sequence that is at least 85%, 90% or 95% identical to any heavy chain variable region described herein (at least 90%, 95%, 97%, 99% or 100% identical in the CDR region, e.g., six CDRs). In some embodiments, the anti-PD-1 antibodies and fragments contemplated herein comprise a light chain variable region and/or any heavy chain variable region of any antibody described herein.

In some embodiments, the anti-PD-1 antibody is any antibody described in WO2015/035606 A1 or US2015-0315274, the entire disclosure of which is incorporated herein by reference in its entirety, and in particular with respect to the description of anti-PD-1 antibodies therein. In some embodiments, the anti-PD-1 antibody is any antibody described in any of the following U.S. Patents: 8,735,553, 9,217,034, 9,834,606, 9,988,450, 10,519,235, and 11,186,637. U.S. Patent Nos. 8,735,553, 9,217,034, 9,834,606, 9,988,450, 10,519,235, and 11,186,637 are incorporated herein by reference in their entirety, and particularly with respect to the description of anti-PD-1 antibodies therein.

In some embodiments, the anti-PD-1 antibody is selected from one of the following: nivolumab (MDX 1106, BMS 936558, ONO-4538, Opdivo®) described in US8008449B2, which is a fully human IgG4 antibody that binds to and blocks the activation of PD-1 by its ligands PD-L1 and PD-L2; pembrolizumab (lambrolizumab, MK-3475 or SCH 900475, Keytruda®) disclosed in US8168757B2, which is a humanized monoclonal IgG4 antibody against PD-1; pidilizumab (CT-011), which is a humanized antibody that binds to PD-1; AMP-224, which is a fusion protein of B7-DC; antibody Fc portion; BMS-936559 (MDX-1105-01) for PD-L1 (B7-H1) blockade to achieve PD-1 blockade. In some embodiments, the anti-PD-1 antibody is pembrolizumab, nivolumab, cemilimab, dostarlimab, or retifanlimab.

In some embodiments, the anti-PD-1 antibody is an antibody comprising a heavy chain variable region (Vh) and a light chain variable region (Vl), wherein the Vh and Vl comprise any one set of complementary determining regions (CDRs) listed below (having three Vh CDRs and three Vl CDRs): Table 3 a) mu317 CDR-H1, CDR-H2 and CDR-H3 (SEQ ID NOs: 11, 12, 13, respectively); and CDR-L1, CDR-L2 and CDR-L3 (SEQ ID NOs: 14, 15, 16, respectively); b) mu326 CDR-H1, CDR-H2 and CDR-H3 (SEQ ID NOs: 17, 18, 19, respectively); and CDR-L1, CDR-L2 and CDR-L3 (SEQ ID NOs: 20, 21, 22, respectively); c) 317-4B6 CDR-H1, CDR-H2 and CDR-H3 (SEQ ID NOs: 31, 32, 33, respectively); and CDR-L1, CDR-L2 and CDR-L3 (SEQ ID NOs: 34, 35, 36, respectively); d) 326-4A3 CDR-H1, CDR-H2 and CDR-H3 (SEQ ID NOs: 37, 38, 39, respectively); and CDR-L1, CDR-L2 and CDR-L3 (SEQ ID NOs: 40, 41, 42, respectively); e) 317-1H CDR-H1, CDR-H2 and CDR-H3 (SEQ ID NOs: 11, 59, 13, respectively); and CDR-L1, CDR-L2 and CDR-L3 (SEQ ID NOs: 14, 15, 16, respectively); f) 317-4B2 CDR-H1, CDR-H2 and CDR-H3 (SEQ ID NOs: 11, 60, 13, respectively); and CDR-L1, CDR-L2 and CDR-L3 (SEQ ID NOs: 61, 15, 16, respectively); g) 317-4B5 CDR-H1, CDR-H2 and CDR-H3 (SEQ ID NOs: 11, 60, 13, respectively); and CDR-L1, CDR-L2 and CDR-L3 (SEQ ID NOs: 61, 15, 16, respectively); h) 317-4B6 CDR-H1, CDR-H2 and CDR-H3 (SEQ ID NOs: 11, 32, 13, respectively); and CDR-L1, CDR-L2 and CDR-L3 (SEQ ID NOs: 61, 15, 16, respectively); i) 326-1 CDR-H1, CDR-H2 and CDR-H3 (SEQ ID NOs: 17, 62, 19, respectively); and CDR-L1, CDR-L2 and CDR-L3 (SEQ ID NOs: 20, 21, 22, respectively); j) 326-3B1 CDR-H1, CDR-H2 and CDR-H3 (SEQ ID NOs: 17, 62, 19, respectively); and CDR-L1, CDR-L2 and CDR-L3 (SEQ ID NOs: 20, 21, 22, respectively); or k) 326-3G1 CDR-H1, CDR-H2 and CDR-H3 (SEQ ID NOs: 17, 62, 19, respectively); and CDR-L1, CDR-L2 and CDR-L3 (SEQ ID NOs: 20, 21, 22, respectively).

In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable region (Vh) comprising complementary determining regions (CDRs) CDR-H1, CDR-H2 and CDR-H3 of SEQ ID NOs: 31, 32, 33, respectively, and a light chain variable region (Vl) comprising CDRs CDR-L1, CDR-L2 and CDR-L3 of SEQ ID NOs: 34, 35, 36, respectively. In some embodiments, the anti-PD-1 antibody comprises the Vh and Vl CDRs of the 317-4B6 antibody described herein.

In some embodiments, the anti-PD-1 antibody is an antibody comprising a heavy chain variable region (Vh) and a light chain variable region (Vl), wherein the Vh and Vl contain any combination of the CDRs listed below (having three Vh CDRs and three Vl CDRs): Table 4 (a) CDR-H1 (SEQ ID NO 31), CDR-H2 (SEQ ID NO 12, 32, 59 or 60) and CDR-H3 (SEQ ID NO 33), CDR-L1 (SEQ ID NO 14, 34 or 61), CDR-L2 (SEQ ID NO 35) and CDR-L3 (SEQ ID NO 36); or (b) CDR-H1 (SEQ ID NO 37), CDR-H2 (SEQ ID NO 18, 38 or 62) and CDR-H3 (SEQ ID NO 39), CDR-L1 (SEQ ID NO 40), CDR-L2 (SEQ ID NO 41) and CDR-L3 (SEQ ID NO 42).

In some embodiments, the anti-PD-1 monoclonal antibody is an antibody comprising a heavy chain variable region (Vh) and a light chain variable region (Vl), wherein the Vh and Vl comprise: Table 5 a) mu317 (SEQ ID NOs: 4 and 6, respectively); b) mu326 (SEQ ID NOs: 8 and 10, respectively); c) 317-4B6 (SEQ ID NOs: 24 and 26, respectively); d) 326-4A3 (SEQ ID NOs: 28 and 30, respectively); e) 317-4B2 (SEQ ID NOs: 43 and 44, respectively); f) 317-4B5 (SEQ ID NOs: 45 and 46, respectively); g) 317-1 (SEQ ID NOs: 48 and 50, respectively); h) 326-3B1 (SEQ ID NOs: 51 and 52, respectively); i) 326-3GI (SEQ ID NOs: 53 and 54, respectively); j) 326-1 (SEQ ID NOs: 56 and 58, respectively); k) 317-3A1 (SEQ ID NOs: 64 and 26, respectively); l) 317-3C1 (SEQ ID NOs: 65 and 26, respectively); m) 317-3E1 (SEQ ID NOs: 66 and 26, respectively); n) 317-3F1 (SEQ ID NOs: 67 and 26, respectively); o) 317-3G1 (SEQ ID NOs: 68 and 26, respectively); p) 317-3H1 (SEQ ID NOs: 69 and 26, respectively); q) 317-311 (SEQ ID NOs: 70 and 26, respectively); r) 317-4B1 (SEQ ID NOs: 71 and 26, respectively); s) 317-4B3 (SEQ ID NOs: 72 and 26, respectively); t) 317-4B4 (SEQ ID NOs: 73 and 26, respectively); u) 317-4A2 (SEQ ID NOs: 74 and 26, respectively); v) 326-3A1 (SEQ ID NOs: 75 and 30, respectively); w) 326-3C1 (SEQ ID NOs: 76 and 30, respectively); x) 326-3D1 (SEQ ID NOs: 77 and 30, respectively); y) 326-3E1 (SEQ ID NOs: 78 and 31, respectively). NO: 78 and 30); z) 326-3F1 (SEQ ID NO: 79 and 30, respectively); aa) 326-3B N55D (SEQ ID NO: 80 and 30, respectively); ab) 326-4A1 (SEQ ID NO: 28 and 81, respectively); or ac) 326-4A2 (SEQ ID NO: 28 and 82, respectively).

In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable region (Vh) comprising the amino acid sequence of SEQ ID NO: 24 and a light chain variable region (Vl) comprising the amino acid sequence of SEQ ID NO: 26. In some embodiments, the anti-PD-1 antibody comprises the Vh and Vl of the 317-4B6 antibody described herein.

In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable region (Vh), wherein Vh comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 24; and a light chain variable region (Vl), wherein Vl comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 26.

In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable region (Vh) or a light chain variable region (Vl) encoded by a cDNA of one or more of SEQ ID NOs: 23, 25, 27, 29, 47, 49, 55, 57.

In some embodiments, the antibody comprises an IgG4 Fc region having a serine to proline mutation at position 228 (EU numbering system). In some embodiments, this mutation is referred to as an S228P mutation. In some embodiments, the antibody comprises an IgG4 Fc region having a mutation at one or more of positions 233, 234, 235, 265, 309, and 409 (EU numbering system). For example, in some embodiments, the antibody comprises an IgG4 region having a mutation at position 228 and at least one other position, wherein the at least one other mutation results in reduced binding to one or more FcγRs. In other embodiments, the antibody comprises an IgG4 region with mutations at position 228 and at least 2, at least 3, at least 4, at least 5, or at least 6 additional positions, wherein one or more additional mutations result in reduced binding to one or more FcγRs. In some embodiments, the antibody comprises an IgG4 region with mutations at positions 234 and 235. In some embodiments, the antibody comprises an IgG4 region with mutations at positions 233, 235, and 235. In some embodiments, the antibody comprises an IgG4 region with mutations at positions 234, 235, and 265. In some embodiments, the antibody comprises an IgG4 region with mutations at positions 233, 234, 235, and 265. In some embodiments, the antibody comprises an IgG4 region with mutations at positions 234, 235, 265, and 409. In some embodiments, the antibody comprises an IgG4 region with mutations at positions 233, 234, 235, 265, and 409. In some embodiments, the antibody comprises an IgG4 region with mutations at positions 234, 235, 265, 309, and 409. In some embodiments, the antibody comprises an IgG4 region with mutations at positions 233, 234, 235, 265, 309, and 409. The mutation at position 234 can be a phenylalanine to valine substitution or a phenylalanine to alanine substitution. The mutation at position 235 can be a leucine to alanine substitution. The mutation at position 233 can be a glutamine to proline substitution. The mutation at position 265 can be an aspartic acid to valine substitution or an aspartic acid to threonine substitution. The mutation at position 309 may be a leucine to valine substitution. The mutation at position 409 may be an arginine to lysine, threonine or methionine substitution.

In some embodiments, the anti-PD-1 antibody comprises an IgG4 heavy chain effector domain or a constant domain comprising any one of SEQ ID NOs: 83-88 or 91-106. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising any one of the following amino acid sequences: SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, and SEQ ID NO: 88. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising any one of the following amino acid sequences: SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, and SEQ ID NO: 106. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 83. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 84. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 85. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 86. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 87. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 88. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 91. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 92. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 93. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 94. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 95. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 96. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 97. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 98. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 99. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 100. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 101. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 102. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 103. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 104. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 105. In some embodiments, the anti-PD-1 antibody comprises an IgG constant region comprising SEQ ID NO: 106.

In some embodiments, the anti-PD-1 antibody is an F(ab) or F(ab)2-containing antibody, which comprises a heavy chain variable region (Vh), a light chain variable region (Vl), and an IgG4 heavy chain effector domain or a constant domain.

In some embodiments, the anti-PD-1 antibody is an antibody comprising a heavy chain variable region (Vh) and a light chain variable region (Vl) and an IgG4 heavy chain effector domain or a constant domain comprising SEQ ID NO: 87 or 88, wherein the heavy chain variable region (Vh) and the light chain variable region (Vl) comprise: Table 6 a) mu317 (SEQ ID NOs: 4 and 6, respectively); b) mu326 (SEQ ID NOs: 8 and 10, respectively); c) 317-4B6 (SEQ ID NOs: 24 and 26, respectively); d) 326-4A3 (SEQ ID NOs: 28 and 30, respectively); e) 317-4B2 (SEQ ID NOs: 43 and 44, respectively); f) 317-4B5 (SEQ ID NOs: 45 and 46, respectively); g) 317-1 (SEQ ID NOs: 48 and 50, respectively); h) 326-3B1 (SEQ ID NOs: 51 and 52, respectively); i) 326-3GI (SEQ ID NOs: 53 and 54, respectively); j) 326-1 (SEQ ID NOs: 56 and 58, respectively); k) 317-3A1 (SEQ ID NOs: 57 and 58, respectively). NO: 64 and 26); l) 317-3C1 (SEQ ID NO: 65 and 26, respectively); m) 317-3E1 (SEQ ID NO: 66 and 26, respectively); n) 317-3F1 (SEQ ID NO: 67 and 26, respectively); o) 317-3G1 (SEQ ID NO: 68 and 26, respectively); p) 317-3H1 (SEQ ID NO: 69 and 26, respectively); q) 317-311 (SEQ ID NO: 70 and 26, respectively); r) 317-4B1 (SEQ ID NO: 71 and 26, respectively); s) 317-4B3 (SEQ ID NO: 72 and 26, respectively); t) 317-4B4 (SEQ ID NO: 73 and 26, respectively); u) 317-4A2 (SEQ ID NO: 74 and 26, respectively); v) 326-3A1 (SEQ ID NO: 75 and 30, respectively); w) 326-3C1 (SEQ ID NO: 76 and 30, respectively); x) 326-3D1 (SEQ ID NO: 77 and 30, respectively); y) 326-3E1 (SEQ ID NO: 78 and 31, respectively). NO:78 and 30); z) 326-3F1 (SEQ ID NO:79 and 30, respectively); aa) 326-3B N55D (SEQ ID NO:80 and 30, respectively); ab) 326-4A1 (SEQ ID NO:28 and 81, respectively); or ac) 326-4A2 (SEQ ID NO:28 and 82, respectively).

In some embodiments, the anti-PD-1 antibody is an antibody comprising a heavy chain variable region (Vh) and a light chain variable region (Vl) and an IgG4 heavy chain effector domain or a constant domain comprising SEQ ID NO: 88.

In some embodiments, the anti-PD-1 antibody is an antibody comprising heavy chain CDR-H1, CDR-H2 and CDR-H3 according to SEQ ID NOs: 11, 32 and 13, respectively, and light chain CDR-L1, CDR-L2 and CDR-L3 according to SEQ ID NOs: 61, 15 and 16, respectively.

In some embodiments, the anti-PD-1 antibody comprises heavy chain CDR-H1, CDR-H2 and CDR-H3 according to SEQ ID NOs: 31, 32, 33, respectively, and light chain CDR-L1, CDR-L2 and CDR-L3 according to SEQ ID NOs: 34, 35, 36, respectively. In some embodiments, the anti-PD-1 monoclonal antibody comprises an antibody comprising a heavy chain variable region (Vh) and a light chain variable region (Vl) of SEQ ID NOs: 24 and 26, respectively.

In some embodiments, the anti-PD-1 antibody is an antibody comprising a heavy chain variable region (Vh) and a light chain variable region (Vl) (comprising SEQ ID NO: 24 and SEQ ID NO: 26, respectively) and an IgG4 heavy chain effector domain or a constant domain (comprising SEQ ID NO: 88). In some embodiments, the anti-PD-1 antibody specifically binds to PD-1, such as to PD-1 residues including K45 and I93; or I93, L95 and P97, and inhibits PD-1-mediated cell signaling and activity in immune cells, wherein the antibody binds to a histidine residue required for binding to its ligand.

In any of the above embodiments, the anti-PD-1 antibody may be monoclonal. In some embodiments, the antibody is monoclonal and humanized. In some embodiments, the antibody is a monoclonal humanized IgG4 antibody. In some embodiments, the anti-PD-1 antibody is a monoclonal antibody or a fragment thereof, comprising a heavy chain variable region (Vh) amino acid sequence of SEQ ID NO: 24, a light chain variable region (Vl) amino acid sequence of SEQ ID NO: 26, and an IgG4 constant domain amino acid sequence of SEQ ID NO: 88. In some embodiments, the anti-PD-1 antibody is tislelizumab. The sequence of tislelizumab is known in the art.

In some embodiments, the present disclosure provides anti-PD1 antibodies and antigen-binding fragments thereof having the sequences provided in the following table. In some embodiments, the anti-PD1 antibody or its antigen-binding fragment specifically binds to human PD1 and comprises the six CDRs provided in the following table. In some embodiments, the anti-PD1 antibody or its antigen-binding fragment specifically binds to human PD1 and comprises a heavy chain variable region and a light chain variable region comprising the sequences provided in the following table. In some embodiments, the anti-PD1 antibody comprises an IgG4 constant domain comprising any of the sequences provided below. In some embodiments, the IgG4 constant domain comprises one of the last two sequences provided in the following table. Table 7 : Sequences of anti-PD1 antibodies Structural domain SEQ ID NO: Amino acid sequence CDR-H1 SEQ ID NO:31 GFSLTSYGVH CDR-H2 SEQ ID NO:32 VIYADGSTNYNPSLKS CDR-H3 SEQ ID NO:33 ARAYGNYWYIDV CDR-L1 SEQ ID NO:34 KSSESVSNDVA CDR-L2 SEQ ID NO:35 YAFHRFT CDR-L3 SEQ ID NO:36 HQAYSSPYT V SEQ ID NO:24 QVQLQESGPGLVKPSETLSLTCTVSGFSLTSYGVHWIRQPPGKGLEWIGVIYADGSTNYNPSLKSRVTISKDTSKNQVSLKLSSVTAADTAVYYCARAYGNYWYIDVWGQGTTVTVSS V SEQ ID NO:26 DIVMTQSPDSLAVSLGERATINCKSSESVSNDVAWYQQKPGQPPKLLINYAFHRFTGVPDRFSGSGYGTDFTLTISSLQAEDVAVYYCHQAYSSPYTFGQGTKLEIK IgG4 constant domain SEQ ID NO:27 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES KYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK IgG4 constant domain SEQ ID NO:28 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES KYGPPCPPCPAPPVAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK IgG4 constant domain SEQ ID NO:29 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES KYGPPCPPCPAPPVAGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK IgG4 constant domain SEQ ID NO:30 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES KYGPPCPPCPAPPVAGGPSVFLFPPKPKDTLMISRTPEVTCVVVTVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK IgG4 constant domain SEQ ID NO:31 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVES KYGPPCPPCPAPPVAGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK IgG4 constant domain SEQ ID NO:32 ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGGPSVFLFPPKPKDTLMISRTPEVTCVVVAVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

In some embodiments, the anti-PD1 antibody or antigen-binding fragment thereof comprises mutated amino acids, but has at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identity in the CDR region with the CDR region depicted in the sequences described herein (such as the table above). In some aspects, it comprises a mutant amino acid sequence, wherein no more than 1, 2, 3, 4 or 5 amino acids are mutated in the CDR region compared to the CDR disclosed herein.

In some embodiments, anti-PD1 antibodies include those in which amino acids or nucleic acids encoding amino acids have been mutated; but have a percent identity of at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% with the sequences described herein (such as in the table above) (e.g., in the heavy chain and light chain variable regions and/or IgG constant regions). In some aspects, it includes mutant amino acid sequences, wherein no more than 1, 2, 3, 4 or 5 amino acids have been mutated in the heavy chain and light chain variable regions compared to the heavy chain and light chain variable regions in the sequences disclosed herein, while retaining substantially the same therapeutic activity.

The anti-PD-1 antibodies and antigen-binding fragments thereof described herein can be prepared by any method known in the art and/or described herein. Methods for preparing monoclonal antibodies are well known in the art. For example, see Harlow E and Lane D, Antibodies: A Laboratory Manual (Cold Spring Harbor Press, 2nd edition, 1988); Hammerling GJ et al., Monoclonal Antibodies and T-Cell Hybridomas 563 (Elsevier, NY, 1981); Kohler G and Milstein C, 1975, Nature 256:495; Goding JW (ed.), Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986). Methods for preparing humanized antibodies are also well known in the art. See, e.g., Padlan EA (1991) Mol Immunol 28(4/5): 489-498; Studnicka GM et al., (1994) Prot Engineering 7(6): 805-814; and Roguska MA et al., (1994) PNAS 91: 969-973; Tan P et al., (2002) J Immunol 169: 1119-25; Caldas C et al., (2000) Protein Eng. 13(5): 353-60; Morea V et al., (2000), Methods 20(3): 267-79; Baca M et al., (1997) J Biol Chem 272(16): 10678-84; Roguska MA et al., (1996) Protein Eng 9(10): 895 904; Couto JR et al., (1995) Cancer Res. 55 (23 Suppl): 5973s-5977s; Couto JR et al., (1995) Cancer Res 55(8): 1717-22; Sandhu JS (1994) Gene 150(2): 409-10; Pedersen JT et al., (1994) J Mol Biol 235(3): 959-73). Methods for preparing human antibodies are also known in the art. See, for example, International Publication Nos. WO 98/46645, WO 98/50433, WO 98/24893, WO 98/16654, WO 96/34096, WO 96/33735, and WO 91/10741.

Anti -PD-1 monoclonal antibodies and antibody fragments thereof can be prepared according to the disclosure of WO2015/035606A1 or US 2015-0315274, the entire disclosure of which is incorporated herein by reference.

In some embodiments, an anti-PD-1 antibody (e.g., any of the antibodies described herein) is administered by any suitable means. In some embodiments, an anti-PD-1 antibody is administered parenterally. In some embodiments, an anti-PD-1 antibody is administered intravenously (IV). In some embodiments, an anti-PD-1 antibody is administered by IV infusion. In some embodiments, an anti-PD-1 antibody is infused over 60 minutes or longer. In some embodiments, an anti-PD-1 antibody is infused over 30 minutes or longer. In some embodiments, an anti-PD-1 antibody is administered subcutaneously. In some embodiments, an anti-PD-1 antibody is administered intramuscularly. In some embodiments, an anti-PD-1 antibody is administered intraperitoneally.

In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered non-enterally. In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered intravenously (IV). In some embodiments, tislelizumab is administered by IV infusion. In some embodiments, IV infusion is performed over 60 minutes or longer. In some embodiments, IV infusion is performed over 30 minutes or longer.

In some embodiments, an anti-PD-1 antibody (e.g., any of the antibodies described herein) is administered at a fixed dose. In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered at a fixed dose.

In some embodiments, the anti-PD-1 antibody is administered at a dose of 200 mg or about 200 mg. In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered at a dose of 200 mg or about 200 mg. In some embodiments, tislelizumab is administered at a dose of 200 mg.

In some embodiments, the anti-PD-1 antibody is administered at a dose of about 2 mg/kg to about 200 mg/kg (and any values therebetween). In some embodiments, the anti-PD-1 antibody is administered at a dose of about 2 mg/kg to about 5 mg/kg (e.g., 2 mg/kg to 5 mg/kg). In some embodiments, the anti-PD-1 antibody is administered at a dose of 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, or 5 mg/kg (or any values therebetween). In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered at a dose of about 2 mg/kg to about 5 mg/kg (e.g., 2 mg/kg to 5 mg/kg). In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered at a dose of 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, or 5 mg/kg (or any value therebetween). In some embodiments, tislelizumab is administered at a dose of 2 mg/kg to 5 mg/kg.

In some embodiments, the anti-PD-1 antibody is administered at a dose of about 2 mg/kg Q3W to about 200 mg/kg once every three weeks (Q3W). In some embodiments, the anti-PD-1 antibody is administered at a dose of about 2 mg/kg Q3W, 5 mg/kg Q3W, or 200 mg Q3W.

In some embodiments, the anti-PD-1 antibody is administered once every three weeks. In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered once every three weeks (e.g., at a 200 mg dose).

In some embodiments, the anti-PD-1 antibody is administered once every three weeks for 4 cycles or at least 4 cycles. In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered once every three weeks for 4 cycles or at least 4 cycles (e.g., at a dose of 200 mg).

In some embodiments, the anti-PD-1 antibody is administered once every three weeks for 3 cycles or at least 3 cycles. In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered once every three weeks for 3 cycles or at least 3 cycles (e.g., at a dose of 200 mg).

In some embodiments, the anti-PD-1 antibody is administered at a dose of 400 mg or about 400 mg. In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered at a dose of 400 mg or about 400 mg. In some embodiments, tislelizumab is administered at a dose of 400 mg.

In some embodiments, the anti-PD-1 antibody is administered at a dose of greater than about 200 mg/kg to about 400 mg/kg.

In some embodiments, the anti-PD-1 antibody is administered once every six weeks (Q6W) at a dose of about 400 mg/kg. In some embodiments, the anti-PD-1 antibody is administered at a dose of about 400 mg/kg Q6W.

In some embodiments, the anti-PD-1 antibody is administered once every six weeks. In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered once every six weeks (e.g., at a 400 mg dose).

In some embodiments, the anti-PD-1 antibody is administered once every six weeks for 8 cycles or at least 8 cycles. In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered once every six weeks for 8 cycles or at least 8 cycles (e.g., at a dose of 400 mg).

In some embodiments, the anti-PD-1 antibody is administered once every six weeks for less than 8 cycles. In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered once every six weeks (e.g., at a 400 mg dose) for less than 8 cycles.

In some embodiments, the anti-PD-1 antibody is administered for one treatment cycle. In some embodiments, the anti-PD-1 antibody is administered for two treatment cycles. In some embodiments, the anti-PD-1 antibody is administered for three treatment cycles. In some embodiments, the anti-PD-1 antibody is administered for four treatment cycles. In some embodiments, the anti-PD-1 antibody is administered for five treatment cycles. In some embodiments, the anti-PD-1 antibody is administered for six treatment cycles. In some embodiments, the anti-PD-1 antibody is administered for seven treatment cycles. In some embodiments, the anti-PD-1 antibody is administered for eight treatment cycles. In some embodiments, the anti-PD-1 antibody is administered for nine treatment cycles. In some embodiments, the anti-PD-1 antibody is administered for ten treatment cycles. In some embodiments, the anti-PD-1 antibody is administered for eleven treatment cycles. In some embodiments, the anti-PD-1 antibody is administered for twelve treatment cycles. In some embodiments, the anti-PD-1 antibody is administered for thirteen treatment cycles. In some embodiments, the anti-PD-1 antibody is administered for fourteen treatment cycles. In some embodiments, the anti-PD-1 antibody is administered for fifteen treatment cycles. In some embodiments, the treatment cycles are three weeks. In some embodiments, the treatment cycles are six weeks.

In some embodiments, the anti-PD-1 antibody is administered on day 1 of a cycle (e.g., day 1 of a 21 day or 3 cycle, or day 1 of a 42 day or 6 cycle).

In some embodiments, the anti-PD-1 antibody is infused IV for 60 minutes or more (e.g., in the lead phase). In some embodiments, the anti-PD-1 antibody is infused IV for 60 minutes or more in cycle 1, and is infused IV for 30 minutes or about 30 minutes in subsequent cycles (e.g., cycles 2 to 4, cycles 2 to 5, or any number of cycles after the first cycle). In some embodiments, the anti-PD-1 antibody is infused IV for 60 minutes or more in cycle 1, and is infused IV for less than 60 minutes in subsequent cycles (e.g., cycles 2 to 4, cycles 2 to 5, or any number of cycles after the first cycle). In some embodiments, the infusion time of the anti-PD-1 antibody is reduced from 60 minutes to 30 minutes if and only if the treated individual tolerates a 60 minute infusion time well. In some embodiments, during the adjuvant phase, the anti-PD-1 antibody is infused IV over 90 minutes or longer (at least during the first cycle of the adjuvant phase). In some embodiments, during the adjuvant phase, the infusion time of the anti-PD-1 antibody is reduced from 90 minutes to 60 minutes to 30 minutes if and only if the treated individual tolerates a longer infusion time well.

In some embodiments, the anti-PD-1 antibody is administered during the induction treatment period (or the leading stage). In some embodiments, the anti-PD-1 antibody is administered during the maintenance treatment period (or the adjuvant stage). In some embodiments, the induction treatment period is followed by the maintenance treatment period. In some embodiments, the tumor is surgically removed after the induction treatment period, followed by the maintenance treatment period. In some embodiments, the dosage of the anti-PD-1 antibody is different between the maintenance period and the induction period. In some embodiments, the dosage of the anti-PD-1 antibody during the induction period (lead period) is 200 mg, and the dosage during the maintenance period (adjuvant period) is 400 mg. In some embodiments, the induction (lead) treatment period comprises an anti-PD-1 antibody administered once every 3 weeks. In some embodiments, the induction treatment period comprises three or four three-week cycles. In some embodiments, the maintenance (adjuvant) treatment period comprises an anti-PD-1 antibody administered once every 6 weeks. In some embodiments, the maintenance treatment period comprises one six-week cycle. In some embodiments, the maintenance treatment period comprises two six-week cycles. In some embodiments, the maintenance treatment period comprises three six-week cycles. In some embodiments, the maintenance treatment period comprises four six-week cycles. In some embodiments, the maintenance treatment period comprises five six-week cycles. In some embodiments, the maintenance treatment period comprises six six-week cycles. In some embodiments, the maintenance treatment period comprises seven six-week cycles. In some embodiments, the maintenance treatment period comprises eight six-week cycles. In some embodiments, the maintenance treatment period comprises nine six-week cycles. In some embodiments, the maintenance treatment period comprises ten six-week cycles.

In some embodiments, the anti-PD-1 antibody is administered intravenously at a fixed dose of 200 mg. In some embodiments, the anti-PD-1 antibody is administered intravenously at a fixed dose of 200 mg once every three weeks. In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered intravenously at a fixed dose of 200 mg. In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered intravenously at a fixed dose of 200 mg once every three weeks. In some embodiments, IV administration is performed by IV infusion.

In some embodiments, the anti-PD-1 antibody is administered intravenously at a dose of 2 mg/kg to 5 mg/kg (e.g., 2 mg/kg or 5 mg/kg). In some embodiments, the anti-PD-1 antibody is administered intravenously once every three weeks at a dose of 2 mg/kg to 5 mg/kg (e.g., 2 mg/kg or 5 mg/kg). In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered intravenously at a dose of 2 mg/kg to 5 mg/kg (e.g., 2 mg/kg or 5 mg/kg). In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered intravenously at a dose of 2 mg/kg to 5 mg/kg (e.g., 2 mg/kg or 5 mg/kg) every three weeks. In some embodiments, IV administration is performed by IV infusion.

In some embodiments, the anti-PD-1 antibody is administered intravenously at a fixed dose of 400 mg. In some embodiments, the anti-PD-1 antibody is administered intravenously at a fixed dose of 400 mg once every three weeks. In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered intravenously at a fixed dose of 400 mg. In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 is administered intravenously at a fixed dose of 400 mg once every three weeks. In some embodiments, IV administration is performed by IV infusion.

In some embodiments, an anti-PD-1 antibody (e.g., tislelizumab) is administered at 200 mg in the leading phase and at 400 mg in the adjuvant phase. In some embodiments, the cancer being treated was resected or removed (completely or partially) between the leading treatment phase and the adjuvant treatment phase.

In some embodiments, the dosages and treatment regimens described herein are for administration to human subjects. Anticancer Agents / Chemotherapeutic Drugs

In some embodiments, an anticancer agent is administered to a subject as described herein. As used herein, the term "anticancer agent" refers to any agent useful for treating a cell proliferative disorder such as cancer, including but not limited to cytotoxic agents, chemotherapeutic agents, radiation therapy and radiotherapeutic agents, targeted anticancer agents, and immunotherapeutic agents, including cellular therapy.

In some embodiments, the anti-PD-1 antibodies and antigen-binding fragments of the present disclosure are used in combination with one or more anti-cancer agents. In some embodiments, an anti-PD-1 antibody is administered to a subject as described herein, and an anti-cancer agent as described herein is further administered.

In some embodiments, the anti-PD-1 antibodies of the present disclosure are used in combination with one or more chemotherapeutic agents or drugs (e.g., one, two, or three chemotherapeutic agents or drugs). In some embodiments, the treatment methods described herein include administering an anti-PD-1 antibody of the present disclosure and one or more chemotherapeutic drugs (e.g., one, two, or three chemotherapeutic drugs) to an individual (e.g., a human).

The types of chemotherapeutic agents that can be used include (but are not limited to): microtubule inhibitors, such as taxanes (paclitaxel, docetaxel) and vinca alkaloids (vincristine, vinblastine, vinorelbine); anti-metabolites (5-fluorouracil, capecitabine, gemcitabine) and antifolates (methotrexate, pemetrexed); kinase inhibitors (crizotinib, erlotinib, sunitinib); topoisomerase inhibitors (drunotecan, topotecan, irinotecan, anthracyclines, etoposide); cell cycle-independent drugs, such as platinum compounds and analogs (orthoclase, oxazolidinone ... thaliplatin), triazenes, alkylating agents (cyclophosphamide), phytoalkaloids (doxorubicin), cytotoxic/antitumor antibiotics (bleomycin, leucomycin, mitomycin), photosensitizers, antiestrogens and selective estrogen receptor modulators (SERMs), antiprogestins, estrogen receptor downregulators (ERDs), estrogen receptor antagonists, luteinizing hormone-releasing hormone agonists, antiandrogens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, and antisense oligonucleotides that inhibit abnormal cell proliferation or expression of genes associated with tumor growth. Current standard of care (SOC) treatment for certain cancers in the early-line setting includes fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, either in combination or sequentially, with monoclonal antibodies targeting vascular endothelial growth factor (VEGF) (e.g., bevacizumab, ziv-aflibercept) or VEGF receptors (e.g., ramucirumab), as appropriate, and, in patients with Ras wild-type tumors, monoclonal antibodies targeting epidermal growth factor (EGF) receptors (e.g., cetuximab, panitumumab). For patients who have been heavily pretreated outside of the second-line setting, treatment options are particularly limited, and associated toxicities can be severe.

In some embodiments, the chemotherapeutic agent is selected from one or more of the following: paclitaxel or paclitaxel agent; (e.g., Abraxane®), docetaxel; carboplatin; topotecan; delunotecan; cisplatin; 5-fluorouracil, irinotecan, doxorubicin, lenalidomide, 5-azacytidine, ifosfamide, oxaliplatin, pemetrexed disodium, cyclophosphamide amine, ethotoposide, decitabine, fludarabine, vincristine, bendamustine, chlorambucil, busulfan, gemcitabine, melphalan, pentostatin, mitoxantrone, and pemetrexed disodium.

In some embodiments, the chemotherapeutic agent is platinum chemotherapy.

In some embodiments, the chemotherapeutic drug is cis-platinum.

In some embodiments, the chemotherapeutic drug is carboplatin.

In some embodiments, the treatment methods described herein include administering an anti-PD-1 antibody of the disclosure and cisplatin or carboplatin to an individual (e.g., a human). In some embodiments, whether to administer cisplatin or carboplatin is at the discretion of the physician.

In some embodiments, the chemotherapeutic drug is pemetrexed. In some embodiments, the treatment methods described herein include administering an anti-PD-1 antibody of the present disclosure and pemetrexed to a subject (e.g., a human).

In some embodiments, the chemotherapeutic drug is paclitaxel. In some embodiments, the treatment methods described herein include administering an anti-PD-1 antibody of the disclosure and paclitaxel to a subject (e.g., a human).

In some embodiments, the chemotherapeutic drug is epoxies. In some embodiments, the treatment methods described herein comprise administering to a subject (e.g., a human) an anti-PD-1 antibody of the disclosure and epoxies.

In some embodiments, the treatment methods described herein comprise administering to a subject (e.g., a human) (i) an anti-PD-1 antibody of the disclosure, (ii) cisplatin or carboplatin, and (iii) pemetrexed or paclitaxel.

In some embodiments, the chemotherapeutic agent is 5-fluorouracil. In some embodiments, the treatment methods described herein include administering to a subject (e.g., a human) (i) an anti-PD-1 antibody of the disclosure, (ii) 5-fluorouracil, and (iii) cisplatin.

The dosage of the chemotherapy drug can be any dosage known in the art (e.g., any dosage and administration regimen known to be effective in the art) or any dosage described herein .

In some embodiments, a patient as described herein is administered a combination of cis platinum and an anti-PD-1 antibody as described herein. In some embodiments, a patient is administered a combination of cis platinum and tislelizumab. In some embodiments, a patient is administered a combination of cis platinum and an anti-PD-1 antibody as described herein and pemetrexed or paclitaxel. In some embodiments, a patient is administered a combination of cis platinum and tislelizumab and one or both of pemetrexed and paclitaxel. In some embodiments, a patient is administered a combination of cis platinum and tislelizumab and 5-fluorouracil.

In some embodiments, cis platinum is administered parenterally. In some embodiments, cis platinum is administered at a dose of about 20 mg/m ² to about 100 mg/m ^2. In some embodiments, cis platinum is administered at about 20 mg/m ² , 25 mg/m ² , 30 mg/m ² , 35 mg/m ² , 40 mg/m ² , 45 mg/m ² , 50 mg/m ² , 55 mg/m ² , 60 mg/m ² , 65 mg/m ² , 70 mg/m ² , 75 mg/m ² , 80 mg/m ² , 85 mg/m ² , 90 mg/m ² , 95 mg/m ² , or 100 mg/m ² (or any value therebetween). In some embodiments, cis-platinum is administered at about 75 mg/m ^2. In some embodiments, cis-platinum is administered at 75 mg/m ² .

In some embodiments, cisplatin is administered intravenously. In some embodiments, cisplatin is administered as an intravenous infusion over at least 2 hours. In some embodiments, cisplatin is administered as an intravenous infusion over 2 hours. In some embodiments, cisplatin is administered once a week. In some embodiments, cisplatin is administered once every 3 weeks. In some embodiments, cisplatin is administered once every 3 weeks on day 1. In some embodiments, cisplatin is administered once every 3 weeks on day 2. In some embodiments, cisplatin is administered on day 1-day 3 every 3 weeks. In some embodiments, cisplatin is administered on day 1-day 5 every 3 weeks.

In some embodiments, cis platinum is administered for 1 cycle. In some embodiments, cis platinum is administered for 2 cycles. In some embodiments, cis platinum is administered for 3 cycles. In some embodiments, cis platinum is administered for 4 cycles. In some embodiments, the cycles are 3 weeks.

In some embodiments, administration of cisplatin is continued for four three-week cycles.

In some embodiments, cisplatin is administered on day 1 of each cycle. In some embodiments, cisplatin is administered on day 2 of each cycle. In some embodiments, cisplatin is administered on day 3 of each cycle. In some embodiments, cisplatin is administered on day 4 of each cycle. In some embodiments, cisplatin is administered on day 5 of each cycle.

In some embodiments, the methods described herein comprise administering cisplatin once per cycle, wherein each cycle is three weeks, on day 1 of each cycle, for four cycles.

In some embodiments, the methods described herein comprise administering 75 mg/ ^m2 of cisplatin intravenously on day 1 of each 21-day cycle (and optionally as a 2-hour infusion of cisplatin), and optionally continuing such administration for 4 cycles or more.

In some embodiments, a patient as described herein is administered carboplatin in combination with an anti-PD-1 antibody as described herein. In some embodiments, a patient is administered carboplatin in combination with tislelizumab. In some embodiments, a patient is administered carboplatin in combination with an anti-PD-1 antibody as described herein and pemetrexed or paclitaxel. In some embodiments, a patient is administered carboplatin in combination with tislelizumab and one or both of pemetrexed and paclitaxel.

In some embodiments, carboplatin is administered parenterally. In some embodiments, carboplatin is administered with a target AUC of 4 mg/mL/min to 6 mg/mL/min (and any value therebetween, e.g., 5 to 6 mg/mL/min). In some embodiments, carboplatin is administered with a target AUC of 4 mg/mL/min. In some embodiments, carboplatin is administered with a target AUC of 5 mg/mL/min. In some embodiments, carboplatin is administered with a target AUC of 6 mg/mL/min. As used herein, the term "area under the curve" or "AUC" defines the dose of carboplatin administered to a subject. AUC is the area under the plasma concentration-time curve. In some embodiments, carboplatin is administered to a subject to achieve the above AUC, e.g., an AUC of 5 mg/mL/min. In some embodiments, the dosage of carboplatin is calculated according to the Calvert formula. One skilled in the art can calculate the amount of carboplatin required to achieve a given AUC in an individual. See Calvert et al., Carboplatin dosage: prospective evaluation of a simple formula based on renal function. Journal of Clinical Oncology, 1989, 7(11): 1748-56, which is incorporated herein by reference in its entirety.

In some embodiments, carboplatin is administered intravenously. In some embodiments, carboplatin is administered as an intravenous infusion over 15 to 60 minutes (or any value therebetween). In some embodiments, carboplatin is administered as an intravenous infusion over 15 minutes. In some embodiments, carboplatin is administered as an intravenous infusion over 30 minutes. In some embodiments, carboplatin is administered as an intravenous infusion over 45 minutes. In some embodiments, carboplatin is administered as an intravenous infusion over 60 minutes.

In some embodiments, the platinum is administered once a week. In some embodiments, the platinum is administered once every 3 weeks. In some embodiments, the platinum is administered once every 3 weeks on day 1.

In some embodiments, the platinum is administered for 1 cycle. In some embodiments, the platinum is administered for 2 cycles. In some embodiments, the platinum is administered for 3 cycles. In some embodiments, the platinum is administered for 4 cycles. In some embodiments, the cycle is 3 weeks.

In some embodiments, the platinum is administered for four three-week cycles. In some embodiments, the platinum is administered on day 1 of each cycle.

In some embodiments, the methods described herein include administering platinum once per cycle, wherein each cycle is three weeks, and administering on day 1 of each cycle for four cycles.

In some embodiments, the methods described herein include administering AUC5 carboplatin intravenously on day 1 of each 21-day cycle (and optionally wherein carboplatin is infused over 15 to 60 minutes), and optionally the administration continues for 4 cycles or more. In some embodiments, carboplatin is administered to achieve an AUC of 5 mg/mL/min according to the Calvert formula dosing (e.g., as described herein). Pemetrexed

In some embodiments, a patient as described herein is administered a combination of pemetrexed and an anti-PD-1 antibody as described herein. In some embodiments, a patient is administered a combination of pemetrexed and tislelizumab. In some embodiments, a patient is administered a combination of an anti-PD-1 antibody as described herein, carboplatin or cisplatin, and pemetrexed. In some embodiments, a patient is administered a combination of tislelizumab, carboplatin or cisplatin, and pemetrexed. In some of these embodiments, the cancer is non-squamous cell carcinoma (e.g., non-squamous cell NSCLC).

In some embodiments, pemetrexed is administered parenterally. In some embodiments, pemetrexed is administered at a dose of about 250 mg/m ² to about 1000 mg/m ² (or any value therebetween). In some embodiments, pemetrexed is administered at about 500 mg/m ^2. In some embodiments, pemetrexed is administered at 500 mg/m ² .

In some embodiments, pemetrexed is administered intravenously. In some embodiments, pemetrexed is administered as an intravenous infusion over about 10 minutes or at least 10 minutes. In some embodiments, pemetrexed is administered as an intravenous infusion over 10 minutes.

In some embodiments, pemetrexed is administered once every three weeks. In some embodiments, pemetrexed is administered on day 1 of a 3-week (21 day) cycle. In some embodiments, pemetrexed is administered on day 2 of a 3-week (21 day) cycle. In some embodiments, pemetrexed is administered on day 3 of a 3-week (21 day) cycle. In some embodiments, pemetrexed is administered on day 4 of a 3-week (21 day) cycle. In some embodiments, pemetrexed is administered on day 5 of a 3-week (21 day) cycle. In some embodiments, pemetrexed is administered on day 1-day 3 every 3 weeks. In some embodiments, pemetrexed is administered on day 1-day 5 every 3 weeks.

In some embodiments, pemetrexed is administered for 1 cycle. In some embodiments, pemetrexed is administered for 2 cycles. In some embodiments, pemetrexed is administered for 3 cycles. In some embodiments, pemetrexed is administered for 4 cycles. In some embodiments, the cycle is 3 weeks.

In some embodiments, administration of pemetrexed is continued for four three-week cycles.

In some embodiments, pemetrexed is administered on day 1 of each cycle.

In some embodiments, the methods described herein comprise administering pemetrexed once per cycle, wherein each cycle is three weeks for 3 or 4 cycles.

In some embodiments, the methods described herein comprise administering 500 mg/m ² of pemetrexed intravenously on day 1 of each 21-day cycle (and optionally wherein pemetrexed is infused over 10 minutes), and optionally the administration continues for 3, 4, or more cycles. Paclitaxel

In some embodiments, a patient as described herein is administered a combination of paclitaxel and an anti-PD-1 antibody as described herein. In some embodiments, a patient is administered a combination of paclitaxel and tislelizumab. In some embodiments, a patient is administered a combination of an anti-PD-1 antibody as described herein, carboplatin or cisplatin, and paclitaxel. In some embodiments, a patient is administered a combination of tislelizumab, carboplatin or cisplatin, and paclitaxel. In some such embodiments, the cancer is squamous cell carcinoma (e.g., squamous cell NSCLC).

In some embodiments, paclitaxel is administered parenterally. In some embodiments, paclitaxel is administered at a dose of about 80 mg/m ² to about 400 mg/m ² (or any value therebetween). In some embodiments, paclitaxel is administered at about 175 mg/m ^2. In some embodiments, paclitaxel is administered at 175 mg/m ² .

In some embodiments, paclitaxel is administered intravenously. In some embodiments, paclitaxel is administered as an intravenous infusion over about 3 hours or at least 3 hours. In some embodiments, paclitaxel is administered as an intravenous infusion over 3 hours.

In some embodiments, paclitaxel is administered once every three weeks. In some embodiments, paclitaxel is administered on day 1 of a 3-week (21 day) cycle. In some embodiments, paclitaxel is administered on day 2 of a 3-week (21 day) cycle. In some embodiments, paclitaxel is administered on day 3 of a 3-week (21 day) cycle. In some embodiments, paclitaxel is administered on day 4 of a 3-week (21 day) cycle. In some embodiments, paclitaxel is administered on day 5 of a 3-week (21 day) cycle. In some embodiments, paclitaxel is administered on day 1-day 3 every 3 weeks. In some embodiments, paclitaxel is administered on day 1-day 5 every 3 weeks.

In some embodiments, paclitaxel is administered for 1 cycle. In some embodiments, paclitaxel is administered for 2 cycles. In some embodiments, paclitaxel is administered for 3 cycles. In some embodiments, paclitaxel is administered for 4 cycles. In some embodiments, the cycle is 3 weeks.

In some embodiments, administration of paclitaxel is continued for four three-week cycles.

In some embodiments, paclitaxel is administered on day 1 of each cycle.

In some embodiments, the methods described herein comprise administering paclitaxel once per cycle, wherein each cycle is three weeks, for 3 or 4 cycles. In some embodiments, the methods described herein comprise administering 175 mg/m ² of paclitaxel intravenously on day 1 of each 21-day cycle (and optionally wherein paclitaxel is administered as a 3-hour infusion), and optionally such administration continues for 3, 4 cycles or more. Etoposide

In some embodiments, a patient as described herein is administered a combination of eptofoside and an anti-PD-1 antibody as described herein. In some embodiments, a patient is administered a combination of eptofoside and tislelizumab. In some embodiments, a patient is administered a combination of an anti-PD-1 antibody as described herein, carboplatin or cisplatin, and eptofoside. In some embodiments, a patient is administered a combination of tislelizumab, carboplatin or cisplatin, and eptofoside.

In some embodiments, etatoposide is administered parenterally. In some embodiments, etatoposide is administered at a dose of about 80 mg/m2 to about 140 mg/m2 (or any value therebetween). In some embodiments, etatoposide is administered at 80 mg/m2. In some embodiments, etatoposide is administered at 90 mg/m2. In some embodiments, etatoposide is administered at 100 mg/m2. In some embodiments, etatoposide is administered at 110 mg/m2. In some embodiments, etatoposide is administered at 120 mg/m2. In some embodiments, etatoposide is administered at 130 mg/m2. In some embodiments, etatoposide is administered at 140 mg/m2.

In some embodiments, etatoposide is administered intravenously. In some embodiments, etatoposide is administered as an intravenous infusion over at least 60 minutes. In some embodiments, etatoposide is administered as an intravenous infusion over 60 minutes.

In some embodiments, edoposide is administered once a week. In some embodiments, edoposide is administered three times within three weeks. In some embodiments, edoposide is administered three times within the first week of a 3-week (21 day) cycle. In some embodiments, edoposide is administered on day 1 of a 3-week (21 day) cycle. In some embodiments, edoposide is administered on day 2 of a 3-week (21 day) cycle. In some embodiments, edoposide is administered on day 3 of a 3-week (21 day) cycle. In some embodiments, edoposide is administered on day 4 of a 3-week (21 day) cycle. In some embodiments, etatoposide is administered on day 5 of a 3 week (21 day) cycle. In some embodiments, etatoposide is administered on day 1-day 3 every 3 weeks. In some embodiments, etatoposide is administered on day 1-day 5 every 3 weeks.

In some embodiments, etatoposide is administered for 1 cycle. In some embodiments, etatoposide is administered for 2 cycles. In some embodiments, etatoposide is administered for 3 cycles. In some embodiments, etatoposide is administered for 4 cycles. In some embodiments, the cycle is 3 weeks.

In some embodiments, administration of etanercept is continued for four three-week cycles.

In some embodiments, etanercept is administered on day 1, day 2, and day 3 of each cycle. In some embodiments, etanercept is administered on day 1, day 2, day 3, day 4, and day 5 of each cycle.

In some embodiments, the methods described herein comprise administering etanercept three times per cycle, wherein each cycle is three weeks for four cycles.

In some embodiments, the methods described herein comprise administering 100 mg/m2 of estolide intravenously on days 1 to 3 of each 21-day cycle (and optionally wherein estolide is infused over 60 minutes), and optionally the administration continues for 4 cycles or more. 5- Fluorouracil

In some embodiments, 5-fluorouracil is administered to a patient as described herein in combination with an anti-PD-1 antibody as described herein. In some embodiments, 5-fluorouracil is administered to a patient in combination with tislelizumab. In some embodiments, 5-fluorouracil is administered to a patient in combination with an anti-PD-1 antibody as described herein and cis-platinum. In some embodiments, cis-platinum is administered to a patient in combination with tislelizumab and 5-fluorouracil.

In some embodiments, 5-fluorouracil is administered intravenously. In some embodiments, 5-fluorouracil is administered in an amount of about 200 mg/m ² to about 3000 mg/m ² . In some embodiments, 5-fluorouracil is administered at about 200 mg/ ^m2 , 300 mg/ ^m2 , 400 mg/ ^m2 , 500 mg/ ^m2 , 600 mg/ ^m2 , 700 mg/ ^m2 , 800 mg/ ^{m2, 900 mg/m2 ,} 1000 mg/ ^m2 , 1200 mg/ ^m2 , 1500 mg/ ^m2 , 1700 mg/ ^m2 , 2000 mg/ ^m2 , 2200 mg/ ^m2 , 2500 mg/ ^m2 , 2700 mg/ ^m2 , or 3000 mg/ ^m2 (or any value therebetween).

In some embodiments, 5-fluorouracil is administered intravenously. In some embodiments, 5-fluorouracil is administered as an intravenous bolus. In some embodiments, 5-fluorouracil is administered as an intravenous infusion. In some embodiments, 5-fluorouracil is administered as an intravenous infusion over 24 hours. In some embodiments, 5-fluorouracil is administered as an intravenous infusion over 46 hours. In some embodiments, 5-fluorouracil is administered weekly. In some embodiments, 5-fluorouracil is administered every two weeks. In some embodiments, 5-fluorouracil is administered weekly for two weeks and then administered again three weeks later.

In some embodiments, 5-fluorouracil is administered for 1 cycle. In some embodiments, 5-fluorouracil is administered for 2 cycles. In some embodiments, 5-fluorouracil is administered for 4 cycles. In some embodiments, 5-fluorouracil is administered for 6 cycles. In some embodiments, 5-fluorouracil is administered for 8 cycles.

In some embodiments, 5-fluorouracil is administered by intravenous bolus at 400 mg/m ² on day 1 of a treatment cycle, followed by 2400 mg/m ² to 3000 mg/m ² administered by continuous infusion over 46 hours every two weeks. In some embodiments, 5-fluorouracil is administered by intravenous bolus at 500 mg/m ² on days 1, 8, 15, 22, 29, and 36 of a treatment cycle in 8 cycles. In some embodiments, 5-fluorouracil is administered intravenously at 500 mg/m ² or 600 mg/m ² on days 1 and 8 of each 28-day treatment cycle for 6 cycles. In some embodiments, 5-fluorouracil is administered intravenously at 200 mg/m ² to 1000 mg/m ² over 24 hours as a continuous infusion. In some embodiments, 5-fluorouracil is administered by intravenous bolus at 400 mg/m ² on day 1 of the treatment cycle, followed by 2400 mg/m ² administered intravenously as a continuous infusion over 46 hours every two weeks. Radiation therapy

In some embodiments, a patient as described herein is administered radiation therapy in combination with an anti-PD-1 antibody as described herein. In some embodiments, a patient is administered radiation therapy in combination with tislelizumab. In some embodiments, a patient is administered radiation therapy in combination with an anti-PD-1 antibody as described herein and one or both of cis-platinum and paclitaxel or cis-platinum and 5-fluorouracil. In some embodiments, a patient is administered radiation therapy in combination with tislelizumab and one or both of cis-platinum and paclitaxel or cis-platinum and 5-fluorouracil.

In some embodiments, radiation therapy is administered at about 10 to about 80 grays. In some embodiments, radiation therapy is administered at about 10 grays. In some embodiments, radiation therapy is administered at about 20 grays. In some embodiments, radiation therapy is administered at about 30 grays. In some embodiments, radiation therapy is administered at about 40 grays. In some embodiments, radiation therapy is administered at about 50 grays. In some embodiments, radiation therapy is administered at about 60 grays. In some embodiments, radiation therapy is administered at about 70 grays. In some embodiments, radiation therapy is administered at about 80 grays.

In some embodiments, the radiation therapy is administered in about 5 divided doses. In some embodiments, the radiation therapy is administered in about 10 divided doses. In some embodiments, the radiation therapy is administered in about 15 divided doses. In some embodiments, the radiation therapy is administered in about 20 divided doses. In some embodiments, the radiation therapy is administered in about 25 divided doses. In some embodiments, the radiation therapy is administered in about 30 divided doses. In some embodiments, the radiation therapy is administered in about 35 divided doses. In some embodiments, the radiation therapy is administered in about 40 divided doses.

In some embodiments, radiation therapy is administered at 40 Gy/min in 20 fractions.

Combination therapy can be administered simultaneously, or in separate or sequential regimens. When administered sequentially, the combination can be administered in two or more administrations. Combination administration includes co-administration using separate formulations as well as consecutive administration in either order, wherein preferably there is a time period during which both (or each) active agents simultaneously exert their biological activities.

In some embodiments, the combination therapies provided herein provide synergistic and/or statistically improved effects relative to either therapy when used as a single agent. For example, the combination therapies disclosed herein significantly improve patient outcomes in early stage NSCLC or intermediate stage NSCLC. For example, in some embodiments, the combination therapy prolongs patient survival and progression-free survival while having a manageable toxicity profile in patients with early stage NSCLC or intermediate stage NSCLC.

Suitable dosages of any of the above co-administered agents are those currently used and may be lowered due to combined effects (synergistic effects), such as increasing the therapeutic index or reducing toxicity or other side effects or consequences.

In some embodiments, anti-PD-1 antibodies and one or more chemotherapy drugs (or combination therapy regimens described herein) can be further combined with any other therapy. In some embodiments, anti-PD-1 antibodies and one or more chemotherapy drugs (or combination therapy regimens described herein) can be further combined with any therapy other than any one or more of the therapies listed in the exclusion criteria described in the Examples section of this application. In some embodiments, anti-PD-1 antibodies and one or more chemotherapy drugs (or combination therapy regimens described herein) can be further combined with, for example, radiation therapy. In some embodiments, an anti-PD-1 antibody and one or more chemotherapy drugs (or a combination treatment regimen described herein) may be further combined with, for example, steroid or hormone therapy, optionally wherein the steroid or hormone therapy is administered to reduce the incidence of immune-mediated adverse events.

In some embodiments, the combination therapy is any combination therapy described herein, including but not limited to the combination therapies, dosages, durations, and schedules described in the Examples section of this application.

In some embodiments, the combination therapies described herein may be combined with additional therapies that meet the inclusion criteria described in the Examples section of this application.

In some embodiments, the combination therapies described herein may be combined with additional therapies that meet the exclusion criteria described in the Examples section of this application (i.e., where the therapies listed in the exclusion criteria are not included or selected for use in the combination).

In some embodiments, the additional therapy may be one or more of the following: tyrosine kinase inhibitors (e.g., EGFR inhibitors (e.g., erlotinib), multikinase inhibitors (e.g., MGCD265, RGB-286638), CD-20 targeting agents (e.g., rituximab, ofatumumab, RO5072759, LFB-R603), CD52 targeting agents (e.g., alemtuzumab), prednisolone, darbepoetin alfa, levofloxacin, Bcl-2 inhibitors (e.g., oblimersen sodium), sodium)), Aurora kinase inhibitors (e.g. MLN8237, TAK-901), proteasome inhibitors (e.g. bortezomib), CD-19 targeting agents (e.g. MEDI-551, MOR208), MEK inhibitors (e.g. ABT-348), JAK-2 inhibitors (e.g. INCB018424), mTOR inhibitors (e.g. temsirolimus, everolimus), BCR/ABL inhibitors (e.g. imatinib), ET-A receptor antagonists (e.g. ZD4054), TRAIL receptor 2 (TR-2) agonists (e.g. CS-1008), EGEN-001, Polo-like kinase 1 inhibitors (e.g. BI 672).

In some embodiments, the additional therapy is radiation therapy. In some embodiments, radiation therapy is administered after surgical resection or removal of a tumor or cancerous tissue. In some embodiments, radiation therapy is administered prior to a maintenance or adjuvant treatment period with an anti-PD-1 antibody (e.g., a 400 mg dose). In some embodiments, radiation therapy is administered 30 to 60 days (e.g., 30, 40, 50, or 60 days) after surgical resection of a tumor or cancer. In some embodiments, radiation therapy is administered at least 30 days after surgical resection of a tumor or cancer. In some embodiments, radiation therapy is administered no more than 60 days after surgical resection of a tumor or cancer. In some embodiments, the maintenance or adjuvant treatment period with an anti-PD-1 antibody (e.g., a 400 mg dose) is initiated between 7 and 30 days (e.g., 7, 14, 21, 28, or 30 days) after radiation therapy. In some embodiments, the maintenance or adjuvant treatment period with an anti-PD-1 antibody (e.g., a 400 mg dose) is initiated at least 7 days after radiation therapy. In some embodiments, the maintenance or adjuvant treatment period with an anti-PD-1 antibody (e.g., a 400 mg dose) is initiated no more than 30 days after radiation therapy. In some embodiments, the individual has not been treated with radiation therapy. In some embodiments, radiation therapy is not performed after surgical resection. In some embodiments, the treatment regimens described herein do not include radiation therapy. In some embodiments, the maintenance or adjuvant treatment period with an anti-PD-1 antibody (e.g., a 400 mg dose) is initiated between 2 and 8 weeks (e.g., 2, 3, 4, 5, 6, 7, or 8 weeks) after surgical resection of the tumor or cancer. In some embodiments, the maintenance or adjuvant treatment period with an anti-PD-1 antibody (e.g., a 400 mg dose) is initiated at least 2 weeks after surgical resection of the tumor or cancer. In some embodiments, the maintenance or adjuvant treatment period with an anti-PD-1 antibody (e.g., a 400 mg dose) is initiated no more than 8 weeks after surgical resection of the tumor or cancer.

In some embodiments, the additional therapy may be an antibody that binds to another immune checkpoint molecule.

In some embodiments, the amounts of the anti-PD-1 antibodies and one or more chemotherapy drugs disclosed herein and their relative administration times are determined by the individual needs of the patient to be treated, the route of administration, the severity of the disease or condition, the dosing schedule, and the evaluation and judgment of the assigning physician.

In some embodiments, the anti-PD-1 antibody is administered prior to (e.g., 60 minutes or longer) the administration of one or more chemotherapeutic drugs. In some embodiments, the anti-PD-1 antibody is administered prior to (e.g., 30 minutes or longer) the administration of one or more chemotherapeutic drugs. In some embodiments, the anti-PD-1 antibody is administered 60 minutes or longer prior to the administration of one or more chemotherapeutic drugs in the 1st cycle and, if appropriate, the 2nd cycle. In some embodiments, the anti-PD-1 antibody is administered 30 minutes or longer prior to the administration of one or more chemotherapeutic drugs in the 3rd cycle, the 4th cycle, and/or any cycle following the 3rd cycle.

In some embodiments, the anti-PD-1 antibody and one or more chemotherapeutic agents are administered at the dosage, frequency, and/or duration as described herein.

In some embodiments, the anti-PD-1 antibody and one or more chemotherapeutic drugs described herein are administered on the same day. In some embodiments, the anti-PD-1 antibody and one or more chemotherapeutic drugs described herein are administered at least 30 minutes apart from each other. In some embodiments, the anti-PD-1 antibody and one or more chemotherapeutic drugs described herein are administered in any order. In some embodiments, the anti-PD-1 antibody is administered prior to (e.g., at least 30 minutes) administration of one or more chemotherapeutic drugs as described herein.

In some embodiments, an anti-PD-1 antibody (e.g., an anti-PD-1 antibody comprising the CDRs of the 317-4B6 antibody described herein, the Vh of SEQ ID NO: 24, and/or the Vl of SEQ ID NO: 26 (e.g., tislelizumab)) is administered intravenously at a dose of 200 mg on Day 1 of each 21-day cycle; cis-platinum or carboplatin is administered intravenously on Day 1 of each 21-day cycle; and pemetrexed or paclitaxel is administered intravenously on Day 1 of each 21-day cycle. In some such embodiments, cisplatin is administered at 75 mg/m2 IV (and optionally infused over 2 hours) or carboplatin is administered at AUC5 IV (and optionally infused over 15-60 minutes to achieve an AUC of 5 mg/mL/min). In some such embodiments, pemetrexed is administered at 500 mg/ ^m2 IV (and optionally infused over 10 minutes) or paclitaxel is administered at 175 mg/ ^m2 IV (and optionally infused over 3 hours). In some such embodiments, in Cycle 1, an anti-PD-1 antibody is administered 60 minutes or more prior to administration of cisplatin, carboplatin, pemetrexed, and/or paclitaxel (and optionally infused over 60 minutes). In some such embodiments, in cycle 2, the anti-PD-1 antibody is administered 60 minutes or more prior to administration of cisplatin, carboplatin, pemetrexed, and/or paclitaxel (and the anti-PD-1 antibody is infused over 30 minutes, as appropriate). In some such embodiments, in cycle 3 and cycle 4, the anti-PD-1 antibody is administered 30 minutes or more (e.g., less than 60 minutes) prior to administration of cisplatin, carboplatin, pemetrexed, and/or paclitaxel (and the anti-PD-1 antibody is infused over 30 minutes, as appropriate). In some of these embodiments, in subsequent cycles (after cycle 4), the anti-PD-1 antibody is administered alone (without chemotherapy), and the anti-PD-1 antibody is infused over 30 minutes or longer (e.g., less than 60 minutes) as appropriate. Treatment of cancer as provided herein

Disclosed herein are treatment regimens for solid cancers (e.g., lung cancer, esophageal cancer). In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is esophageal cancer.

In some embodiments, the solid cancer is resectable (can be removed surgically). In some embodiments, the solid cancer is not locally advanced or metastatic.

In some embodiments, the entity cancer is stage I. In some embodiments, the entity cancer is stage IIA. In some embodiments, the entity cancer is stage IIB. In some embodiments, the entity cancer is stage IIIA. In some embodiments, the entity cancer is stage IIIB.

In some embodiments, the cancer is resistant to chemotherapy. In some embodiments, the cancer has progressed after prior chemotherapy.

In some embodiments, NSCLC is squamous cell carcinoma. In some embodiments, NSCLC is non-squamous carcinoma. In some embodiments, NSCLC is adenocarcinoma. In some embodiments, NSCLC is large cell carcinoma. In some of these embodiments, esophageal cancer is esophageal squamous cell carcinoma. In some of these embodiments, esophageal cancer is esophageal adenocarcinoma.

In some embodiments, NSCLC is resectable. In some embodiments, NSCLC is not locally advanced or metastatic. In some embodiments, esophageal cancer is resectable (e.g., resectable esophageal squamous cell carcinoma). In some embodiments, esophageal cancer (e.g., esophageal squamous cell carcinoma) is not locally advanced or metastatic.

In some embodiments, the NSCLC is stage I. In some embodiments, the NSCLC is stage IIA. In some embodiments, the NSCLC is stage IIB. In some embodiments, the NSCLC is stage IIIA. In some embodiments, the NSCLC is stage IIIB. In some embodiments, the NSCLC is stage IV. In some embodiments, the cancer is diffuse small cell lung cancer (NSCLC). In some embodiments, diffuse stage cancer has spread outside the lungs where it started or has spread to other parts of the body. In some embodiments, the NSCLC is unresectable. In some embodiments, the NSCLC is locally advanced. In some embodiments, the NSCLC is metastatic. In some embodiments, esophageal cancer is stage I. In some embodiments, esophageal cancer is stage IIA. In some embodiments, esophageal cancer is stage IIB. In some embodiments, the esophageal cancer is stage IIIA. In some embodiments, the esophageal cancer is stage IIIB. In some embodiments, the esophageal cancer is stage IV. In some embodiments, the esophageal cancer is unresectable. In some embodiments, the esophageal cancer is locally advanced. In some embodiments, the esophageal cancer is metastatic.

In some embodiments, the lung cancer is characterized by one or more of liver, lung, lymph node, bone, or adrenal metastasis. In some embodiments, the cancer is characterized by liver metastasis. In some embodiments, the cancer is characterized by lung metastasis. In some embodiments, the cancer is characterized by lymph node metastasis. In some embodiments, the cancer is characterized by bone metastasis. In some embodiments, the cancer is characterized by adrenal metastasis.

In some embodiments, for example, a tumor biopsy is used to evaluate the expression of immune-mediated biomarkers in cancer (such as lung cancer, such as NSCLC), which are associated with the response or clinical benefit of anti-PD-1 antibodies (such as tislelizumab). The biomarkers may be (but are not limited to) PD-L1, TMB, GEP and MSI. Biomarker expression can be evaluated by multiplex immunohistochemistry analysis (IHC). The cancer to be treated may be a cancer in which PD-L1 expression can be detected. The cancer to be treated may be a cancer in which TMB expression can be detected. The cancer to be treated may be a cancer with a detectable gene expression pattern (GEP, such as immune-mediated GEP). The cancer to be treated may be a cancer in which MSI expression can be detected.

In some embodiments, the lung cancer cells comprise a high level of PD-L1 expression as measured by the percentage of PD-L1 positive tumor or immune cells or as measured by the area occupied by PD-L1 positive tumor and immune cells divided by the total tumor area. In some embodiments, the subject has a low level of PD-L1 expression as measured by the percentage of PD-L1 positive tumor or immune cells or as measured by the area occupied by PD-L1 positive tumor and immune cells divided by the total tumor area. In some embodiments, the subject has less than 1% PD-L1 expression as measured by PD-L1 positive tumor or immune cells or as measured by the area occupied by PD-L1 positive tumor and immune cells divided by the total tumor area. In some embodiments, the subject has equal to or greater than 1% PD-L1 expression as measured by PD-L1 positive tumor or immune cells or as measured by the area occupied by PD-L1 positive tumor and immune cells divided by the total tumor area.

In some embodiments, the lung cancer cells have a moderate or high tumor mutation burden, where the tumor has more than 5 or 5 to 20 mutations, more than 20 or 20 to 50 mutations, or more than 50 mutations.

In some embodiments, the lung cancer cells comprise an epidermal growth factor (EGFR) mutation. In some embodiments, the lung cancer cells comprise a v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. In some embodiments, the lung cancer cells comprise an ALK mutation.

In some embodiments, the lung cancer cells are negative for EGFR genomic aberrations. In some embodiments, the lung cancer cells are negative for KRAS genomic aberrations. In some embodiments, the lung cancer cells are negative for ALK genomic aberrations.

In some embodiments, the NSCLC is characterized by expression of one or more of INSM1, CD56/NCAM, synaptotagmin, or chromogranin A. In some embodiments, the NSCLC is characterized by expression of INSM1. In some embodiments, the NSCLC is characterized by expression of CD56/NCAM. In some embodiments, the NSCLC is characterized by expression of synaptotagmin. In some embodiments, the NSCLC is characterized by expression of chromogranin.

In some embodiments, NSCLC is characterized by neuron-specific enolase (NSE) greater than 16.3 ng/ml. In some embodiments, NSCLC is characterized by pro-gastrin releasing peptide (ProGRP) greater than 66 pg/ml. In some embodiments, NSCLC is characterized by carcinoembryonic antigen (CEA) greater than 2.5 ng/ml. In some embodiments, NSCLC is characterized by carcinoembryonic antigen (CEA) greater than 10 ng/ml. In some embodiments, NSCLC is characterized by neuron-specific enolase (NSE) greater than 16.3 ng/ml, pro-gastrin releasing peptide (ProGRP) greater than 66 pg/ml, and carcinoembryonic antigen (CEA) greater than 2.5 ng/ml or greater than 10 ng/ml. Patient populations treated as provided herein

In some embodiments, the patient is a mammal. In some embodiments, the mammal is a human. In some embodiments, the patient is an adult. In some embodiments, the patient is 18 years of age or older. In some embodiments, the patient is 40 years of age or older, 45 years of age or older, 50 years of age or older, 55 years of age or older, 60 years of age or older, 65 years of age or older, 70 years of age or older, 75 years of age or older, or 80 years of age or older. In some embodiments, the patient is 65 years of age or older.

In some embodiments, the patient is male. In some embodiments, the patient is female.

In some embodiments, the patient is a current smoker. In some embodiments, the patient is a former smoker. In some embodiments, the patient has never smoked or has never been a smoker.

In some embodiments, the individual has (e.g., is diagnosed with) a solid cancer. In some embodiments, the individual has (e.g., is diagnosed with) a resectable solid cancer. In some embodiments, the individual has (e.g., is diagnosed with) lung cancer. In some embodiments, the individual has (e.g., is diagnosed with) esophageal cancer. In some embodiments, the individual has any of the cancers described herein. In some embodiments, the individual has intermediate stage lung cancer. In some embodiments, the individual has (e.g., is diagnosed with) small cell lung cancer. In some embodiments, the individual has (e.g., is diagnosed with) non-small cell lung cancer (NSCLC). In some embodiments, the individual has (e.g., is diagnosed with) stage I NSCLC. In some embodiments, the individual has (e.g., is diagnosed with) stage IIA NSCLC. In some embodiments, the individual has (e.g., is diagnosed with) stage IIB or stage IIIA NSCLC. In some embodiments, the individual has (e.g., is diagnosed with) squamous cell carcinoma. In some embodiments, the individual has (e.g., is diagnosed with) non-squamous small cell carcinoma.

In some embodiments, the individual has (e.g., is diagnosed with) esophageal cancer. In some embodiments, the individual has (e.g., is diagnosed with) esophageal squamous cell carcinoma (e.g., resectable esophageal squamous cell carcinoma). In some embodiments, the individual has (e.g., is diagnosed with) stage I esophageal squamous cell carcinoma. In some embodiments, the individual has (e.g., is diagnosed with) stage IIA esophageal squamous cell carcinoma. In some embodiments, the individual has (e.g., is diagnosed with) stage IIB or stage IIIA esophageal squamous cell carcinoma. In some embodiments, the individual has (e.g., is diagnosed with) stage IV esophageal squamous cell carcinoma. In some embodiments, the individual has (e.g., is diagnosed with) cT1-2N+M0 esophageal squamous cell carcinoma. In some embodiments, the individual has (e.g., is diagnosed with) cT3NanyM0 esophageal squamous cell carcinoma. In some embodiments, the individual has (e.g., is diagnosed with) esophageal adenocarcinoma.

In some embodiments, the individual has (e.g., is diagnosed with) metastatic cancer. In some embodiments, the individual has one or more of liver, lung, lymph node, bone, and/or adrenal metastasis. In some embodiments, the individual has liver, lung, or lymph node metastasis. In some embodiments, the individual has liver metastasis. In some embodiments, the individual has lung metastasis. In some embodiments, the individual has lymph node metastasis. In some embodiments, the individual has bone metastasis. In some embodiments, the individual has adrenal metastasis. In some embodiments, the individual has 1, 2, 3, or more metastatic sites. In some embodiments, the individual has 1 or more metastatic sites. In some embodiments, the individual has 2 or more metastatic sites. In some embodiments, the individual has 3 or more metastatic sites. In some embodiments, the individual does not have brain metastases. In other embodiments, the individual has brain metastases.

In some embodiments, the individual has been diagnosed using histological markers. In some embodiments, the individual has been diagnosed using cytological markers. In some embodiments, the individual has been diagnosed using both histological and cytological markers. In some embodiments, the individual has been diagnosed using a biopsy. In some embodiments, the individual has been diagnosed using a solid biopsy. In some embodiments, the individual has been diagnosed by a fluid biopsy. A solid tissue biopsy involves taking a piece of tissue sample from a lymph node or tumor for examination. Fluid biopsy is a minimally invasive method of obtaining samples, mostly body fluids, and is used to detect molecular alterations in shed circulating tumor cells.

In some embodiments, the individual has not been previously treated with immunotherapy. In some embodiments, the individual has not been previously treated with chemotherapy (e.g., platinum-based chemotherapy). In some embodiments, the individual has not been previously treated with any immune checkpoint inhibitors. In some embodiments, the individual has not been previously treated with immunotherapy or chemotherapy. In some embodiments, the individual has not been previously treated with immunotherapy and/or chemotherapy for a cancer treated according to the methods described herein. In some embodiments, the individual has not received prior chemotherapy for NSCLC. In some embodiments where the subject has received limited-term NSCLC treatment, there was a treatment-free interval of 6 months or more prior to diagnosis of NSCLC and/or initiation of a treatment described herein. In some embodiments, the subject has not received prior treatment (e.g., chemotherapy) for esophageal squamous cell carcinoma. In some embodiments, the subject has not received systemic treatment with corticosteroids or other immunosuppressants within 14 days of a treatment described herein.

In some embodiments, the subject has received prior chemotherapy treatment (e.g., for the cancer being treated). In some embodiments, the subject has received prior immunotherapy treatment (e.g., for the cancer being treated).

In some embodiments, a subject has adequate organ function, e.g., as measured by one or more of the criteria described herein.

In some embodiments, the individual has no renal dysfunction. In some embodiments, the individual has no severe renal dysfunction. In some embodiments, the individual has moderate renal dysfunction as described herein. In some embodiments, the individual has a glomerular filtration rate greater than 30 mL/min/1.73 m2 and less than 60 mL/min/1.73 m2 according to the Chronic Kidney Disease Epidemiology Collaboration equation. Therapeutic Uses and Methods Provided herein

In some embodiments, for patients with comorbidities or who cannot tolerate cisplatin, lead and adjuvant treatment for resectable NSCLC comprises platinum-based doublet chemotherapy using cisplatin or carboplatin (NCCN Guideline 2019, Postmus et al. 2017; CSCO 2018). Each platinum can be combined with a variety of chemotherapeutic agents, including vinorelbine, ethioposide, gemcitabine, docetaxel, paclitaxel, and pemetrexed. In some embodiments, lead chemotherapy can consist of a combination of platinum and pemetrexed or paclitaxel, for patients with non-squamous and squamous histology, respectively. The administration of chemotherapeutic agents is summarized in the table below.

In some embodiments, the disclosure relates to a method of treating lung cancer (such as NSCLC) or esophageal cancer (such as esophageal squamous cell carcinoma) in an individual (e.g., a human), the method comprising administering to the individual an effective amount of an anti-PD-1 antibody and one or more chemotherapeutic drugs (e.g., platinum chemotherapeutic drugs). In some embodiments, the one or more chemotherapeutic drugs are cisplatin or carboplatin. In some embodiments, the one or more chemotherapeutic drugs are pemetrexed or paclitaxel. In some embodiments, the one or more chemotherapeutic drugs are etanercept. In some embodiments, the one or more chemotherapeutic drugs are 5-fluorouracil.

In some embodiments, the disclosure relates to a method of treating lung cancer (such as NSCLC) or esophageal cancer (such as esophageal squamous cell carcinoma) in an individual (e.g., human), the method comprising administering to the individual an effective amount of an anti-PD-1 antibody, cisplatin or carboplatin, and pemetrexed or paclitaxel or 5-fluorouracil. In some embodiments, the individual is treated according to the treatment regimen described herein (e.g., treatment dose, frequency, and duration).

The anti-PD-1 antibodies and one or more chemotherapeutic drugs disclosed herein may be administered parenterally. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. In some embodiments, the anti-PD-1 antibody and the chemotherapeutic drug may be administered by different routes. In some embodiments, the anti-PD-1 antibody is administered intravenously, and the one or more chemotherapeutic drugs are also administered intravenously.

In some embodiments, described herein is a method of treating lung cancer (e.g., NSCLC) or esophageal cancer (e.g., esophageal squamous cell carcinoma) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an anti-PD-1 antibody and a therapeutically effective amount of one or more chemotherapeutic agents, wherein the PD-1 antibody comprises (i) a heavy chain variable region comprising a complementation determining region (CDR)-H1 comprising SEQ ID NO: 31, a CDR-H2 comprising SEQ ID NO: 32, and a CDR-H3 comprising SEQ ID NO: 33, and (ii) a light chain variable region comprising a CDR-L1 comprising SEQ ID NO: 34, a CDR-L2 comprising SEQ ID NO: 35, and a CDR-L3 comprising SEQ ID NO: 36. In some embodiments, described herein is a method for treating lung cancer (e.g., NSCLC) or esophageal cancer (e.g., esophageal squamous cell carcinoma) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an anti-PD-1 antibody and a therapeutically effective amount of one or more chemotherapeutic agents, wherein the PD-1 antibody comprises a heavy chain variable region (Vh) and a light chain variable region (Vl) comprising SEQ ID NO: 24 and SEQ ID NO: 26, respectively. In some embodiments, described herein is a method for treating lung cancer (e.g., NSCLC) or esophageal cancer (e.g., esophageal squamous cell carcinoma) in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of an anti-PD-1 antibody, wherein the PD-1 antibody is a monoclonal antibody or a fragment thereof (e.g., a humanized antibody or fragment) comprising a heavy chain variable region (Vh) amino acid sequence of SEQ ID NO: 24, a light chain variable region (Vl) amino acid sequence of SEQ ID NO: 26, and an IgG4 constant domain amino acid sequence of SEQ ID NO: 88. In some embodiments, described herein are methods of treating lung cancer (e.g., NSCLC) or esophageal cancer (e.g., esophageal squamous cell carcinoma) in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of tislelizumab and a therapeutically effective amount of one or more chemotherapeutic agents. In some embodiments, one or more or all of the study drugs provided in Table 8 are administered to the individual according to the treatment regimen described in the table. In some embodiments, the choice of cis-platinum or carboplatin is determined by the treating physician. Table 8: Dose selection and schedule for each patient Study Drugs Dosage Dosing frequency Investment channels Duration of treatment Tislelizumab 200 mg Every 3 weeks on the 1st day IV 3 to 4 cycles during the pre-induction phase Placebo NA Every 3 weeks on the 1st day IV Tislelizumab 400 mg Every 6 weeks on the 1st day IV Up to 8 cycles during the Assist Phase Placebo NA Every 6 weeks on the 1st day IV Platinum 75 mg/m ² Every 3 weeks on the 1st day IV 3 to 4 cycles during the pre-induction phase Card plating AUC is 5 mg/mL/min Every 3 weeks on the first day IV Pemetrexed 500 mg/ ^m2 Every 3 weeks on the first day IV 3 to 4 cycles during the prodromal phase (for non-scaly) Pacific Taxol 175 mg/m ² Every 3 weeks on the 1st day IV 3 to 4 cycles during the prodromal phase (for scaling) Abbreviations: AUC, area under the curve; IV, intravenous; NA, not applicable. In the lead-in phase, the anti- PD-1 antibody was given at a dose of 200 mg every 3 weeks

The present invention provides an anti-PD-1 antibody (tislelizumab) at a dose of 200 mg once every 3 weeks. Specifically, the present invention provides for intravenous administration of a fixed dose of 200 mg of tislelizumab once every 3 weeks during the lead-in phase. In the adjuvant phase, the anti- PD-1 antibody dose is 400 mg once every 6 weeks .

Further provided herein is an anti-PD-1 antibody (tislelizumab) at a dose of 400 mg once every 6 weeks. This dose was selected for the adjuvant phase by matching dose and exposure (AUC) to the 200 mg exposure of the once every 3 weeks regimen during the lead-in phase. In some embodiments, provided herein is a dosing regimen comprising administering 200 mg of tislelizumab once every 3 weeks during the lead-in phase, followed by 400 mg once every 6 weeks during the adjuvant phase. Chemotherapy

In some embodiments, patients may be treated with platinum-based doublet chemotherapy during the lead-in phase ( Table 8 ). In some embodiments, patients may be treated with 5-fluorouracil and cis-platinum during the lead-in phase.

In some embodiments, 75 mg/m2 cisplatin may be administered as an intravenous infusion over 2 hours on day 1 of each 3-week cycle for 3 to 4 cycles.

In some embodiments, carboplatin at an AUC of 5 mg/mL/min may be administered as an intravenous infusion over 1 hour on day 1 of each 3-week cycle for 3 to 4 cycles. Considering the patient's tolerability to cisplatin, the investigator may decide to replace cisplatin with carboplatin.

In some embodiments, for non-squamous: 500 mg/m2 of pemetrexed may be administered as an intravenous infusion over 10 minutes on day 1 of each 3-week cycle for 3 to 4 cycles.

In some embodiments, for squamous cells: 175 mg/m2 of paclitaxel may be administered as an intravenous infusion over 3 hours on day 1 of each 3-week cycle for 3 to 4 cycles.

In some embodiments, the infusion period length of cisplatin, carboplatin, pemetrexed, paclitaxel, and 5-fluorouracil may also follow the approved label or local practice. The investigator may adjust the administered dose within ±5% of the calculated dose at his/her discretion.

Embodiments of the present disclosure also include the agents and compositions described herein (i) for use in the following, (ii) for use as an agent or composition for use in the following, or (iii) for use in the preparation of a medicament for use in the following: a. therapy (e.g., in a human body); b. medicine; c. inducing or enhancing an anti-tumor immune response; d. reducing the amount of one or more tumor markers in a patient; e. preventing or delaying the growth of a cancer described herein; f. preventing or delaying the progression of a cancer described herein; g. preventing or delaying the progression of a cancer described herein; h. stabilizing a cancer; i. inhibiting the growth or survival of cancer cells; j. eliminating or reducing the size of one or more cancerous lesions; k. Reduce the progression, onset, or severity of a cancer as described herein; l. Reduce the severity or duration of clinical symptoms of a cancer as described herein; m. Prolong the survival of a patient relative to the expected survival of a similar untreated patient; n. Induce a major pathological response (MPR), or complete or partial remission of a cancer as described herein; or o. Treat a cancer as described herein. Response to Treatment

In some embodiments, a treatment is clinically effective, or an individual is a treatment responder according to at least one measure of response to a treatment. In some embodiments, response to a treatment is measured by overall survival, progression-free or event-free survival, major pathological response ("MPR"), pathological complete response ("pCR"), overall response, partial response, duration of response, and/or tumor volume, diameter, or size. In some embodiments, response to a treatment is measured by tumor volume. In some embodiments, a treatment reduces tumor volume by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, or at least 75%. In some embodiments, the probability of survival of an individual at 24 months is greater than 30%. In some embodiments, the treatment is effective as evidenced by an overall survival rate of greater than 30% in the patient population at 24 months. In some embodiments, the probability of event-free survival of an individual at 12 months is greater than 15% or 20%. In some embodiments, the treatment is effective as evidenced by an event-free survival rate of greater than 20% in the patient population at 12 months.

In some embodiments, the response to treatment is measured by major pathological response ("MPR"), which is defined as less than 10% of residual viable tumor after leading therapy. In some embodiments, the MPR is twice the MPR observed in a control group. In some embodiments, the MPR is at least 25%. In some embodiments, the treatment produces an MPR in an individual. In some embodiments, the MPR is at least twice the MPR observed in a control group not treated with an anti-PD-1 antibody. In some embodiments, an individual has a probability of an MPR of at least 25%, 35%, 40%, 45%, or 50%. In some aspects, the treatment is effective as evidenced by an MPR of at least 25%, 35%, 40%, 45%, or 50% in a patient population. In some embodiments, treatment results in a pCR in an individual. In some embodiments, the individual has a pCR probability of at least 15%, 20%, 25%, 30%, 35%, or 40%. In some embodiments, treatment is effective as evidenced by a pCR of at least 15%, 20%, 25%, 30%, 35%, or 40% in a patient population.

The use of meaningful surrogate endpoints can expedite the evaluation of new therapies in cancer treatment. Pathological response has been used as a surrogate endpoint in breast cancer. Pathological complete response (pCR) has been used in breast cancer studies to assess the efficacy of lead therapy. However, the incidence of pCR rates has varied in leading NSCLC studies. Therefore, major pathological response (MPR) after surgical resection of NSCLC was proposed as a surrogate endpoint based on the following 3 findings: 1) pathological response is closely associated with OS; 2) pathological response reflects leading chemotherapy; and 3) the degree of pathological response is associated with the degree of OS benefit (Hellmann et al., 2014).

In some embodiments, the patient responds to treatment according to one, two, three or more criteria described herein and/or known in the art. In some embodiments, the responsiveness criteria are any criteria described herein, including (but not limited to) those described in the Examples section of this application.

In some embodiments, the treatments described herein reduce tumor volume, size, or diameter. In some embodiments, the treatments described herein reduce tumor volume, size, or diameter by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In some embodiments, the treatment described herein reduces the diameter of the cancer lesion by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In some embodiments, the measurement is performed by CT or MRI. In some embodiments, the measurement is performed as described herein and the results are evaluated (e.g., see the Examples section). In some embodiments, the reduction is relative to the tumor volume, size, or diameter in the individual before the treatment was started.

In some embodiments, the methods described herein improve overall survival. In some embodiments, the improvement is relative to the probability of survival without treatment or with standard of care treatment.

In some embodiments, the response of an individual to a treatment is measured by overall survival, progression-free survival, event-free survival, overall response rate, objective response rate, partial response, duration of response, or a combination thereof. In some embodiments, the response of an individual to a treatment is measured by overall survival. In some embodiments, the response of an individual to a treatment is measured by progression-free survival. In some embodiments, the response of an individual to a treatment is measured by event-free survival. In some embodiments, the response of an individual to a treatment is measured by overall response rate. In some embodiments, the response of an individual to a treatment is measured by objective response rate. In some embodiments, the response of an individual to a treatment is measured by partial response. In some embodiments, a subject's response to a treatment is measured by the duration of the response.

In some embodiments, the patient survives at least 24 months. In some embodiments, the patient survives at least 27 months. In some embodiments, the patient survives at least 30 months. In some embodiments, the patient survives at least 36 months. In some embodiments, the patient survives at least 39 months. In some embodiments, the patient survives at least 42 months. In some embodiments, the patient survives at least 45 months. In some embodiments, the patient survives at least 48 months or at least 4 years. In some embodiments, the patient survives at least 5 years. In some embodiments, the survival period is measured starting at the start of self-treatment (e.g., a specified month for the start of self-treatment).

In some embodiments, the probability of survival of an individual at 24 months after initiation of a treatment regimen as described herein is greater than 30%. In some embodiments, treatment prolongs the survival of a human patient, and the prolonged survival may be free of progression of lung cancer. In some embodiments, treatment prolongs the survival of a human patient, and the prolonged survival may be free of progression of small cell lung cancer. In some embodiments, the probability of event-free survival of an individual at 12 months after initiation of a treatment regimen as described herein is greater than 15%. In some embodiments, the probability of event-free survival of an individual at 12 months after initiation of a treatment regimen as described herein is greater than 20%.

In some embodiments, the patient survives at least 4 months without progression of NSCLC. In some embodiments, the patient survives at least 5 months without progression of NSCLC. In some embodiments, the patient survives at least 6 months without progression of NSCLC. In some embodiments, the patient survives at least 7 months without progression of NSCLC. In some embodiments, the patient survives at least 8 months without progression of NSCLC. In some embodiments, the patient survives at least 9 months without progression of NSCLC. In some embodiments, the patient survives at least 10 months without progression of NSCLC. In some embodiments, the patient survives at least 11 months without progression of NSCLC. In some embodiments, the patient survives at least 12 months without progression of NSCLC. In some embodiments, the patient survives at least 15 months without progression of NSCLC. In some embodiments, the patient survives at least 18 months without progression of NSCLC. In some embodiments, the patient survives at least 21 months without progression of NSCLC. In some embodiments, the patient survives at least 24 months without progression of NSCLC. In some embodiments, the patient survives at least 30 months without progression of NSCLC. In some embodiments, the patient survives at least 34 months without progression of NSCLC. In some embodiments, the patient survives at least 35 months without progression of NSCLC. In some embodiments, the patient survives at least 36 months or 3 years without progression of NSCLC. In some embodiments, the patient survives at least 39 months without progression of NSCLC. In some embodiments, the patient survives at least 42 months without progression of NSCLC. In some embodiments, the patient survives at least 45 months without progression of NSCLC. In some embodiments, the patient survives at least 48 months or 4 years without progression of NSCLC. In some embodiments, the patient survives at least 5 years without progression of NSCLC. In some embodiments, the progression-free survival period is measured starting from the start of autonomous treatment (e.g., a specified month of the start of autonomous treatment).

In some embodiments, the patient survives at least 4 months without progression of esophageal squamous cell carcinoma (ESCC), such as resectable ESCC. In some embodiments, the patient survives at least 5 months without progression of ESCC, such as resectable ESCC. In some embodiments, the patient survives at least 6 months without progression of ESCC, such as resectable ESCC. In some embodiments, the patient survives at least 7 months without progression of ESCC, such as resectable ESCC. In some embodiments, the patient survives at least 8 months without progression of ESCC, such as resectable ESCC. In some embodiments, the patient survives at least 9 months without progression of ESCC, such as resectable ESCC. In some embodiments, the patient survives at least 10 months without progression of ESCC, such as resectable ESCC. In some embodiments, the patient survives at least 11 months without progression of ESCC (e.g., resectable ESCC). In some embodiments, the patient survives at least 12 months without progression of ESCC (e.g., resectable ESCC). In some embodiments, the patient survives at least 15 months without progression of ESCC (e.g., resectable ESCC). In some embodiments, the patient survives at least 18 months without progression of ESCC (e.g., resectable ESCC). In some embodiments, the patient survives at least 21 months without progression of ESCC (e.g., resectable ESCC). In some embodiments, the patient survives at least 24 months without progression of NSCLC. In some embodiments, the patient survives at least 30 months without progression of ESCC (e.g., resectable ESCC). In some embodiments, the patient survives at least 34 months without progression of ESCC (e.g., resectable ESCC). In some embodiments, the patient survives at least 35 months without progression of ESCC (e.g., resectable ESCC). In some embodiments, the patient survives at least 36 months or 3 years without progression of ESCC (e.g., resectable ESCC). In some embodiments, the patient survives at least 39 months without progression of ESCC (e.g., resectable ESCC). In some embodiments, the patient survives at least 42 months without progression of ESCC (e.g., resectable ESCC). In some embodiments, the patient survives at least 45 months without progression of ESCC (e.g., resectable ESCC). In some embodiments, the patient survives at least 48 months or 4 years without progression of ESCC (e.g., resectable ESCC). In some embodiments, the patient survives at least 5 years without progression of ESCC (e.g., resectable ESCC). In some embodiments, progression-free survival is measured starting at the start of autonomous therapy (e.g., a specified month after the start of autonomous therapy).

In some embodiments, patients exhibit a duration of response of at least 6 months. In some embodiments, patients exhibit a duration of response of at least 12 months. In some embodiments, patients exhibit a duration of response of at least 18 months. In some embodiments, patients exhibit a duration of response of at least 24 months. In some embodiments, patients exhibit a duration of response of at least 30 months. In some embodiments, patients exhibit a duration of response of at least 33 months. In some embodiments, patients exhibit a duration of response of at least 36 months. In some embodiments, patients exhibit a duration of response of at least 39 months. In some embodiments, patients exhibit a duration of response of at least 42 months. In some embodiments, the patient exhibits a duration of response of at least 45 months. In some embodiments, the patient exhibits a duration of response of at least 48 months or 4 years. In some embodiments, the patient exhibits a duration of response of at least 5 years. In some embodiments, the responsiveness is measured starting at the start of self-treatment (e.g., a specified month of the start of self-treatment).

In some embodiments, the response of an individual to treatment is measured by overall response rate, complete response and/or partial response. In some embodiments, the determination of these responsiveness endpoints is determined using RECIST version 1.1.

In some embodiments, a human who responds to treatment exhibits stable disease. In some embodiments, a human who responds to treatment exhibits stable disease for or at least for 3 months, 6 months, 9 months, 12 months, 18 months, 21 months, 24 months, 30 months, 36 months, 42 months, 48 months, or 5 years. In some embodiments, the determination begins at the start of self-treatment (e.g., a specified month of start of self-treatment).

In some embodiments, a human who responds to treatment does not exhibit progressive disease and/or exhibits a delay in cancer progression. In some embodiments, a human who responds to treatment does not exhibit progressive disease and/or exhibits a delay in cancer progression or at least a delay of 3 months, 6 months, 9 months, 12 months, 18 months, 21 months, 24 months, 30 months, 36 months, 42 months, 48 months, or 5 years. In some embodiments, the determination begins at the start of autonomous treatment (e.g., a specified month of the start of autonomous treatment).

In some embodiments, a human who responds to treatment demonstrates a response (e.g., improvement or delay in progression response) in one or more patient-reported outcome (PRO) assessments, such as any PRO assessment described herein (including, but not limited to, quality of life assessment using any questionnaire described herein). In some embodiments, a positive response in a PRO assessment is observed to persist or persist for at least 3 months, 6 months, 9 months, 12 months, 18 months, 21 months, 24 months, 30 months, 36 months, 42 months, 48 months, or 5 years starting at the start of self-treatment.

In some embodiments, a human who has responded to a treatment as described herein has been diagnosed as having resectable NSCLC and is being treated. In some embodiments, a human who has responded to a treatment as described herein has been diagnosed as having stage I NSCLC and is being treated. In some embodiments, a human who has responded to a treatment as described herein has been diagnosed as having stage IIA NSCLC and is being treated. In some embodiments, a human who has responded to a treatment as described herein has been diagnosed as having stage IIB NSCLC and is being treated. In some embodiments, a human who has responded to a treatment as described herein has been diagnosed as having stage IIIA NSCLC and is being treated. In some embodiments, a human who has responded to a treatment as described herein has been diagnosed with and treated for stage IIIB NSCLC. In some embodiments, a human who has responded to a treatment as described herein has been diagnosed with and treated for stage IV NSCLC. In some embodiments, a human who has responded to a treatment as described herein has been diagnosed with and treated for NSCLC. In some embodiments, a human who has responded to a treatment as described herein has been diagnosed with and treated for metastatic NSCLC.

In some embodiments, a human who responds to treatment has no progression of resectable NSCLC. In some embodiments, a human who responds to treatment has no progression of stage I NSCLC. In some embodiments, a human who responds to treatment has no progression of stage IIA NSCLC. In some embodiments, a human who responds to treatment has no progression of stage IIB NSCLC. In some embodiments, a human who responds to treatment has no progression of stage IIIA NSCLC. In some embodiments, a human who responds to treatment has no progression of stage IIIB NSCLC. In some embodiments, a human who responds to treatment has no progression of stage IV NSCLC. In some embodiments, a human who responds to treatment has no progression of NSCLC. In some embodiments, the human who responds to treatment does not have progression of metastatic NSCLC.

In some embodiments, a human who has responded to a treatment as described herein has been diagnosed with and treated for resectable ESCC. In some embodiments, a human who has responded to a treatment as described herein has been diagnosed with and treated for stage I ESCC. In some embodiments, a human who has responded to a treatment as described herein has been diagnosed with and treated for stage IIA ESCC. In some embodiments, a human who has responded to a treatment as described herein has been diagnosed with and treated for stage IIB ESCC. In some embodiments, a human who has responded to a treatment as described herein has been diagnosed with and treated for stage IIIA ESCC. In some embodiments, a human who has responded to a treatment as described herein has been diagnosed with and treated for stage IIIB ESCC. In some embodiments, a human who has responded to a treatment as described herein has been diagnosed with and treated for stage IV ESCC. In some embodiments, a human who has responded to a treatment as described herein has been diagnosed with and treated for ESCC (e.g., resectable ESCC). In some embodiments, a human who has responded to a treatment as described herein has been diagnosed with and treated for metastatic ESCC.

In some embodiments, a human who responds to treatment has no progression to resectable ESCC. In some embodiments, a human who responds to treatment has no progression to stage I ESCC. In some embodiments, a human who responds to treatment has no progression to stage IIA ESCC. In some embodiments, a human who responds to treatment has no progression to stage IIB ESCC. In some embodiments, a human who responds to treatment has no progression to stage IIIA ESCC. In some embodiments, a human who responds to treatment has no progression to stage IIIB ESCC. In some embodiments, a human who responds to treatment has no progression to stage IV ESCC. In some embodiments, a human who responds to treatment has no progression to ESCC. In some embodiments, a human who responds to treatment has no progression to metastatic ESCC. Pharmaceutical compositions

Provided herein are compositions (including pharmaceutical formulations) comprising an anti-PD-1 antibody or an antigen-binding fragment thereof as described herein. Also provided herein are compositions (including pharmaceutical formulations) comprising one or more chemotherapeutic agents as described herein. In some embodiments, the compositions (including pharmaceutical formulations) comprise an anti-PD-1 antibody or an antigen-binding fragment thereof and one or more chemotherapeutic agents.

The pharmaceutical formulation of the anti-PD-1 antibody or antigen-binding fragment as described herein is prepared by mixing such antibody or antigen-binding fragment having the desired purity with one or more pharmaceutically acceptable carriers selected as appropriate (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. ed. (1980)), in the form of a lyophilized formulation or an aqueous solution. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to, buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; chloride); phenol, butyl alcohol, or benzyl alcohol; alkyl 4-hydroxybenzoates such as methyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycerol The pharmaceutically acceptable carriers include amino acids, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates, including glucose, mannose or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants, such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersions, such as soluble neutral active hyaluronidase glycoprotein (sHASEGP), such as human soluble PH-20 hyaluronidase glycoprotein, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in U.S. Patent Nos. 7,871,607 and 2006/0104968. In one aspect, sHASEGP is combined with one or more additional glycosaminoglycanases (such as chondroitinase).

Exemplary lyophilized antibody formulations are described in U.S. Patent No. 6,267,958. Aqueous antibody formulations include those described in U.S. Patent No. 6,171,586 and WO2006/044908, the latter formulation including a histidine-acetate buffer. Sustained release formulations can be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing antibodies, which matrices are in the form of shaped articles, such as films or microcapsules. Formulations intended for intravital administration are generally sterile. Sterility can be easily achieved, for example, by filtering through a sterile filter membrane.

The term "pharmaceutical composition" refers to a preparation in a pharmaceutically acceptable formulation in a form that renders the active ingredient effective and does not contain additional components that are toxic to the subject to which the composition is administered. In some embodiments, the pharmaceutical composition may be formulated for administration in solid or liquid form, including but not limited to forms suitable for: oral administration, such as drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., intended for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; parenteral administration, such as by Subcutaneous, intramuscular, intravenous or epidural injection, for example as a sterile solution or suspension, or a sustained release formulation; topical application, for example as a cream, ointment or controlled release patch or spray applied to the skin, lungs or mouth; intravaginal or rectal, for example as a pessary, cream or foam; sublingual; ocular; transdermal; or nasal, pulmonary and to other mucosal surfaces. In some aspects, the present disclosure provides a composition, for example a pharmaceutically acceptable composition, comprising an anti-PD-1 antibody described herein formulated with at least one pharmaceutically acceptable excipient.

The term "pharmaceutically acceptable" refers to a molecule or composition that, when administered to a recipient, is not harmful to the recipient or that the benefits to the recipient outweigh any harmful effects.

Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil , corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic water; Ringer's solution; ethanol; pH buffering solutions; polyesters, polycarbonates, and/or polyanhydrides; and other nontoxic compatible substances used in pharmaceutical formulations.

"Pharmaceutically acceptable formulations" include any and all solvents, dispersion media, isotonic agents, and absorption delaying agents, and the like, that are physiologically compatible. Formulations may be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g., by injection or infusion).

The compositions disclosed herein may be in a variety of forms. Such forms include, for example, liquid, semisolid, and solid dosage forms, such as liquid solutions (e.g., injectable solutions and infusible solutions), dispersions or suspensions, liposomes, and suppositories. The appropriate form depends on the intended mode of administration and the therapeutic application. Typical suitable compositions are in the form of injectable solutions or infusible solutions. One suitable mode of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In some embodiments, the antibody is administered by intravenous infusion or injection. In some embodiments, the antibody is administered by intramuscular or subcutaneous injection. In some embodiments, the antibody is administered by means of a syringe infusion system. Kits

The present disclosure provides, among other things, kits comprising an anti-PD-1 antibody or antigen-binding fragment thereof, and instructions for use and/or administration. In some embodiments, the kit comprises at least one anti-PD-1 antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier, and instructions for use and/or administration. In some embodiments, the kit comprises at least one anti-PD-1 antibody or antigen-binding fragment thereof, at least one chemotherapeutic agent and a pharmaceutically acceptable carrier, and instructions for use and/or administration. In some embodiments, the kit comprises tislelizumab in any dose described herein or known in the art and one or more chemotherapeutic agents, such as cisplatin, carboplatin, pemetrexed, paclitaxel, and/or 5-fluorouracil, or any combination thereof.

Kits for use in the various methods disclosed herein are also provided. The instructions may include instructions for administering one or more pharmaceutical compositions described herein to a subject to achieve a desired activity in the subject. The kit may further include instructions for selecting a subject suitable for treatment based on identifying whether the subject is in need of treatment. In some embodiments, the instructions include instructions for administering at least one anti-PD-1 antibody or an antigen-binding fragment thereof to a subject in need of treatment.

Instructions associated with the administration of one or more doses of at least one anti-PD-1 antibody or antigen-binding fragment thereof and/or one or more chemotherapeutic agents typically include information about the dose, dosing schedule, and route of administration for the intended treatment. The container may be in unit dose, bulk packaging (e.g., multi-dose packaging), or subunit dose. The instructions provided in the kit of the present disclosure are typically written instructions on a label or package insert. The label or package insert may indicate that one or more pharmaceutical compositions described herein are used to treat, delay the onset of, and/or alleviate a disease, disorder, or condition in an individual.

In some embodiments, the kits provided herein are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, cans, flexible packaging, and the like. Packaging used in combination with a specific device, such as an infusion device, is also contemplated. The kit may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic needle). The container may also have a sterile access port.

The kit may include additional components, such as a buffer and interpretive information. The kit may include a container and a label or one or more package inserts located on or attached to the container. In some embodiments, the present disclosure provides an article of manufacture comprising the contents of the above-described kit. Examples Example 1. Clinical Trial in Human Patients with Resectable Non-Small Cell Lung Cancer Pathological Response of Patients with Resectable Stage II -IIIA NSCLC to Lead Tislelizumab + Platinum Doublet (PtDb) Chemotherapy

This example describes a randomized, double-blind, placebo-controlled, multicenter, phase 3 study comparing tislelizumab (i.e., anti-PD-1 antibody) + a platinum doublet (e.g., cisplatin or carboplatin + epoxaban) (Group A) and placebo + a platinum doublet (Group B) as first-line treatment in 453 patients with previously untreated, resectable, confirmed squamous or non-squamous stage II-IIA NSCLC .

To assess and compare the major pathological response (MPR) rate in patients who received tislelizumab plus platinum-based doublet chemotherapy as lead therapy with that in patients who received placebo plus platinum-based doublet chemotherapy as lead therapy as assessed by Blinded Independent Pathology Review (BIPR), where the MPR rate according to BIPR is defined as the proportion of patients with ≤10% viable tumor remaining in the resected primary tumor and all resected lymph nodes after completion of lead therapy as assessed by BIPR. The 10% cutoff was determined based on previous studies of pathological evaluation of resected lungs after lead-in chemoradiotherapy (Junker K et al., J Cancer Res Clin Oncol . 1997; Pataer A et al., JTO 2012).

MPR is assessed at the time of surgery and has been proposed by several groups as a surrogate marker for recurrence and survival after lead (perioperative) treatment in patients with solid tumor types such as colorectal cancer (Adam, R., 2014. Annals of Surgical Oncology , 21, pp. 1763-1764), breast cancer (Conforti, F. et al., 2021 Bmj , 375), and NSCLC.

Another primary objective was to assess and compare event-free survival (EFS) as assessed by Blinded Independent Central Review (BICR) between patients who received tislelizumab plus platinum-based doublet chemotherapy as lead therapy followed by tislelizumab as adjuvant therapy and patients who received placebo plus platinum-based doublet chemotherapy as lead therapy followed by placebo as adjuvant therapy, where EFS according to BICR was defined as the time from randomization until any of the following events, whichever occurred first: disease progression excluding surgery, local or distant recurrence as assessed by BICR, or death from any cause. Secondary Objectives

MPR is observed more frequently than pathological complete response (pCR), which is defined as the absence of viable residual tumor. The secondary objective was to assess and compare the BIPR-assessed pCR rate of prior therapy with tislelizumab versus prior therapy with placebo plus platinum-based doublet chemotherapy, where the pCR rate is defined as the proportion of patients with no residual tumor in the resected primary tumor and all resected lymph nodes after completion of the lead therapy as assessed by BIPR.

Another secondary objective was to assess and compare overall survival (OS), defined as the time from the date of randomization to the date of death from any cause, between tislelizumab plus platinum-based doublet chemotherapy followed by lead therapy with adjuvant tislelizumab and placebo plus platinum-based doublet chemotherapy followed by lead therapy with placebo. The 2-year/3-year OS rate was defined as the proportion of patients alive 2 and 3 years after randomization estimated using the Kaplan-Meier method. Preliminary results support the continuation of this treatment combination for these patients. Other Objectives

The correlation between programmed death ligand-1 (PD-L1) expression and clinical efficacy was also evaluated.

Tissue-based and blood-based biomarkers were also evaluated for association with the clinical efficacy, function and resistance mechanisms of tislelizumab and patient outcomes, such as other exploratory tissue-based biomarkers (including gene expression profiling [GEP], tumor mutational burden [TMB]/microsatellite instability (MSI)/mutational pattern, multiplex immunohistochemistry [mIHC]) in archival and/or fresh tumor tissue before lead therapy, at the time of surgery and/or at disease progression/end of treatment (EOT) and blood-based biomarkers before and after treatment (including T cell receptor [TCR] sequencing, peripheral blood immunophenotyping and circulating tumor DNA [ctDNA]) to explore the clinical efficacy, function and resistance mechanism of tislelizumab and the predictive value of patient prognosis.

The study enrolled 453 patients with untreated, resectable confirmed squamous or non-squamous stage II-IIA NSCLC who were eligible for platinum doublet chemotherapy with ECOG PS < 1 and no known EGFR mutation (non-squamous) or ALK gene translocation (squamous and non-squamous). Patients stratified by histology, disease stage, and PD-L1 expression were randomized (1:1) to 3-4 cycles of tislelizumab 200 mg IV (Q3W) or placebo plus platinum doublet chemotherapy, followed by surgery + 8 cycles of adjuvant tislelizumab 400 mg IV Q6W or placebo. The primary endpoint was major pathological response rate (MPR) after completion of lead-in treatment plus event-free survival (EFS) as determined by blinded independent review (BIRC) according to RECIST version 1.1. Key secondary endpoints were pCR and safety. Tumor lesions were measured by CT scan or X-ray before treatment and then after 200 mg. Study Design Summary Test Product (Investigational Drug) (Arm A): ● Tislelizumab: During the lead-in phase, 200 mg was administered as an intravenous (IV) infusion on Day 1 of each 3-week cycle for 3 to 4 cycles. ● Tislelizumab: 400 mg as an IV infusion on Day 1 of each 6-week cycle for up to 8 cycles during the adjuvant phase. Comparator (Group B): ● Placebo: Administered as an IV infusion on Day 1 of each 3-week cycle for 3 to 4 cycles during the lead-in phase ● Placebo: Administered as an IV infusion on Day 1 of each 6-week cycle for up to 8 cycles during the adjuvant phase.

This study consists of a screening phase, a treatment phase (including a lead-in phase, surgery, and adjuvant phase). The study ends with a safety follow-up phase and a survival follow-up phase. Key inclusion criteria for the screening phase : ● Age ≥ 18 years old on the day of signing the informed consent (or the legal commitment age in the jurisdiction where the study is conducted). ● ECOG performance status of 0 or 1. ● Histologically confirmed stage II or IIIA NSCLC (according to the 8th edition of the American Joint Committee on Cancer/Union International Contre le Cancer NSCLC staging system). ● The investigator assessed the disease as measurable according to RECIST version 1.1. ● Eligibility for R0 resection with curative intent as assessed by the attending thoracic surgeon. ● Adequate cardiopulmonary function, eligible for surgical resection with curative intent. ● Eligible for platinum-based doublet chemotherapy regimen. ● Adequate hematologic and end-organ function (defined by protocol-specified laboratory test results), obtained within 14 days before randomization. Key Exclusion Criteria: ● Any prior treatment for current lung cancer, including chemotherapy or radiation therapy. ● Patients with large cell neuroendocrine carcinoma (LCNEC). ● Known EGFR mutation or ALK gene translocation. ● Patients with non-squamous NSCLC and unknown EGFR mutation status are required to be tested in a local or central laboratory before inclusion. ● Patients with squamous NSCLC and unknown EGFR mutation status are not required to undergo testing at screening. ● Patients with unknown ALK fusion oncogene status (non-squamous or squamous histology) are not required to undergo testing. ● Presence of locally advanced unresectable, or metastatic disease (stage IV), regardless of stage. Clinical staging requires a diaphragmatic lymph node sample to evaluate lymph node involvement in patients with diaphragmatic lymphadenopathy on CT scan to exclude stage IIIB/C disease. ● Any condition requiring systemic treatment with corticosteroids (>10 mg prednisone or equivalent daily) or other immunosuppressive agents within 14 days prior to randomization. ● Adrenal replacement steroids (≤ 10 mg pramoxazole or equivalent per day) and topical, ocular, intra-articular, intranasal, or inhaled corticosteroids with minimal systemic absorption are permitted , as are short-term (≤ 7 days) corticosteroids prescribed prophylactically or for treatment of non-autoimmune diseases.

Eligible patients were stratified by disease stage (II vs. IIIA), histology (squamous vs. non-squamous), and PD-L1 expression (≥ 1% vs. < 1%/not evaluable/uncertain) and randomized 1:1 to 1 of the following treatment arms: ● Arm A: Tislelizumab (200 mg) + platinum-based doublet chemotherapy in 3-cycle cycles for 3 to 4 cycles, followed by surgical resection, and then adjuvant tislelizumab (400 mg) in 6-cycle cycles for up to 8 cycles ● Group B: Placebo + platinum-based doublet chemotherapy in 3-week cycles for 3 to 4 cycles, followed by surgical resection, and then placebo in 6-week cycles for up to 8 cycles This study allows the following platinum-based doublet chemotherapy options: ● Cisplatin/Carboplatin + Pemetrexed (non-squamous). ● Cisplatin/Carboplatin + Paclitaxel (squamous).

Considering the patient's tolerance to cisplatin, the investigator may decide to replace cisplatin with carboplatin. The reason for intolerance was recorded. Patients with progressive disease during the lead-in phase (at the time of the scheduled tumor evaluation or at any time during the lead-in treatment) or patients who discontinued lead-in treatment early while the tumor was still considered resectable and non-metastatic underwent surgery if feasible. Surgery

After completing lead therapy, patients underwent surgical resection of the tumor. Pathological responses (MPR and pCR) of surgical specimens were evaluated by BIPR. In addition, exploratory biomarker analysis was performed on surgical specimens (primary tumor tissue and dissected lymph nodes).

Before surgery, the investigators evaluated the patients to reconfirm the resectability of the disease. The preoperative visit and related evaluations were performed within 14 days of surgery and were based on local institutional practices.

The surgical procedure was performed 4 to 6 weeks after the last dose of the lead -in study treatment. Before surgery, patients underwent CT tumor evaluation every 6 weeks (± 1 week) after the last tumor evaluation due to ethical considerations.

Patients treated in the adjuvant phase must meet the following criteria: ● Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 ● Recovery from surgery with laboratory values confirmed by the investigator indicating adequate organ function

During the adjuvant phase, patients received either tislelizumab (400 mg) (Group A) or placebo (Group B) as adjuvant therapy. For patients who did not undergo postoperative radiation therapy (PORT), the first dose of tislelizumab/placebo was administered 2 to 8 weeks after surgery (Cycle 1 of the adjuvant phase); initial dosing beyond 8 weeks was discussed with the medical monitor. Patients with pathologically confirmed N2+ disease after surgery received PORT at the discretion of the investigator. PORT was initiated 30 to 60 days after surgery and was based on the guidelines recommended by the American Society for Radiation Oncology or local guidelines. Adjunctive therapy was administered 7 to 30 days after the last scheduled PORT treatment and while the patient was recovering from any radiation-related toxicity.

Patients continued to receive adjuvant tislelizumab (400 mg) (Group A) or placebo (Group B) in 6-week cycles until any of the following occurred: 8 cycles of tislelizumab/placebo as adjuvant therapy, disease recurrence, unacceptable AE, death, or patient and/or investigator decision to discontinue study treatment. Disease Measures

At screening, patients underwent scheduled chest and abdominal tumor evaluation scans by computed tomography (CT) (CT contrast medium unless contraindicated), brain scan by contrast-enhanced magnetic resonance imaging (MRI), and whole-body scan by positron emission tomography (PET). Within 14 days before the third cycle of lead therapy and before surgery, patients underwent scheduled chest and abdominal tumor evaluation scans by CT. Chest CT + abdominal CT + pelvic CT + bone scan is an alternative to sites where PET scanning is not available for various reasons. Before surgery, patients were re-evaluated by the investigator to reconfirm resectability of the disease. Preoperative visits and related evaluations were performed within 14 days of surgery and were based on local institutional practices. After surgery, disease follow-up and tumor evaluation were performed using chest and upper abdominal CT.

During the lead-in and adjuvant phases, all patients were evaluated for safety and tolerability on Day 1 of each cycle. Patients returned to the clinic for a safety follow-up no more than 30 days (± 7 days) after the last dose of study treatment.

In this trial, response and progression were assessed using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (v1.1) (Eisenhauer EA, Therasse P, Bogaerts J et al., New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer . 2009;45(2):228-47). The RECIST criteria only use changes in the maximum diameter of the tumor lesion (a one-dimensional measurement).

The minimum size of the tumor lesion measured in at least 1 dimension (longest diameter in the plane of measurement recorded) is: ● 10 mm by CT and MRI (no less than twice the slice thickness and a minimum of 10 mm). ● 10 mm by clinical examination (when superficial). ● 20 mm by chest X-ray ( if well defined and surrounded by inflated lung ). Primary Efficacy Analysis

MPR as assessed by BIPR and EFS as assessed by BICR: The MPR rate as assessed by BIPR is defined as the proportion of patients with ≤ 10% viable tumor remaining in the resected primary tumor and all resected lymph nodes after completion of lead therapy as assessed by BIPR. Patients who did not undergo surgical resection were considered non-responders in the analysis.

EFS according to BICR evaluation was defined as the time from randomization to any of the following events, whichever occurred first: disease progression excluding surgery, local or distant recurrence as assessed by BICR, or death from any cause. According to BICR, disease progression that did not meet RECIST version 1.1 criteria but still excluded surgery (investigator-assessed progressive disease or tumor unresectable) was still considered an event. Patients who did not undergo surgery due to reasons other than progressive disease and tumor unresectable were considered to have experienced a progression event or death event as defined by RECIST version 1.1 according to BICR.

EFS was calculated using the actual tumor assessment visit date. Patients who died without progression/disease recurrence were considered to have experienced an event on the date of their death. MPR according to BIPR was compared between tislelizumab plus platinum-based doublet chemotherapy (Group A) and placebo plus platinum-based doublet chemotherapy (Group B) using the Cochran-Mantel-Haenszel chi-square test. EFS according to BICR was compared between Group A and Group B using the stratified log-rank test. Biomarkers

Archival tumor tissue (formalin-fixed paraffin-embedded [FFPE] blocks or approximately 15 [≥ 6] unstained slides) will be sent for immunohistochemistry (IHC) analysis of PD-L1 status. In addition to PD-L1 expression, other predictive biomarkers such as TMB and immune-mediated GEP (gene expression profile), biomarker expression by multiplex IHC, and other immune-mediated markers that correlate with response or clinical benefit to tislelizumab will be assessed. If archival samples are not available, perform a new tumor biopsy at screening, if feasible. For fresh biopsy specimens, acceptable samples include core needle biopsies of deep tumor tissue or excision, incision, puncture or tweezer biopsies of skin, subcutaneous or mucosal lesions.

Blood samples were collected from all randomized patients at baseline (pre-dose on Day 1 of Cycle 1) and, as appropriate, at disease progression and/or first tumor response (CR/PR) (10 mL at each time point) to explore the association of blood-based biomarkers with response, resistance, and prognosis to tislelizumab in combination with chemotherapy or chemotherapy alone.

The distribution of PD-L1 expression was examined in the ITT analysis set. Any potential association between PD-L1 expression and the efficacy of tislelizumab treatment relative to control (PFS, OS, ORR, DOR, and DCR) was explored. Other potential predictive markers including (but not limited to) GEP, TMB, and MSI (microsatellite instability) in archival and/or fresh tumor tissue and bTMB were evaluated before study treatment and/or at disease progression. Associations with disease status and/or response to tislelizumab in combination with chemotherapy were evaluated. Results Summary of results

The study enrolled patients with untreated, resectable confirmed squamous or non-squamous stage II-IIA NSCLC who were eligible for platinum doublet chemotherapy with ECOG PS < 1 and no known EGFR mutation (non-squamous) or ALK gene translocation (squamous and non-squamous). Patients stratified by histology, disease stage, and PD-L1 expression were randomized (1:1) to 3-4 cycles of tislelizumab 200 mg IV (Q3W) or placebo plus platinum doublet chemotherapy, followed by surgery + 8 cycles of adjuvant tislelizumab 400 mg IV Q6W or placebo. The primary endpoint was major pathological response rate after completion of lead therapy plus event-free survival (EFS) as determined by blinded independent review according to RECIST version 1.1. Key secondary endpoints were pCR and safety.

After a median follow-up of 16.8 months, 453 patients (TIS+CT, n=226; CT, n=227) were randomized to the intention-to-treat (ITT) population with similar baseline characteristics. Of the 452 patients (99.8%; n=226, both groups) treated in the lead-in phase, 421 (92.9%) completed the lead-in treatment (TIS+CT, n=211 [93.4%]; CT, n=210 [92.5%]); 90 (19.9%) did not undergo surgery (TIS+CT, n=36 [15.9%]; CT, n=54 [23.8%]). Efficacy data from the lead-in phase are summarized in Table 3 below. Table 9. Efficacy data from the pilot phase TIS + CT CT Intent-to-treat (ITT) set n=226 n=227 MPR, % (95% CI) ^a 56.2 (49.5-62.8) 15.0 (10.6-20.3) Difference, % (95% CI); P ^valueb 41.1 (33.2-49.1); P <.0001 OR (95% CI); P ^valueb 7.5 (4.8-11.8); P < .0001 pCR, % (95% CI) 40.7 (34.2-47.4) 5.7 (3.1-9.6) Difference, % (95% CI); P ^valueb 35.0 (27.9-42.1); P <.0001 OR (95% CI); P ^valueb 11.5 (6.2-21.5); P < .0001 ^aAssessed by a blinded independent review committee (IRC) ^bUnilateral abbreviation: MPR, major pathological response; OR, odds ratio; pCR, pathological complete response. Efficacy conclusion of the clinical trial of leading anti- PD-1 therapy + chemotherapy for the treatment of lung cancer

Compared with placebo plus chemotherapy, the combination of tislelizumab and chemotherapy significantly improved the major pathological response (MPR) and pathological complete response (pCR) rates (56.2% for the combination of tislelizumab and chemotherapy before surgery and 15.0% for placebo plus chemotherapy alone).

In conclusion, the combination of preoperative tislelizumab and chemotherapy showed significant clinical benefit and a manageable safety profile as first-line treatment for previously untreated NSCLC patients compared with preoperative placebo plus chemotherapy alone. Example 2 : A study comparing the efficacy and safety of lead-in treatment with tislelizumab (BGB-A317 , anti- PD-1 antibody ) or placebo plus platinum-based doublet chemotherapy followed by adjuvant tislelizumab or placebo in resectable stage II or IIIA non-small cell lung cancer

This example describes a randomized, double-blind, placebo-controlled, phase 3 study in resectable stage II or IIIA non-small cell lung cancer to compare the efficacy and safety of lead treatment with tislelizumab (BGB-A317, an anti-PD-1 antibody) or placebo plus platinum-based doublet chemotherapy followed by adjuvant tislelizumab or placebo. Primary Objectives and Endpoints: i. Objective - To assess and compare the major pathological response (MPR) rate assessed by blinded independent pathology review (BIPR) in patients who received tislelizumab + platinum-based doublet chemotherapy with that in patients who received placebo + platinum-based doublet chemotherapy as lead treatment. - To assess and compare event-free survival (EFS) in patients who received tislelizumab + platinum-based doublet chemotherapy as lead therapy followed by tislelizumab as adjuvant therapy with patients who received placebo + platinum-based doublet chemotherapy as lead therapy followed by placebo as adjuvant therapy as assessed by blinded independent central review (BICR). i. Endpoints - MPR rate according to BIPR is defined as the proportion of patients with ≤ 10% viable tumor remaining in the resected primary tumor and all resected lymph nodes after completion of lead therapy as assessed by BIPR. - EFS according to BICR was defined as the time from randomization until any of the following events, whichever occurred first: disease progression excluding surgery, local or distant recurrence as assessed by BICR, or death from any cause. Secondary Objectives and Endpointsi . Objectives - To assess and compare the BICR-assessed pathological complete response (pCR) rate with tislelizumab versus placebo + platinum-based doublet chemotherapy as lead therapy. - To assess and compare the overall survival (OS) with tislelizumab + platinum-based doublet chemotherapy as lead therapy followed by adjuvant tislelizumab versus placebo + platinum-based doublet chemotherapy as lead therapy followed by placebo. - To assess and compare the objective response rate (OR) assessed by BICR and investigators before surgery with tislelizumab as lead treatment versus placebo + platinum-based doublet chemotherapy. - To assess and compare BICR-assessed disease-free survival (DFS) with adjuvant tislelizumab versus placebo after complete resection (R0). - To assess and compare investigator-assessed EFS with lead treatment with tislelizumab + platinum-based doublet chemotherapy followed by adjuvant tislelizumab versus lead treatment with placebo + platinum-based doublet chemotherapy followed by adjuvant placebo. - To assess and compare the safety and tolerability of lead-in treatment with tislelizumab plus platinum-based doublet chemotherapy followed by adjuvant tislelizumab versus lead-in treatment with placebo plus platinum-based doublet chemotherapy followed by placebo, based on treatment-emergent adverse events (TEAEs). - To assess and compare health-related quality of life (HRQoL) with lead-in treatment with tislelizumab plus platinum-based doublet chemotherapy followed by adjuvant tislelizumab versus lead-in treatment with placebo plus platinum-based doublet chemotherapy followed by placebo. ii. Endpoints - pCR rate was defined as the proportion of patients with no residual tumor in the resected primary tumor and all resected lymph nodes after completion of lead therapy as assessed by BIPR. - OS was defined as the time from the date of randomization to the date of death from any cause. The 2-year/3-year OS rate was defined as the proportion of patients alive 2 and 3 years after randomization estimated using the Kaplan-Meier method. - Objective response rate was the proportion of patients with a complete response (CR) or partial response (PR) as assessed by BICR and investigator-based response evaluation criteria in solid tumors, version 1.1 (RECIST version 1.1) among all randomized patients with measurable disease at baseline. - DFS according to BICR was defined as the time from the first disease-free day to local or distant recurrence or death from any cause (whichever occurred first) as measured by BICR during adjuvant therapy and safety follow-up. - Investigator's EFS was defined as the time from randomization to any of the following events (whichever occurred first): disease progression excluding surgery, local or distant recurrence assessed by the investigator, or death from any cause. The 2-year/3-year EFS rate was defined as the proportion of patients without EFS events 2 and 3 years after randomization, estimated using the Kaplan-Meier method. - The incidence and severity of TEAEs, including serious adverse events (SAEs) and immune-mediated adverse events (imAEs), where the severity is determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE version 5.0). - HRQoL - measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer (EORTC QLQ-LC13), Core 30 (EORTC QLQ C30), and European Quality of Life 5 Dimensions (EQ-5D-5L), defined as changes in most relevant lung cancer symptoms (dyspnea, dysphagia, cough, chest pain, arm and shoulder pain, hemoptysis, peripheral neuropathy, and fatigue), global health status (GHS), and physical function. Other study objectives and end points i. Objectives - To evaluate surgical outcomes, including feasibility and perioperative and postoperative complication rates. - Characterize the pharmacokinetics (PK) of tislelizumab in patients with resectable stage II or IIIA non-small cell lung cancer (NSCLC). - Assess host immunogenicity to tislelizumab by evaluating anti-drug antibodies (ADA) against tislelizumab. - Assess the correlation of programmed death ligand-1 (PD-L1) expression with clinical efficacy. - Assess the association of potential tissue-based and blood-based biomarkers of tislelizumab with clinical efficacy, functional and resistance mechanisms, and patient outcomes. ii. Endpoints - Feasibility assessments include surgery (delayed or cancelled), duration of surgery, length of hospital stay, type and method of surgery, resection status, and incidence of surgery-related AEs/SAEs. - Summary of serum concentrations of tislelizumab. - Evaluation of the immunogenicity of tislelizumab by measuring the incidence of ADA. - PD-L1 expression as a predictive biomarker of efficacy (including but not limited to MPR and EFS). - Additional exploratory tissue-based biomarkers (including gene expression profiling [GEP], tumor mutation burden [TMB]/microsatellite instability (MSI)/mutational pattern, multiplex immunohistochemistry [mIHC]) in archival and/or fresh tumor tissue before lead therapy, at the time of surgery and/or at disease progression/end of treatment (EOT) and blood-based biomarkers (including T cell receptor [TCR] sequencing, peripheral blood immunophenotyping and circulating tumor DNA [ctDNA]) before and after treatment to explore the clinical efficacy, function and resistance mechanisms of tislelizumab and the predictive value of patient outcomes. Study Design

This study was designed as a randomized, double-blind, placebo-controlled, phase 3 study in patients with resectable stage II or IIIA NSCLC to compare the efficacy and safety of initial treatment with tislelizumab plus platinum-based doublet chemotherapy followed by adjuvant tislelizumab with initial treatment with placebo plus platinum-based doublet chemotherapy followed by placebo.

This study consists of a screening phase, a treatment phase (including a pilot phase, surgery, and adjuvant phase), a safety follow-up phase, and a survival follow- up phase. The study protocol is presented in Figure 1 .

Eligible patients were stratified by disease stage (II vs. IIIA), histology (squamous vs. non-squamous), and PD-L1 expression (≥ 1% vs. < 1%/not evaluable/unclear) and randomized 1:1 to 1 of the following treatment arms: Arm A : Tislelizumab (200 mg) + platinum-based doublet chemotherapy in 3-cycle cycles for 3 to 4 cycles, followed by surgical resection, and then adjuvant tislelizumab (400 mg) in 6-cycle cycles for up to 8 cycles Arm B : Placebo + platinum-based doublet chemotherapy in 3-week cycles for 3 to 4 cycles, followed by surgical resection, and then placebo in 6-week cycles for up to 8 cycles The following platinum-based doublet chemotherapy options are available: Cisplatin/Carboplatin + Pemetrexed (non-squamous) Cisplatin/Carboplatin + Paclitaxel (squamous)

Considering the patient's tolerance to cis-platinum, the physician may decide to replace cis-platinum with carboplatin at his or her discretion . For patients with mixed histology tumors (squamous and non-squamous), the physician decides on the appropriate chemotherapy regimen based on the pathologist's evaluation of the major histological components.

After completing lead therapy, patients underwent surgical resection of the tumor. Pathological responses (MPR and pCR) of surgical specimens were evaluated by BIPR. In addition, exploratory biomarker analysis was performed on surgical specimens (primary tumor tissue and dissected lymph nodes).

Before surgery, the doctor will re-evaluate the patient to reconfirm the resectability of the disease. The preoperative visit and related evaluation should be conducted within 14 days of surgery and is based on local institutional practices.

The surgical procedure should be performed 4 to 6 weeks after the last dose of lead -in study treatment, if possible. Before surgery, patients underwent CT tumor evaluation every 6 weeks (± 1 week) after the last tumor evaluation for ethical considerations.

Patients treated in the adjuvant phase must meet the following criteria: ● Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 ● Recovery from surgery with laboratory values confirmed by the investigator indicating adequate organ function

During the adjuvant phase, patients received either tislelizumab (400 mg) (Group A) or placebo (Group B) as adjuvant therapy. For patients who did not undergo postoperative radiation therapy (PORT), the first dose of tislelizumab/placebo should be administered 2 to 8 weeks after surgery (Cycle 1 of the adjuvant phase); initial dosing beyond 8 weeks should be discussed with the medical monitor. Patients with pathologically confirmed N2+ disease after surgery received PORT at the discretion of the investigator. Patients with positive surgical margins were administered PORT or another surgical procedure before initiating adjuvant therapy according to standard of care. PORT should be started 30 to 60 days after surgery and according to the American Society of Radiation Oncology recommended guidelines or local guidelines. Adjuvant therapy should be administered 7 to 30 days after the last scheduled PORT treatment, and the patient should have recovered from any radiation-related toxicity.

Patients continued to receive adjuvant tislelizumab (400 mg) (Group A) or placebo (Group B) in 6-week cycles until any of the following occurred: 8 cycles of tislelizumab/placebo as adjuvant therapy, disease recurrence, unacceptable AE, death, or patient and/or investigator decision to discontinue study treatment.

No crossover between the 2 study groups was allowed.

At screening, patients undergo scheduled chest and abdominal tumor evaluation scans by computed tomography (CT) (CT contrast medium unless contraindicated), brain scan by contrast-enhanced magnetic resonance imaging (MRI), and whole body scan by positron emission tomography (PET). Within 14 days before the third cycle of lead therapy and before surgery, patients undergo scheduled chest and abdominal tumor evaluation scans by CT. Chest CT + abdominal CT + pelvic CT + bone scan should be an alternative for sites where PET scans are not available for various reasons. Before surgery, the physician re-evaluates the patient to reconfirm the resectability of the disease. Preoperative visits and related evaluations should be performed within 14 days of surgery and are based on local institutional practice. After surgery, disease follow-up tumor evaluations by chest and upper abdominal CT are performed every 12 weeks for the first 2 years after surgery, every 24 weeks in years 3 to 5, and then annually thereafter based on RECIST version 1.1. Tumor evaluations must continue per protocol until disease recurrence/progression confirmed by BICR according to RECIST version 1.1, withdrawal of consent, death, loss to follow-up, or study termination by the sponsor, whichever occurs first.

Safety was assessed throughout the study by monitoring AEs/SAEs (toxicity grades were assigned according to NCI-CTCAE version 5.0) and laboratory results. Vital signs, physical examinations, ECOG performance status changes, electrocardiogram (ECG) results, and other tests were also used in safety assessments. Dosage and Administration

The dosing schedule for the 2 study arms is provided by group in Table 1. The first dose of study drug will be administered within 2 working days after randomization. All patients will be monitored continuously for AEs. Treatment modifications (e.g., dose delays, reductions, or interruptions) or discontinuations will be based on specific laboratory and AE criteria.

During the lead-in phase, tislelizumab or placebo was administered before chemotherapy in each cycle. The order of chemotherapy was based on relevant local guidelines and/or clinical practice.

Patients should receive antiemetics and intravenous hydration for chemotherapy according to standard of care and manufacturer instructions. Premedication with steroids should be limited when clinically feasible due to the patient's immunomodulatory effects. In addition, if a chemotherapy-related rash occurs, treatment with topical steroids is recommended when clinically feasible.

In special circumstances (e.g., delayed dosing due to AE management or in the case of infusion-related reactions), subsequent administration of study drug may be delayed to the second day of each cycle. Table 10: Dose selection and schedule for each patient Study Drugs Dosage Dosing frequency Investment channels Duration of treatment Tislelizumab 200 mg Every 3 weeks on the first day IV 3 to 4 cycles during the pre-induction phase Placebo NA Every 3 weeks on the first day IV Tislelizumab 400 mg Every 6 weeks on the 1st day IV Up to 8 cycles during the Assist Phase Placebo NA Every 6 weeks on the 1st day IV Platinum 75 mg/m ² Every 3 weeks on the first day IV 3 to 4 cycles during the pre-induction phase Card plating AUC is 5 mg/mL/min Every 3 weeks on the first day IV Pemetrexed 500 mg/ ^m2 Every 3 weeks on the first day IV 3 to 4 cycles during the prodromal phase (for non-scaly) Pacific Taxol 175 mg/m ² Every 3 weeks on the first day IV 3 to 4 cycles during the prodromal phase (for scaling) Abbreviations: AUC, area under the curve; IV, intravenous; NA, not applicable. Tislelizumab or placebo

In the lead-in phase, tislelizumab 200 mg (or placebo) was administered on day 1 of each 21-day cycle (once every 3 weeks), and in the adjuvant phase, tislelizumab 400 mg (or placebo) was administered on day 1 of each 42-day cycle (once every 6 weeks).

Tislelizumab or placebo is administered by intravenous infusion through an intravenous line containing a sterile, nonpyrogenic, low protein-binding 0.2 or 0.22 micron inline or attached filter. Specific instructions for product preparation and administration are provided in the Pharmacy Manual.

The initial infusion during the lead-in phase (Cycle 1, Day 1) was delivered over 60 minutes; if well tolerated, subsequent infusions were administered over 30 minutes, which was the shortest allowed infusion duration. The initial infusion during the adjuvant phase (Cycle 1, Day 1) was delivered over 90 minutes; if well tolerated, the second infusion was administered over 60 minutes; and for each subsequent infusion, if a 60-minute infusion was tolerated, over 30 minutes. Tislelizumab or placebo should not be administered concurrently with any other medication. Chemotherapy

Patients were treated with platinum-based doublet chemotherapy during the lead-in phase ( Table 1 ).

Administer 75 mg/m ² of cisplatin as an IV infusion over 2 hours on day 1 of each 3-week cycle for 3 to 4 cycles. All patients should receive adequate hydration (including pre-treatment hydration) and diuretics. Urinary insufficiency must be maintained for at least 24 hours after administration of cisplatin. Monitor according to local guidelines and clinical practice.

Carboplatin at an AUC of 5 mg/mL/min was administered as an intravenous infusion over 1 hour on day 1 of each 3-week cycle for 3 to 4 cycles. Considering the patient's tolerability to cs-platin, the investigator may decide to replace cs-platin with carboplatin. The reason for intolerance should be recorded.

For non-squamous: Administer 500 mg/ ^m2 of pemetrexed as an IV infusion over 10 minutes on day 1 of each 3-week cycle for 3 to 4 cycles. All patients should receive appropriate vitamin B12 and folic acid supplementation according to approved product labeling and/or standard practice. In addition, all patients should receive appropriate corticosteroid premedication according to local approved labeling. Additional premedication should be administered according to standard practice.

For squamous cells: 175 mg/m ² of paclitaxel administered as an intravenous infusion over 3 hours on day 1 of each 3-week cycle for 3 to 4 cycles. In addition, all patients should receive appropriate premedication per local approved labeling. Additional premedication should be administered according to standard practice.

The infusion duration of cisplatin, carboplatin, pemetrexed, and paclitaxel may also follow the approved labeling or local practice. The investigator may adjust the administered dose within ± 5% of the calculated dose at his/her discretion.

Continue to monitor patients for AEs and instruct them to notify their physicians promptly of any and all AEs. Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of each regimen. Dose delay or modification of tislelizumab or placebo

There were no dose reductions of tislelizumab or placebo in this study.

Study treatment may be temporarily withheld if a patient experiences toxicity believed to be related to tislelizumab and dose interruption is required. Patients should resume tislelizumab or placebo as soon as possible after the AE recovers to baseline or Grade 1 (whichever is more severe) and within 12 weeks after the last dose of tislelizumab or placebo. Patients should discontinue treatment if they are unable to resume tislelizumab or placebo within 12 weeks after the last dose of tislelizumab or placebo.

If the patient benefits from study treatment while meeting the discontinuation criteria, study treatment may be resumed. Dose Delays, Interruptions, or Modifications in Chemotherapy

Chemotherapy treatment should be modified based on the investigator's clinical judgment, based on prescribing information and based on local practice.

Use baseline weight to calculate chemotherapy doses. If the patient's weight changes ≥ 10% from baseline (or new reference weight), a modification in treatment is indicated. Chemotherapy doses should not be modified for any weight change < 10%.

Study drug-related toxicity must resolve to baseline or to Grade 0 or 1 (except for alopecia or Grade 2 fatigue) before the next dose is administered. A maximum of 2 dose reductions are permitted for each chemotherapy except carboplatin. Only 1 dose reduction is permitted for carboplatin. Once a dose reduction is made, all subsequent doses should remain reduced or further reduced if necessary. There will be no dose escalations in this study. If additional dose reductions are necessary, the chemotherapy must be discontinued.

When a treatment cycle is delayed or interrupted due to toxicity caused by any component of the chemotherapy regimen, all study drugs (including tislelizumab or placebo) should generally be withheld and resumed together to maintain synchronization. In a follow-up cycle, if chemotherapy cannot be given due to prolonged AEs and toxicity, tislelizumab or placebo should be given alone in that cycle. If chemotherapy has been discontinued for 42 days (delay cycle + follow-up cycle), it should be permanently discontinued. Study Population

The study population included approximately 450 patients with histologically confirmed stage II or IIIA NSCLC. Patient inclusion criteria included:

Each patient eligible for participation in this study must meet all of the following criteria: 1. Able to provide written informed consent and understand and agree to comply with the study requirements and assessment schedule. 2. Aged ≥ 18 years old (or the legal age of commitment in the jurisdiction where this study is conducted) on the day of signing the ICF. 3. Histologically confirmed squamous or non-squamous stage II or IIIA NSCLC: ● Staging should be based on the 8th edition of the American Joint Committee on Cancer/International Union Against Cancer NSCLC staging system. ● Only based on size allowing T4 primary NSCLC (tumor > 7 cm). Invasion of the diaphragm, septum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebrae, carina, and solitary tumor nodules in different ipsilateral lobes are not allowed. ● Patients with mixed NSCLC histology (squamous and non-squamous) or NSCLC of unspecified type are eligible. ● Patients can be included based on clinical stage, but it is strongly recommended to document lymph node involvement by endobronchial ultrasound or septal examination before surgery. 4. Archival tumor tissue (FFPE block or approximately 15 [≥ 6] freshly cut unstained FFPE slides) and relevant pathology reports at baseline are required for PD-L1 and other biomarker analysis (≥ 6 slides are required if EGFR central laboratory testing is applicable). If archival samples are not available or considered inappropriate, a fresh biopsy is required at baseline. 5. Solid or subsolid NSCLC with no pure ground-glass opacities on CT scan. ● For subsolid lesions, tumor size (i.e., clinical T stage) should be measured based on the solid component only, excluding the ground-glass opacity component. 6. Evaluation by the attending thoracic surgeon to confirm that the conditions for R0 resection with curative intent are met. 7. Pulmonary function testing within 6 months of planned resection and repeated at screening if clinically indicated, including lung volume, spirometry, and diffusion capacity. ● Abnormal pulmonary function tests can be further evaluated with quantitative ventilation/perfusion scanning or cardiopulmonary exercise testing. ● Postoperative percentage of predicted forced expiratory volume in 1 second (FEV1) and evaporation capacity must be ≥ 40% and/or maximal oxygen consumption (VO2 max) should be > 10 mL/kg/min. 8. Adequate cardiopulmonary function to meet the conditions for surgical resection for curative purposes. ● Patients with underlying ischemic, valvular, or other significant heart disease should be evaluated by a cardiologist before surgery if clinically indicated. 9. Disease assessed as measurable by the investigator according to RECIST version 1.1. 10. Eligible for platinum-based doublet chemotherapy regimen. ● For patients who wish to receive cisplatin: no hearing loss. 11. ECOG performance status of 0 or 1. 12. Adequate organ function as indicated by the following laboratory values obtained ≤ 14 days before randomization. ● Patients must not require transfusions or growth factor support ≤ 14 days prior to sample collection when the following screening is performed: ● Absolute neutrophil count ≥ 1.5 × 109/L ● Platelets ≥ 100 × 109/L ● Hemoglobin ≥ 90 g/L ● Calculated creatinine clearance (CrCl) (Cockcroft-Gault formula) ● For patients intending to receive cis-platinum: creatinine clearance ≥ 60 mL/min ● For patients intending to receive carboplatin: creatinine clearance ≥ 45 mL/min ● Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) (For patients with Gilberts syndrome, total bilirubin must be < 3 × ULN). ● AST and ALT ≤ 2.5 × ULN ● For patients not receiving anticoagulation therapy: International Normalized Ratio or activated partial thromboplastin time ≤ 1.5 × ULN. Patient exclusion criteria include:

Patients meeting any of the following criteria are not eligible for inclusion: 1. Any prior treatment for current lung cancer, including chemotherapy or radiation therapy. 2. Prior treatment with antibodies or drugs targeting immune checkpoint pathways, including (but not limited to) anti-cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4), anti-PD-1, and anti-PD-L1 therapeutic antibodies. 3. Patients with large cell neuroendocrine carcinoma (LCNEC). 4. Known EGFR mutation or ALK gene translocation. ● For non-squamous patients, documentation of wild-type EGFR reported by tissue-based testing is required. For non-squamous patients without documented EGFR status, EGFR mutation testing must be performed locally or at a central laboratory prior to inclusion. ● Patients with squamous NSCLC and unknown EGFR mutation status will not be required to undergo testing at screening. ● Patients with unknown ALK fusion oncogene status (non-squamous or squamous histology) will not be required to undergo testing. 5. Presence of locally advanced unresectable, or metastatic disease (stage IV) regardless of stage. Clinical staging requires a diaphragmatic lymph node sample to evaluate lymph node involvement in patients with diaphragmatic lymphadenopathy on CT scan to exclude stage IIIB/C disease. 6. Active autoimmune disease or history of autoimmune disease with the potential for recurrence. Note: Patients with the following diseases are not excluded and may be further screened: ● Controlled type 1 diabetes ● Hypothyroidism (provided that it is managed with hormone replacement therapy alone) ● Controlled chylous diarrhea ● Skin diseases that do not require systemic treatment (e.g., vitiligo, psoriasis, alopecia) ● Any other disease that is not expected to recur in the absence of external triggering factors 7. Any active malignancy ≤ 2 years before randomization, excluding the specific cancer being studied in this study and any cancer that has locally recurred after curative treatment (e.g., resected basal or squamous cell skin carcinoma, superficial bladder cancer, cervical or breast carcinoma in situ). 8. Any disease requiring systemic treatment with corticosteroids (> 10 mg pramoxazole or equivalent daily) or other immunosuppressive agents ≤ 14 days before randomization. Note: Patients who are currently or have previously received any of the following steroid regimens are not excluded: ● Adrenal replacement steroids (≤ 10 mg daily dose of pramipexole or equivalent) ● Topical, ocular, intra-articular, intranasal, or inhaled corticosteroids with minimal systemic absorption ● Short-term (≤ 7 days) corticosteroids prescribed prophylactically (e.g., for contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed allergic reactions caused by contact allergens) 9. Uncontrolled diabetes or laboratory abnormalities > Grade 1 for potassium, sodium, or corrected calcium, or ≥ Grade 3 hypoalbuminemia ≤ 14 days prior to randomization despite standard medical management 10. History of interstitial lung disease, non-infectious pneumonia, or uncontrolled lung disease (including pulmonary fibrosis, acute lung disease, etc.). 11. Severe chronic or active infection requiring systemic antibacterial, antifungal, or antiviral therapy, including tuberculosis infection, etc. Severe infection within 4 weeks prior to randomization, including (but not limited to) hospitalization due to infectious complications, bacteremia, or severe pneumonia. Receiving therapeutic oral or intravenous antibiotics within 2 weeks prior to randomization. 12. Known history of HIV infection. 13. Untreated chronic hepatitis B patients or chronic hepatitis B virus (HBV) carriers with HBV DNA ≥500 IU/mL or active hepatitis C virus (HCV) patients should be excluded. Note: Inactive HBsAg carriers, treated and stable hepatitis B (HBV DNA < 500 IU/mL), and cured hepatitis C patients can be included. 14. Any major surgical procedure requiring general anesthesia ≤ 28 days before randomization. 15. Previous allogeneic stem cell transplantation or organ transplantation. 16. Any of the following cardiovascular/cerebrovascular risk factors: ● Cardiac chest pain, defined as moderate pain limiting instrumental activities of daily living, ≤ 28 days before randomization ● Pulmonary embolism, ≤ 28 days before randomization ● Any history of acute myocardial infarction, ≤ 6 months before randomization ● Any history of heart failure of New York Heart Association Classification III or IV, ≤ 6 months before randomization ● Any ventricular arrhythmia event of severity ≥ Grade 2, ≤ 6 months before randomization ● Any history of cerebrovascular accident, ≤ 6 months before randomization ● Uncontrolled hypertension not controlled by standard antihypertensive medications, ≤ 28 days before randomization ● Any history of heart failure, ≤ 6 months before randomization Any convulsion or seizure within 28 days 17. History of severe allergic reaction to chimeric or humanized antibodies or fusion proteins. 18. Has received any chemotherapy, immunotherapy (e.g., interleukins, interferons, thymosins), or any investigational therapy within 14 days or 5 half-lives (whichever is shorter) after the first administration of study drug. 19. Patients whose toxicity (caused by previous anticancer therapy) has not recovered to baseline or stabilized, except for AEs that are not considered possible safety risks (e.g., alopecia, neuropathy, and specific laboratory abnormalities). 20. Administered with live vaccines ≤ 4 weeks before randomization. Note: Seasonal influenza vaccines are usually inactivated vaccines and are allowed. Intranasal vaccines and live vaccines are not allowed. 21. Medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that would adversely affect administration of study drug or the interpretation of drug toxicity or AEs or that would result in inadequate compliance with study procedures or that could compromise compliance. Prior and Concomitant Therapy i. Prior Therapy

Exclusion criteria stipulated that patients must not have received prior treatment for current lung cancer, including chemotherapy and radiation therapy, and prior treatment with antibodies or drugs targeting immune checkpoint pathways, including (but not limited to) anti-PD-1, anti-PD-L1, or anti-CTLA-4.

All prior and concomitant medications (e.g., prescription, over-the-counter, herbal or homeopathic medications, nutritional supplements) received within 30 days before randomization and within 30 days after the last dose of study treatment (up to the time of the safety visit) should be recorded. ii. Permitted Concomitant Medication and Procedures

Investigators are permitted to use most concomitant medications and therapies deemed necessary and consistent with local standards of care for supportive care (e.g., antiemetics, antidiarrhea) and patient concerns at their discretion. Patients should receive comprehensive supportive care, including epoetin and other hematopoietic growth factors, blood and blood product transfusions, antibiotics, antiemetics, and/or other appropriate medications as needed. Control of prophylactic antiviral therapy in patients with HBsAg-inactive, treated, and stable hepatitis B (HBV DNA < 500 IU/mL) is at the discretion of the investigator, per local guidelines; however, if a patient with active hepatitis B is not receiving antiviral prophylaxis, the reason must be documented in the patient's medical record and recorded in the eCRF.

Systemic corticosteroids administered for the management of imAEs must be tapered to a non-immunosuppressive dose (≤ 10 mg/day of tislelizumab or equivalent) before the next dose of tislelizumab/placebo. Short-term use of steroids as prophylactic therapy is permitted (e.g., in patients with contrast allergy to diagnostic imaging contrast dyes). iii. Concomitant medications and procedures prohibited

The following medications are contraindicated during the study: ● Any concurrent antineoplastic therapy (i.e., chemotherapy, hormonal therapy, immunotherapy, or standard or investigational agents [including Chinese (or other countries) herbal medicines] used to treat cancer) is not allowed. ● Live vaccines within 28 days before randomization and within 60 days after the last dose of study drug ● Herbal therapies with immunostimulatory properties (e.g., mistletoe extract) or herbal therapies known to interfere with liver or other major organ function (e.g., hypericin). Patients must inform the investigator of all herbal therapies used during the study. ● Patients with creatinine clearance between 45 mL/min and 79 mL/min should avoid or limit ibuprofen administration. ● If concomitant use of ibuprofen cannot be avoided, ibuprofen should be avoided at least 2 days before and 2 days after the day of pemetrexed administration, and patients should be monitored more frequently for adverse reactions, including bone marrow suppression, renal toxicity, and gastrointestinal toxicity (pemetrexed prescribing information). iv. Restricted concomitant medications and procedures

During the study, the following medications are restricted: ● Immunosuppressants (except for treatment of drug-related AEs) ● Systemic corticosteroids (prespasone or equivalent) > 10 mg per day, except for treatment or control of drug-related AEs (as per protocol) or short-term prophylaxis ● Patients should not abuse alcohol or other drugs during the study. ● Patients with impaired liver function should be carefully monitored when using potentially hepatotoxic drugs. ● Radiation therapy is not allowed, except for postoperative radiation therapy.

Patients must inform the investigators of all concomitant medications taken during the study. Tumor and Response Assessment

At screening, patients undergo scheduled chest and abdominal tumor evaluation scans by computed tomography (CT) (CT contrast medium unless contraindicated), brain scan by contrast-enhanced magnetic resonance imaging (MRI), and whole body scan by positron emission tomography (PET). Within 14 days before the third cycle of lead therapy and before surgery, patients undergo scheduled chest and abdominal tumor evaluation scans by CT. Chest CT + abdominal CT + pelvic CT + bone scan should be an alternative for sites where PET scans are not available for various reasons. Before surgery, reconfirm the resectability of the disease. Preoperative visits and related evaluations should be performed within 14 days of surgery and are based on local institutional practice. After surgery, disease follow-up tumor evaluations by chest and upper abdominal CT are performed every 12 weeks for the first 2 years after surgery, every 24 weeks in years 3 to 5, and then annually thereafter based on RECIST version 1.1. Tumor evaluations must continue per protocol until disease recurrence/progression confirmed by BICR according to RECIST version 1.1, withdrawal of consent, death, loss to follow-up, or study termination by the sponsor, whichever occurs first.

During the lead-in and adjuvant phases, all patients were evaluated for safety and tolerability on Day 1 of each cycle. Patients returned to the clinic for a safety follow-up no more than 30 days (± 7 days) after the last dose of study treatment.

AEs were assessed according to NCI-CTCAE version 5.0. All AEs and SAEs (regardless of relationship to study drug) were reported after initiation of study drug until 30 days after the last dose of study drug or until end of treatment, whichever occurred later. Immune-mediated AEs (serious or non-serious) were reported until 90 days after the last dose of tislelizumab or placebo, regardless of whether patients started new anticancer therapy.

HRQoL was assessed using the EORTC QLQ-LC13, EORTC QLQ-C30, and EQ-5D-5L at baseline (before dosing on Day 1 of Cycle 1); at Cycle 3 during the lead-in phase; at Cycles 1, 3, 5, and 7 during the adjuvant phase; and at the safety follow-up visit.

The same radiographic procedures used to evaluate the disease site at screening (e.g., the same contrast regimen used for CT scans) need to be used throughout the study. ● Screening evaluations should be performed within 28 days prior to randomization. ● If the patient has a known contraindication to CT contrast media or develops during the study, non-contrast CT of the chest plus contrast-enhanced magnetic resonance imaging (MRI) of the abdomen should be performed (if possible). ● If CT scans for tumor evaluation are performed on a PET/CT scanner, the CT acquisition must be consistent with the standard for diagnostic CT scans. This substitution should be evaluated and confirmed at the site level using BICR.

With immunotherapy (such as tislelizumab), pseudoprogression may occur due to significant enlargement of existing tumor masses or the appearance of new tumor lesions due to immune cell infiltration and other mechanisms. The following criteria must be met to treat patients with suspected pseudoprogression or definite evidence of disease progression: ● No clinical symptoms and signs of disease progression (including clinically significant worsening of laboratory values) ● ECOG performance status of 0 or 1 ● No rapidly progressive disease or progressive tumors in critical anatomical sites requiring urgent alternative medical intervention (e.g., spinal cord compression) Pharmacokinetic and anti-drug antibody testing

ADA will be detected at multiple time points throughout the study using validated screening and confirmatory assays. Immunogenicity assessment utilizes a risk-based immunogenicity strategy (Koren et al., J Immunol Methods. 2008;333(1-2):1-9; Worobec and Rosenberg, BioPharm Intl 2004a;17(11); Worobec and Rosenberg, BioPharm Intl 2004b;17(12)) to characterize ADA responses to tislelizumab. This stratification strategy will include an evaluation of whether ADA responses are associated with relevant clinical endpoints. The following evaluations are performed in the bioanalytical laboratory: ● ADA assay: Testing serum samples for the presence of ADA against tislelizumab using a validated immunoassay ● PK assay: Analysis of serum samples for tislelizumab concentration biomarker testing using a validated immunoassay

For biomarker evaluation, archived tumor tissue at baseline (FFPE blocks or approximately 15 [≥ 6] additional unstained slides) was sent for immunohistochemistry evaluation of PD-L1 status as one of the stratification factors. Other baseline tissue-based biomarkers were also evaluated, including mIHC, immune-related GEPs, and TMB/MSI/mutation patterns. Surgical tumor tissue (FFPE blocks or approximately 15 [≥ 6] unstained slides) was collected and sent for biomarker analysis (including PD-L1 expression, mIHC, immune-related GEPs, and TMB/MSI/mutation patterns). For fresh biopsy specimens, acceptable samples include core needle biopsies of deep tumor tissue or excision, incision, puncture or tweezer biopsies of skin, subcutaneous or mucosal lesions.

During the lead-in and adjuvant phases, blood samples (approximately 15 mL per time point) were collected on Day 1 of Cycle 1 and Cycle 2 to explore the association of blood-based biomarkers (including TCR sequencing, peripheral blood immunophenotyping) with response, resistance, and prognosis. Blood samples (approximately 20 mL per time point) were collected on Day 1 of Cycle 1 and Day 1 of Cycle 3 prior to dosing during the lead-in phase, and on Day 1 of Cycle 1 prior to dosing during the adjuvant phase to assess biomarkers, including ctDNA, by molecular methods. Changes in biomarkers, such as ctDNA, can provide evidence for the biological activity of tislelizumab combination therapy in humans. Correlations between these biomarkers and efficacy endpoints were explored to identify blood-based biomarkers that could help identify patients who are more likely to benefit from tislelizumab combination therapy.

Patients were randomized using the IRT system by permuted block stratified randomization with stratification factors of histology (non-squamous vs. squamous), disease stage (stage II vs. stage IIIA), and PD-L1 expression (≥ 1% vs. < 1%/not evaluable/uncertain). Analysis Sets ● The ITT analysis set includes all randomized patients. Patients were analyzed according to their randomized treatment group. This will be the primary analysis set for all efficacy analyses, including those of the MPR, pCR, and EFS endpoints. ● The safety analysis set includes all randomized patients who received ≥ 1 dose of any component of the study drug; it will be the analysis set used for safety analyses. Patients were analyzed according to the actual treatment regimen received. ● The PK analysis set included all patients who received ≥ 1 dose of tislelizumab per protocol and for whom any post-baseline PK data were available. ● The immunogenicity analysis set included all patients who received ≥ 1 dose of tislelizumab and for whom both baseline ADA and ≥ 1 post-baseline ADA results were available. Efficacy Analysis

The ITT analysis set is the primary analysis set for all efficacy analyses. i. Primary Efficacy Analysis

The MPR rate according to BIPR assessment was defined as the proportion of patients with ≤ 10% residual viable tumor in the resected primary tumor and all resected lymph nodes after completion of lead therapy as assessed by BIPR. Patients who did not undergo surgical resection were considered non-responders in the analysis.

EFS according to BICR evaluation was defined as the time from randomization to any of the following events, whichever occurred first: disease progression excluding surgery, local or distant recurrence as assessed by BICR, or death from any cause. According to BICR, disease progression that did not meet RECIST version 1.1 criteria but still excluded surgery (investigator-assessed progressive disease or tumor unresectability) was considered an event. Patients who did not undergo surgery due to reasons other than progressive disease and tumor unresectability were considered to have experienced a progression event or death event as defined by RECIST version 1.1 according to BICR.

EFS was calculated using the actual tumor assessment visit date. Patients who died without progression/recurrence of disease were considered to have experienced an event on the date of their death. Patients who did not report disease progression/recurrence or death were censored on the date of the last evaluable tumor assessment. Patients who did not have any on-study tumor assessment and did not die were censored on the date of randomization. Patients who started any subsequent anticancer therapy other than protocol-specified adjuvant therapy and had not previously reported progression/recurrence were censored at the last evaluable tumor assessment before initiation of subsequent anticancer therapy.

The Cochran-Mantel-Haenszel chi-square test method was used to compare the MPR according to BIPR between tislelizumab combined with platinum-based doublet chemotherapy (Group A) and placebo combined with platinum-based doublet chemotherapy (Group B). The stratified log-rank test method was used to compare the EFS according to BICR between Group A and Group B. Two double main hypothesis tests were formed as follows: One-sided test of the MPR advantage of Group A over Group B : The null hypothesis to be tested is: H ₀ : MPR in Group A ≤ MPR in Group B. The alternative hypothesis against: H _a : MPR in Group A > MPR in Group B

The MPR rate according to the BIPR was calculated in each group with exact 95% CI using the Clopper-Pearson method. The odds ratios and 95% CIs between group A and group B stratified by histology, disease stage, and PD-L1 expression were provided using the Mantel-Haenszel method. In addition, estimates of the differences in MPR and corresponding 95% CIs were calculated using the Cochran-Mantel-Haenszel method and adjusted by the stratification factor. One-sided test of the EFS advantage of group A over group B : The null hypothesis to be tested is: H ₀ : EFS in group A ≤ EFS in group B. The alternative hypothesis to be tested is: H _a : EFS in group A > EFS in group B

p-values for the hierarchical log-rank test are presented using the stratified factors in the IRT during randomization. HRs for EFS in group A versus group B are estimated using a hierarchical Cox regression model. 95% CIs for the HRs are provided. Unstratified analyses are also presented. The median EFS for each treatment group was estimated using the Kaplan-Meier method, and Kaplan-Meier curves were constructed to provide a visual depiction of the differences between the groups. Subgroup Analyses of MPR and EFS

Subgroup analyses of the primary endpoints of MPR and EFS were performed to determine whether the treatment effect was consistent across subgroups. Based on the information available at the time of planning this analysis, the following factors should be noted: ● Histology (non-squamous vs. squamous) ● Disease stage (stage II vs. stage IIIA) ● PD-L1 expression in TC (≥ 1% vs. < 1%/not evaluable/uncertain) ● Smoking status (smokers vs. non-smokers) ● Age (≤ 65 years vs. > 65 years) ● Gender (female vs. male) ● ECOG performance status (0 vs. 1) ● Surgical margin (positive vs. negative) ii. Secondary efficacy analyses Key secondary analyses such as pCR assessed by BIPR

The pCR rate according to BIPR was defined as the proportion of patients with no residual tumor in the resected primary tumor and all resected lymph nodes after completion of leading therapy. Patients who did not undergo surgical resection were considered non-responders in the analysis. After successful MPR testing, the pCR according to BIPR was compared between tislelizumab combined with platinum-based doublet chemotherapy (Group A) and placebo combined with platinum-based doublet chemotherapy (Group B) using the Cochran-Mantel-Haenszel chi-square test. A similar approach used to assess MPR according to BIPR was applied to the analysis of pCR according to BIPR. Other secondary analyses Overall survival

OS was defined as the time from the date of randomization to the date of death from any cause. Data for patients who had not reported death at the time of analysis were censored at the last known date of survival. Data for patients who did not have postbaseline information on the date of randomization were censored. OS distributions were estimated using the Kaplan-Meier method. Comparisons of OS between Group A and Group B were tested at the earliest data cutoff when the MPR, pCR, and EFS tests were statistically significant using the stratified log-rank test. 2- year /3 -year OS rates

The 2-year/3-year OS rates were defined as the proportion of patients alive 2 and 3 years after randomization, estimated using the Kaplan-Meier method. The differences in OS rates and corresponding 95% CIs were calculated using the Cochran-Mantel-Haenszel method and were adjusted for stratification factors for descriptive purposes.

The investigator-based EFS was defined as the time from randomization until any of the following events, whichever occurred first: disease progression excluding surgery, local or distant recurrence as assessed by the investigator, or death from any cause. The same analysis methods and testing rules as the EFS according to BICR were applied to the analysis of the investigator-based EFS, except that the log-rank test of the investigator-based EFS was used for descriptive purposes only. 2- year /3 -year EFS rates

The 2-year/3-year EFS rate was defined as the proportion of patients without EFS events 2 and 3 years after randomization, estimated using the Kaplan -Meier method. A similar approach to that used to estimate OS rate was applied to the EFS rate analysis.

Objective response rate (not confirmed according to RECIST, version 1.1) was the proportion of patients with CR or PR according to RECIST, version 1.1, assessed by the BICR and by the investigator among all randomized patients with measurable disease at baseline. Patients without any post-baseline assessment were considered non-responders. A similar approach to that used to assess MPR according to the BICR was applied to the objective response rate analysis. DFS according to the BICR

DFS according to BICR is defined as the time from the first disease-free day to local or distant recurrence or death from any cause (whichever occurs first) as determined by BICR during adjuvant treatment and safety follow-up. DFS analysis was performed only on patients who underwent R0 resection. If the patient survived without recurrence, DFS was determined from the first disease-free day to the last known day and censored on the last known day. DFS was estimated using the Kaplan-Meier method. iii. Other efficacy analyses

Explore any potential associations between PD-L1 expression and the efficacy of tislelizumab treatment relative to control (MPR, EFS, pCR, objective response rate, and DFS). Assess other biomarkers including GEP, TMB/MSI/mutation profile, mIHC and TCR sequencing in archival and/or fresh tumor tissue, peripheral blood immunophenotyping, and ctDNA in blood before, during, or after study treatment or at disease progression/relapse, and evaluate their association with efficacy, mechanism, and patient outcomes. Response Criteria Assessment of Target Lesions ● Complete Response (CR): Disappearance of all target lesions. Any pathological lymph node (whether target or non-target) must shrink to < 10 mm in the short axis. ● Partial response (PR): At least a 30% decrease in the sum of target lesion diameters relative to the baseline sum ● Progressive disease (PD): At least a 20% increase in the sum of target lesion diameters relative to the smallest sum in the study (including the baseline sum if that is the smallest sum in the study). In addition to the 20% relative increase, the sum must also demonstrate an absolute increase of at least 5 mm (note: the appearance of one or more new lesions is also considered progression). ● Stable Disease (SD): Duration of global response during the study period with neither sufficient shrinkage to qualify as a PR nor sufficient increase to qualify as a PD, using the smallest summed diameter as reference. ● Duration of global response measured from the time a CR/PR (whichever was first recorded) first met the measurement criteria, until the first day of objectively documented relapse or progressive disease (using the smallest measurement recorded in the study as reference for progressive disease). ● Duration of total CR measured from the time a CR first met the measurement criteria, until the first day of objectively documented relapse. Duration of stable disease ● During the study, stable disease was measured from the start of treatment (from the date of randomization in randomized trials) to the minimum sum (if the baseline sum was the minimum, this was the reference for PD calculation) until the progression criteria were met. Example 3 : Tislelizumab and chemotherapy / chemoradiotherapy as lead therapy for resectable esophageal squamous cell carcinoma

Perioperative chemoradiotherapy (CRT) followed by esophagectomy is the current standard of care for patients with locally advanced resectable esophageal squamous cell carcinoma (R-ESCC). However, the use of CRT before surgery is not satisfactory for various reasons, including, for example, greater safety concerns compared with induction chemotherapy alone.

This example describes an ongoing phase 2, multicenter, open-label, 2-arm study investigating the efficacy and safety of positron emission tomography ( PET)-guided tislelizumab (BGB-A317) plus chemotherapy/chemoradiotherapy as leading therapy in patients with R-ESCC. The objective of this study was to assess pathological complete response (pCR) in participants who received tislelizumab plus chemotherapy/chemoradiotherapy as leading therapy. This article presents the results of the primary analysis. Study Design Summary

Patients with R-ESCC who had not received prior therapy were enrolled and, after a baseline PET/CT scan, received one cycle of induction paclitaxel + cisplatin chemotherapy followed by a second PET/CT scan. Patients were divided into “responder” or “non-responder” groups and were assigned to tislelizumab + chemotherapy or tislelizumab + CRT, respectively, followed by surgery ( Figure 3 ).

Cohort A (responders): Participants with a ≥ 35% reduction in positron emission tomography (PET) standardized uptake value (SUV) maximum received 3 cycles of tislelizumab (200 mg/cycle) + 2 cycles of chemotherapy doublet (cisplatin + paclitaxel). Tislelizumab was administered intravenously as specified in the treatment group.

Cohort B (non-responders): Participants with a PET SUV maximum decrease of < 35% received 3 cycles of tislelizumab (200 mg/cycle) + 2 cycles of doublet chemotherapy of investigator's choice (paclitaxel + cisplatin or 5-fluorouracil + cisplatin) + synchronous radiotherapy (40 Gy/min 20 fractions). Tislelizumab was administered intravenously as specified in the treatment group. Study Objectives

The primary and secondary outcome measures are summarized below. The major pathological response (MPR) rate was evaluated as an exploratory endpoint. Primary outcome measures: ● Pathological complete response (pCR) rate: pCR is defined as the proportion of participants with no residual tumor in the resected primary tumor and all resected lymph nodes after completion of lead therapy. pCR will be monitored for approximately 5 years. Secondary outcome measures: ● R0 resection rate: defined as the proportion of participants with R0 resection. R0 resection rate will be monitored for approximately 5 years. ● 1-year/3-year disease-free survival (DFS) rate: DFS is defined as the proportion of participants without disease events at 1 and 3 years from the first disease-free day. DFS is defined as the time from the first disease-free day (R0 resection as a surgical outcome) to local or distant recurrence or death from any cause, whichever occurs first. DFS rates will be analyzed only for participants who undergo an R0 resection. DFS rates will be monitored for approximately 5 years. ● 1-year/3-year event-free survival (EFS) rates: EFS is defined as the proportion of participants without EFS events at 1 and 3 years after the first dose. EFS is defined as the time from the first dose until any of the following events, whichever occurs first: disease progression excluding radical surgery, local or distant recurrence, or death from any cause. EFS rates will be monitored for approximately 5 years. ● Objective response rate (ORR): ORR is defined as the proportion of participants with complete response or partial response before surgery as assessed by the investigator according to RECIST version 1.1, among all participants with measurable disease at baseline. ORR will be monitored for approximately 5 years. ● The number of participants experiencing adverse events during treatment will be monitored for approximately 5 years. Key inclusion criteria during the screening phase : ● Eastern Coast Collaborative on Cancer performance status of 0 or 1. ● Histologically confirmed esophageal squamous cell carcinoma (ESCC). ● cT1-2N+M0 and cT3NanyM0 (according to the American Joint Committee on Cancer, 8th edition). ● Evidence of eligibility for R0 resection for curative intent, as assessed by the investigator. ● Adequate hematologic and organ function (defined by protocol-specified laboratory test results) obtained within 14 days prior to the first dose. Key Exclusion Criteria: ● Not eligible for treatment with any doublet chemotherapy as specified in the protocol. ● Any prior therapy for current ESCC, including investigational agents, chemotherapy, radiation therapy, targeted therapy agents, or prior therapy utilizing anti-programmed cell death protein-1, anti-programmed cell death protein ligand-1, anti-programmed cell death protein ligand-2, or any other antibodies or drugs that specifically target T-cell co-stimulatory or checkpoint pathways. ● History of fistula due to primary tumor invasion. ● Participants assessed by the investigator to be at high risk for fistula or signs of perforation. ● Any condition requiring systemic treatment with corticosteroids (> 10 mg pramexane or equivalent daily) or other immunosuppressive agents within 14 days prior to the first dose. ● *Adrenal replacement steroids (daily dose ≤ 10 mg pramexane or equivalent) and topical, ocular, intra-articular, intranasal, or inhaled corticosteroids with minimal systemic absorption are permitted, as well as short-term (≤ 7 days) corticosteroids prescribed prophylactically or for treatment of non-autoimmune conditions. ● History of active autoimmune disease or autoimmune disease with the potential for recurrence. ● *Inclusion is allowed for controlled type 1 diabetes, hypothyroidism requiring hormone replacement only, controlled chylous diarrhea, skin diseases not requiring systemic therapy (such as vitiligo, psoriasis, or alopecia), or diseases that are not expected to relapse in the absence of external triggers. ● History of interstitial lung disease, non-infectious pneumonia, or uncontrolled illness (including pulmonary fibrosis, acute lung disease). ● Infections requiring systemic antibacterial, antifungal, or antiviral therapy, including tuberculosis infection. o Serious infection within 4 weeks prior to the first dose, including (but not limited to) hospitalization due to infectious complications, bacteremia, or severe pneumonia. o Receipt of therapeutic oral or intravenous antibiotics within 2 weeks prior to the first dose. Results

As lead-in therapy for patients with resectable esophageal squamous cell carcinoma (R-ESCC) guided by positron emission tomography/computed tomography (PET/CT) response after chemotherapy induction, tislelizumab plus chemotherapy/chemoradiotherapy demonstrated promising pathological complete response (pCR) rates in both PET/CT-assessed responders (chemotherapy group) and non-responders (chemoradiotherapy group) with a tolerable safety profile. Baseline Characteristics and Treatment Exposure

Seventy patients were enrolled in this study, with the majority (68.6%) having stage III disease at initial diagnosis ( Table 11 ). All patients received induction chemotherapy. Thirty patients were responders by PET/CT evaluation, and 40 patients were evaluated as non-responders ( Table 11 ). Of the 30 responders, 39 received three cycles of tislelizumab and 27 received two cycles of paclitaxel and cisplatin. Of the 40 non-responders, 34 received three cycles of tislelizumab and two cycles of paclitaxel and cisplatin, and 34 received 40 Gy radiation therapy. At the time of data cutoff, the median study follow-up time was 9.7 months (range, 3.6-19.9). Table 11 : Patient Baseline Characteristics ( Safety Analysis Set ) Responders (n=30) Non-responders (n=40) Total (n=70) Median age, years (range) Age ≥ 65 years, n (%) 67.5 (47-75) 18 (60.0) 63.5 (51-79) 16 (40.0) 64.0 (47-79) 34 (48.6) Male, n (%) 24 (80.0) 38 (95.0) 62 (88.6) ECOG PS, n (%) 0 1 15 (50.0) 15 (50.0) 17 (42.5) 23 (57.5) 32 (45.7) 38 (54.3) Disease stage at initial diagnosis, n (%) II III IVA 7 (23.3) 18 (60.0) 5 (16.7) 8 (20.0) 30 (75.0) 2 (5.0) 15 (21.4) 48 (68.6) 7 (10.0) Primary location of esophageal cancer, n (%) Upper chest, middle chest, lower chest, esophageal and gastric junction 3 (10.0) 16 (53.3) 10 (33.3) 1 (3.3) 8 (20.0) 16 (40.0) 15 (37.5) 1 (2.5) 11 (15.7) 32 (45.7) 25 (35.7) 2 (2.9) Abbreviation: ECOG PS, Eastern Cooperative on Cancer Performance Status Scale

Of the 30 responders, 21 underwent surgery, with a pCR rate of 28.6% (n=6/21; 95% CI: 11.3, 52.2) and an R0 resection rate of 95.2% (n=20/21) ( Table 12 ). Of the 40 non-responders, 33 underwent surgery, with a pCR rate of 33.3% (n=11/33; 95% CI: 18.0, 51.8) and an R0 resection rate of 90.9% (n=30/33) ( Table 12 ). The percentage of residual viable tumor in responders and non-responders is presented in Figures 4A- 4B .

Data cutoff: April 17, 2023. ^aThe efficacy-evaluable analysis set includes all patients who received lead ^therapy followed by surgery; b95% CI estimated using the Clopper-Pearson method; ^cDefined as the proportion of patients with ≤ 10% residual viable tumor in the resected primary tumor and all resected lymph nodes after completion of lead therapy; ^dThe safety analysis set includes all included patients who received one or more doses of any component of the study drug; ^eORR before surgery. Abbreviations: CI, confidence interval; MPR, major pathological response; ORR, objective response rate; pCR, pathological complete response. Safety

Grade ≥3 treatment-related treatment-emergent adverse events (TRAEs) were reported in 46.7% and 82.5% of responders and nonresponders, respectively ( Table 6 ). Grade ≥3 TRAEs reported in ≥10% of patients included decreased neutrophil counts in responders (36.7%) and decreased neutrophil counts (65.0%), decreased white blood cell counts (47.5%), decreased lymphocyte counts (17.5%), and anemia (12.5%) in nonresponders. Most grade ≥3 TRAEs were related to the chemotherapy or radiation components of treatment. Grade ≥ 3 tislelizumab-related treatment-emergent adverse events (TEAEs) were reported in 10.0% and 22.5% of patients in the responder and non-responder groups, respectively.

No TRAEs leading to death were reported, few patients experienced TEAEs leading to treatment discontinuation or surgery delay, and no patient canceled surgery due to TEAEs

All immune-mediated adverse events were grade 1 or 2. 76.2% of responders and 63.6% of non-responders reported procedure-related adverse events. Data cutoff: April 17, 2023. aTEAEs related to ^any study treatment component, including tislelizumab, chemotherapy, or radiation therapy; ^bDefined as adverse events from the day of surgery to 30 days after surgery; ^cData reported in the efficacy evaluable analysis set. Abbreviation: TEAE, treatment-emergent adverse event. Incorporated by reference

Various references, such as patents, patent applications, and publications, are cited herein, the disclosures of which are hereby incorporated by reference in their entirety.

without

Figure 1 is a schematic diagram showing the clinical trial treatment groups in a randomized, double-blind, placebo-controlled phase 3 study in patients with resectable stage II or IIIA NSCLC to compare the efficacy and safety of leading treatment with tislelizumab plus platinum-based doublet chemotherapy followed by adjuvant tislelizumab versus leading treatment with placebo plus platinum-based doublet chemotherapy followed by placebo. This study consisted of a screening phase, a treatment phase (including a leading phase, surgery, and adjuvant phase), a safety follow-up phase, and a survival follow-up phase. Abbreviations: AE, adverse event; d1, day 1; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IV, intravenous; N, number of patients; NSCLC, non-small cell lung cancer; Q3W, every 3 weeks; Q6W, every 6 weeks; Sq, squamous; R, randomization ratio; R0, pathological safe resection of the primary tumor; WT, wild type. Figure 2 provides a table showing that in the study described in Example 1, in 453 untreated patients with resectable confirmed squamous or non-squamous stage II-IIA NSCLC, when comparing the efficacy of tislelizumab (i.e., anti-PD-1 antibody) + platinum doublet (e.g., cisplatin or carboplatin + etoposide) (Group A) and placebo + platinum doublet (Group B) as first-line treatment, the major pathological response (MPR) and pathological complete response (pCR) rates were significantly improved. Figure 3 provides a schematic diagram of the study design, which is used to evaluate tislelizumab + chemotherapy/chemoradiotherapy as a lead treatment for resectable esophageal squamous cell carcinoma. Figures 4A- 4B show the results of the percentage of residual viable tumors in responders ( Figure 4A ) and non-responders ( Figure 4B ).

TW202515903A_113111271_SEQL.xml

Claims (58)

A method for treating cancer in an individual in need thereof, wherein the cancer is a solid cancer that is surgically resectable, the method comprising: (a) during a first treatment period, parenterally administering to the individual a first dose of an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the first dose of the anti-PD-1 antibody is 200 mg once every three weeks, and wherein the anti-PD-1 antibody comprises: (i) _VH CDR1, _VH CDR2, and _VH CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 31, 32, and 33, and (ii) _VL CDR1, _VL CDR2, and _VL CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 34, 35, and 36; (b) after (i), surgically resecting the cancer in the individual; and (c) During a second treatment period after (ii), a second dose of the anti-PD-1 antibody or an antigen-binding fragment thereof is parenterally administered to the subject, wherein the second dose of the anti-PD-1 antibody is 400 mg, once every 6 weeks. The method of claim 1, wherein the cancer is an early stage cancer. The method of claim 1, wherein the cancer is breast cancer, colon cancer or lung cancer. The method of claim 4, wherein the cancer is non-small cell lung cancer (NSCLC). The method of claim 6, wherein the cancer is squamous cell carcinoma. The method of claim 6, wherein the cancer is non-squamous cell carcinoma. The method of any one of claims 1 to 6, wherein the cancer is stage II or stage IIIA. The method of any one of claims 1 to 7, wherein the cancer is not locally advanced or metastatic. The method of any one of claims 1 to 8, wherein the heavy chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID NO: 24, and the light chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID NO: 26. The method of claim 9, wherein the anti-PD-1 antibody comprises an IgG constant region comprising the amino acid sequence of SEQ ID NO: 88. The method of any one of claims 1 to 10, wherein the anti-PD-1 antibody is administered intravenously, optionally wherein the administration is by IV infusion. The method of any one of claims 1 to 11, wherein the individual has not previously received treatment for the cancer or the treatment is a first-line therapy. The method of any one of claims 1 to 11, wherein the individual has not been previously treated with chemotherapy, radiation therapy and/or immunotherapy. The method of any one of claims 1 to 11, wherein the treatment is a second-line therapy. The method of any one of claims 1 to 14, wherein the first treatment period comprises 3 or 4 cycles, each cycle being three weeks. The method of any one of claims 1 to 15, wherein the second treatment period comprises less than or equal to 8 cycles, each cycle being six weeks. The method of any one of claims 1 to 16, wherein the second treatment period comprises at least 8 cycles, each cycle being six weeks. The method of any one of claims 1 to 17, wherein the second treatment period begins within 8 weeks after the surgical resection. The method of any one of claims 1 to 18, wherein the surgical resection is followed by radiation therapy before the start of the second treatment period. The method of claim 19, wherein the radiation therapy is administered 30 to 60 days after the surgical resection and the second treatment period is initiated between 7 to 30 days after the radiation therapy. The method of any one of claims 1 to 18, wherein the surgical resection is not followed by radiation therapy. The method of claim 21, wherein the second treatment period begins between 2 and 8 weeks after the surgical resection. The method of any one of claims 1 to 22, wherein the first treatment period further comprises administering a therapeutically effective amount of one or more chemotherapeutic agents. The method of claim 23, wherein the one or more chemotherapeutic agents comprises a platinum chemotherapeutic agent. The method of claim 23 or 24, wherein the one or more chemotherapeutic drugs are carboplatin or cisplatin. The method of claim 25, wherein the cisplatin is administered intravenously at about 75 mg/ ^m2 , or the cisplatin is administered intravenously at an area under the plasma or serum concentration-time curve of about 5 (AUC5), optionally wherein the administration is once every three weeks (Q3W), optionally wherein the administration is performed by IV infusion. The method of claim 23, wherein the one or more chemotherapeutic drugs further comprise pemetrexed or paclitaxel, as appropriate, wherein the pemetrexed is used when the NSLC is non-squamous cell carcinoma, and the paclitaxel is used when the NSLC is squamous cell carcinoma. The method of claim 27, wherein the pemetrexed is administered intravenously at about 500 mg/ ^m2 , optionally wherein the administration is once every three weeks (Q3W), optionally wherein the administration is performed by IV infusion. The method of claim 27, wherein the paclitaxel is administered intravenously at about 175 mg/ ^m2 , optionally wherein the administration is once every three weeks (Q3W), optionally wherein the administration is performed by IV infusion. The method of any one of claims 1 to 29, wherein the treatment is clinically effective or the individual is a responder to the treatment based on at least one measure of response to the treatment. The method of claim 30, wherein the response to treatment is measured by overall survival, progression-free or event-free survival, major pathological response ("MPR"), pathological complete response ("pCR"), overall response, partial response, duration of response, and/or tumor volume, diameter or size. The method of claim 31, wherein the subject is a responder as measured by MPR. The method of claim 32, wherein the MPR is at least twice the MPR observed in a control group of individuals not treated with the anti-PD-1 antibody. The method of claim 33, wherein the individual has a probability of MPR of at least 25%, 35%, 40%, 45% or 50%, or the treatment is effective as evidenced by a patient population MPR of at least 25%, 35%, 40%, 45% or 50%. The method of claim 31, wherein the response to treatment is measured by tumor volume, size or diameter, and wherein the treatment reduces the individual's tumor volume, size or diameter by at least or more than 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% or 90%. The method of claim 31, wherein the subject is a responder based on pCR, wherein the subject has a probability of pCR of at least 15%, 20%, 25%, 35% or 40%, or wherein the treatment is effective as evidenced by a pCR of at least 15%, 20%, 25%, 35% or 40% in the patient population. The method of any one of claims 1 to 36, wherein the individual does not have an EGFR mutation, a ROS1 mutation, or an ALK gene translocation. The method of claim 37, wherein the individual's genomic tumor aberration is EGFR negative. The method of claim 37, wherein the individual is negative for ALK genomic tumor aberration. The method of any one of claims 1 to 39, wherein the individual is a human. The method of claim 40, wherein the human is an adult. (New) A method for treating cancer in an individual in need thereof, wherein: the cancer is a solid cancer, and the solid cancer is selected from the group consisting of lung cancer, breast cancer and colon cancer, the method comprises parenterally administering a first dose of an anti-PD-1 antibody or an antigen-binding fragment thereof to the individual, wherein the anti-PD-1 antibody is administered at a dose of about 2 mg/kg to about 5 mg/kg, and the anti-PD-1 antibody comprises: (i) _VH CDR1, _VH CDR2 and _VH CDR3, which comprise the amino acid sequences shown in SEQ ID NOs:31, 32 and 33, and (ii) _VL CDR1, _VL CDR2 and _VL CDR3, which comprise the amino acid sequences shown in SEQ ID NOs:34, 35 and 36. (New) A method for treating cancer in an individual in need thereof, wherein the cancer is a solid cancer, the method comprising parenterally administering an anti-PD-1 antibody or an antigen-binding fragment thereof to the individual, wherein: (a) the anti-PD-1 antibody is administered at a dose of about 2 mg/kg to about 5 mg/kg, and (b) the anti-PD-1 antibody comprises: (i) _VH CDR1, _VH CDR2, and _VH CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 31, 32, and 33, and (ii) _VL CDR1, _VL CDR2, and _VL CDR3 comprising the amino acid sequences shown in SEQ ID NOs: 34, 35, and 36; and (c) The method further comprises administering a therapeutically effective amount of a chemotherapeutic agent comprising (i) a platinum chemotherapeutic agent, or (ii) carboplatin and paclitaxel or nanoparticle albumin-bound paclitaxel (nab-paclitaxel). (New) The method of claim 43, further comprising administering a therapeutically effective amount of one or more chemotherapeutic agents. (New) The method of claim 43 or 44, wherein the one or more chemotherapeutic agents comprises a platinum chemotherapeutic agent. (New) The method of claim 43 or 44, wherein the one or more chemotherapy drugs include pemetrexed and platinum chemotherapy drugs. (New) The method of claim 45 or 46, wherein the platinum chemotherapy drug is carboplatin or cisplatin. (New) The method of claim 43 or 44, wherein the one or more chemotherapeutic agents comprise (a) carboplatin, and (b) paclitaxel or nanoparticle albumin-bound paclitaxel. (New) A method as described in any of claims 42 to 48, wherein the cancer is lung cancer, wherein the lung cancer is locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC), wherein the lung cancer is negative for epidermal growth factor receptor (EGFR) aberrations and anaplastic lymphoma kinase (ALK) genomic tumor aberrations, and the method further comprises administering pemetrexed and platinum chemotherapy drugs. (New) The method of any one of claims 42 to 48, wherein the cancer is locally advanced or metastatic squamous non-small cell lung cancer (NSCLC), and the method further comprises administering (a) carboplatin, and (b) paclitaxel or nanoparticle albumin-bound paclitaxel. (New) The method of any one of claims 42 to 50, wherein the individual has not previously received treatment for the cancer or the treatment is a first-line treatment. (New) The method of any one of claims 42 to 52, wherein the heavy chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID NO: 24, and the light chain variable region of the anti-PD-1 antibody comprises the amino acid sequence of SEQ ID NO: 26. (New) The method of claim 52, wherein the anti-PD-1 antibody comprises an IgG constant region comprising an amino acid sequence of SEQ ID NO:88. (New) The method of any one of claims 42 to 53, wherein the anti-PD-1 antibody is administered intravenously, optionally wherein the administration is performed by IV infusion. (New) The method of claim 46, 48 or 50, wherein the carboplatin is administered intravenously at an area under the plasma or serum concentration-time curve of about 5 (AUC5), optionally wherein the administration is once every three weeks (Q3W), optionally wherein the administration is performed by IV infusion. (New) The method of claim 49, wherein the pemetrexed is administered intravenously at about 500 mg/ ^m2 , optionally wherein the administration is once every three weeks (Q3W), optionally wherein the administration is performed by IV infusion. (New) The method of claim 49, wherein the paclitaxel is administered intravenously at about 175 mg/ ^m2 , optionally wherein the administration is once every three weeks (Q3W), optionally wherein the administration is performed by IV infusion. (New) The method of any one of claims 42 to 57, wherein the anti-PD-1 antibody is administered at a dose of about 2 mg/kg to 5 mg/kg, optionally wherein the anti-PD-1 antibody is administered at a dose of about 2 mg/kg Q3W, 5 mg/kg Q3W or 200 mg Q3W, optionally wherein the anti-PD-1 antibody is administered at a dose of about 400 mg, and optionally wherein the anti-PD-1 antibody is administered at a dose of about 400 mg Q6W.