JP2014510793A - Combination of motesanib, taxane, and platinum-containing anticancer agents for use in the treatment of non-small cell lung cancer in a subset of the population - Google Patents

Abstract

  The present invention provides a method for improving survival related to cancer in a subset of the general population. The present invention provides a method for improving cancer-related survival in patients of Asian ethnic background. In addition, this application relates to the treatment of angiogenesis-related diseases in Asian patients with kinase inhibitors. In addition, this application relates to the treatment of non-small cell lung cancer in Asian patients with motesanib.

Description

  The present invention provides a method of improving survival related to cancer in a special subset of the general population. The present invention provides a method for improving cancer-related survival in patients of Asian ethnic / racial background. In addition, this application relates to the treatment of angiogenesis-related diseases in Asian patients with kinase inhibitors. In addition, this application relates to the treatment of non-small cell lung cancer in Asian patients with motesanib.

  Certain diseases such as retinopathy (including diabetic retinopathy), ocular neovascularization such as age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, rheumatoid or rheumatic inflammatory diseases In particular, inflammatory diseases such as arthritis (including rheumatoid arthritis), or other inflammatory diseases such as chronic asthma, arterial or post-transplant atherosclerosis, endometriosis, and neoplastic diseases, such as So-called solid tumors are known to be associated with dysregulation of angiogenesis.

  For example, angiogenesis plays a critical role in tumor progression. Early stage and small tumors can obtain sufficient oxygen and nutrients to maintain their growth by simple diffusion. However, once the diameter exceeds 1-2 mm, diffusion cannot supply the amount of these elements necessary for further growth. For growth beyond that size, all tumors require the vasculature, regardless of their cause, origin, type, age or location. Thus, tumor growth with a diameter greater than 1 to 2 mm requires angiogenesis. Thus, angiogenesis has been seen as a promising target for developing effective general therapies for tumors.

  Three major mechanisms play an important role in the activity of angiogenesis inhibitors against tumors: (i) Inhibition of growth of blood vessels, particularly capillaries, into avascular resting tumors. As a result, there is no net tumor growth due to the balance achieved between cell death and proliferation; (ii) prevention of tumor cell migration due to the absence of blood flow to and from the tumor; and (Iii) Inhibition of endothelial cell proliferation. For this reason, the paracrine growth stimulating action normally exerted on the surrounding tissue by the endothelial cells lining the blood vessels is avoided. Exp. Opin. Ther. See Patents, 11: 77-114 (2001).

  Efforts to develop therapeutically effective angiogenesis inhibitors have targeted all three major mechanisms. As a result of these efforts, various promising anti-angiogenic agents have been identified.

  During both embryonic development and normal growth, and in a number of pathological abnormalities and diseases, at the heart of the network that regulates the growth and differentiation of the vasculature and its components, “vascular endothelial growth factor” (VEGF; initially This cellular receptor is present with an angiogenic factor known as “vascular permeability factor”, VPF) (see Trends in Cell Biology, 6: 454-456 (1996)).

  VEGF is a disulfide-linked 46-kDa dimeric glycoprotein related to “platelet-derived growth factor” (PDGF). It is produced by normal and tumor cell lines; is an endothelial cell specific mitogen; exhibits angiogenic activity in in vivo test systems (eg, rabbit cornea); is chemotactic for endothelial cells and monocytes Yes; induces plasminogen activator in endothelial cells that is involved in proteolysis of the extracellular matrix during capillary formation. Many isoforms of VEGF are known and these show similar biological activity, but differ in the type of cells that secrete them and their ability to bind heparin. In addition, there are other members of the VEGF family, such as “placental growth factor” (PIGF) and VEGF-C.

  The VEGF receptor (VEGFR) is a transmembrane receptor tyrosine kinase. These are characterized by an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types of VEGF receptors are known, eg, VEGFR-1 (also known as flt-1), VEGFR-2 (also known as KDR), and VEGFR-3.

  Lung cancer is the most common cancer in the world, accounting for about 18% of cancer deaths. Most patients show advanced stage disease and more than 80% are non-small cell lung cancer (NSCLC). Among patients receiving standard two-drug chemotherapy regimens as first-line treatment, median survival is about 8 months.

  Vascular endothelial growth factor (VEGF), a pro-angiogenic cytokine, and its receptor are important targets for NSCLC treatment. In the E4599 trial, treatment with the anti-VEGF-A monoclonal antibody bevacizumab + carboplatin / paclitaxel resulted in response rates among patients with stage IIIB or IV non-squamous epithelial NSCLC compared to carboplatin / paclitaxel + placebo ( ORR), progression free survival (PFS) and overall survival (OS) improved. Bevacizumab plus carboplatin / paclitaxel is the only anti-angiogenic therapy currently approved in the United States for the treatment of NSCLC. The addition of bevacizumab to cisplatin / gemcitabine has been shown to improve the PFS of NSCLC but did not have a statistically significant effect on overall survival. Other anti-angiogenic drugs failed to show improved clinical outcome when combined with chemotherapy as the first line treatment for advanced disease.

  Motesanib, an orally administered small molecule antagonist of VEGF receptor (VEGFR) 1, 2 and 3, platelet derived growth factor receptor and Kit, is promising in solid tumors as monotherapy and in combination with chemotherapy Shows antitumor activity. A Phase I dose-setting study evaluated the safety, pharmacokinetics and pharmacodynamics of AMG 706 in patients with refractory advanced solid tumors. Journal of Clinical Oncology (2007), 25 (17), 2369-2376. In the NSCLC Phase 1b trial, treatment with motesanib + carboplatin / paclitaxel was tolerated at doses up to 125 mg once daily (QD), with pharmacokinetics supporting its dosing regimen as a combination therapy. Clinical Cancer Research (2010), 16 (1), 279-290. Objectives: This phase II study is for vascular endothelial growth factor receptors 1, 2 and 3, platelet-derived growth factor receptor, and Motesanib, a highly selective inhibitor of Kit, in advanced medullary thyroid carcinoma (MTC). Efficacy and tolerability were investigated. Patients and Methods: Patients with locally advanced or metastatic, progressive or symptomatic MTC will be given motesanib 125 mg orally for up to 48 weeks or until toxic or disease progression is unacceptable. It was. New England Journal Medicine 2008 359: 31-42. Results of an open-label phase II study of motesanib combined with paclitaxel and carboplatin for advanced non-squamous non-small cell lung cancer were reported at ASCO. Journal of Clinical Oncology, 28, 15s, 2010 (Abstract 7528). Results of a phase II multicenter open-label randomized trial of motesanib or bevacizumab combined with paclitaxel and carboplatin for advanced non-squamous non-small cell lung cancer reported in Anals of Oncology, 22, 2057-2067 (2011) It was done. A phase I study investigated the safety and pharmacokinetics of motesanib (AMG706) in Japanese patients with advanced solid tumors. Cancer Chemotherapy and Pharmacology (2010), 66 (5), 935-943. A phase II clinical trial evaluated the efficacy and safety of motesanib alone in Japanese patients with advanced gastrointestinal stromal tumors previously exposed to imatinib mesylate. Cancer Chemotherapy and Pharmacology (2010), 65 (5), 961-967.

Exp. Opin. Ther. Patents, 11: 77-114 (2001). Trends in Cell Biology, 6: 454-456 (1996). Journal of Clinical Oncology (2007), 25 (17), 2369-2376. Clinical Cancer Research (2010), 16 (1), 279-290 New England Journal Medicine 2008 359: 31-42. Journal of Clinical Oncology, 28, 15s, 2010 (Abstract 7528) Anals of Oncology, 22, 2057-2067 (2011) Cancer Chemotherapy and Pharmacology (2010), 66 (5), 935-943 Cancer Chemotherapy and Pharmacology (2010), 65 (5), 961-967

  However, as the incidence of lung cancer is increasing in Asian countries, there is a need in the art for new and more effective treatments for cancer in Asian patients.

2 shows overall survival of patients treated with motesanib in the NSCLC Phase 3 study. The median progression-free survival for the largest analysis population (full analysis set) is shown. Shows overall survival of patients from Japan, Korea, Taiwan, China (Hong Kong), Philippines and Singapore treated with motesanib in the NSCLC Phase 3 study. The median progression-free survival for the Asian patient subset analysis is shown. 2 shows overall survival of a subset analysis of non-Asian patients treated with motesanib in a NSCLC Phase 3 study. Shows median progression-free survival for non-Asian patient subset analysis. Figure 2 shows the latest overall survival of a Japanese patient subset analysis treated with motesanib in the NSCLC Phase 3 trial. Shows the latest median progression-free survival for Japanese patient subset analysis. Shows the latest median progression-free survival for the Asian patient subset analysis. Shows the latest overall survival of patients from Japan, Korea, Taiwan, China (Hong Kong), Philippines and Singapore treated with motesanib in the NSCLC Phase 3 study.

  In the present invention, the results of the MONET1 phase 3 clinical trial, including the overall survival of patients receiving motesanib, were reviewed and re-evaluated for the subset. Responses to motesanib treatment by patients in Japan, South Korea, Hong Kong, Singapore, Taiwan and the Philippines resulted in unexpected survival benefits compared to non-Asian patients.

  The present application relates to methods and kits for treating cancer in Asian patients.

  This application relates to the treatment of cancer in Asian patients with kinase inhibitors.

  The invention also relates to the treatment of neoplasms including cancer and metastasis, including but not limited to lung cancer. The invention also relates to the treatment of non-small cell lung cancer. The invention also relates to the treatment of non-squamous non-small cell lung cancer. The invention also relates to the treatment of adenocarcinoma.

  The present application relates to a method of first-line treatment of non-squamous non-small cell lung cancer in an Asian patient comprising administering motesanib.

  The present application relates to a method for improving survival related to non-squamous non-small cell lung cancer in an Asian patient comprising treating the Asian patient with a combination of motesanib, a taxane, and a platinum-containing anticancer agent.

  The present application relates to a method for extending the overall survival of an Asian patient diagnosed with non-squamous non-small cell lung cancer, comprising the step of treating the Asian patient with a combination comprising motesanib and a taxane.

  The application relates to a method wherein the combination comprises a platinum-containing anticancer agent.

  The invention relates to a method for extending the overall survival of an Asian patient diagnosed with non-squamous non-small cell lung cancer comprising the step of treating the Asian patient with a combination comprising motesanib and a platinum-containing anticancer agent.

  The present application relates to a method wherein the combination comprises a taxane.

  The present application relates to methods wherein motesanib is administered in combination with one or more chemotherapeutic agents.

  The application relates to a method wherein the chemotherapeutic agent is paclitaxel or carboplatin.

  The present application relates to a method wherein the taxane is paclitaxel and the platinum-containing anticancer agent is carboplatin.

The present application relates to a method wherein paclitaxel is administered at 200 mg / m ² .

  The present application relates to a method wherein carboplatin is administered at AUC 6 mg / mL / min.

  This application includes methods wherein the non-small cell lung cancer is an adenocarcinoma.

  The present application relates to a method wherein non-small cell lung cancer is non-squamous.

  The present application relates to a method wherein the treatment is a first line treatment.

  The application relates to a method wherein motesanib is administered in a daily dose of 100 mg or 125 mg.

  This application relates to a method wherein motesanib is administered in a daily dose of 125 mg.

  The present application relates to a method wherein the Asian patient is a Japanese, Korean, Taiwanese, Chinese (Hong Kong), Filipino or Singaporean / ethnic patient. This decision is similar to that described in the description of the US Census. For further clarity, such racial / ethnic determination includes those whose at least one parent is that racial / ethnic group.

  The present application relates to a method in which Asian patients are Japanese.

  The present application relates to a method of extending progression free survival associated with non-squamous non-small cell lung cancer in an Asian patient comprising treating the Asian patient with a combination of motesanib, taxane, and a platinum-containing anticancer agent.

  The application relates to non-squamous epithelium in Asian patients beyond the progression-free survival observed with taxanes and platinum-containing anticancer agents alone, comprising treating Asian patients with a combination of motesanib, taxane, and platinum-containing anticancer agents. It relates to a method for prolonging progression-free survival associated with non-small cell lung cancer.

  The present application is directed to non-squamous non-squamous cells in Asian patients beyond the overall survival observed with taxanes and platinum-containing anticancer agents alone, comprising treating Asian patients with a combination of motesanib, taxane, and platinum-containing anticancer agents. It relates to a method for prolonging overall survival associated with small cell lung cancer.

  Another aspect of the invention relates to the use of a compound according to any of the above embodiments as a medicament.

  Another aspect of the invention relates to the use of a compound according to any of the above embodiments in the manufacture of a medicament for the treatment of cancer.

Another aspect of the invention relates to the following 19 specific uses and corresponding methods:
1. Related to non-squamous NSCLC in Asian patients beyond the survival observed with taxanes and platinum-containing anticancer drugs alone, including treating Asian patients with a combination of motesanib, taxane, and platinum-containing anticancer drugs Use of motesanib in the manufacture of a drug to effectively prolong overall survival.

  2. The use according to claim 1, wherein the medicament prolongs overall survival compared to treatment with paclitaxel and carboplatin.

  3. Use according to claim 1, wherein the non-squamous non-small cell lung cancer is progressive.

  4). Use according to claim 1, wherein the non-squamous non-small cell lung cancer is stage IIIB or stage IV or recurrent.

  5. Non-squamous non-small cell lung cancer in Asian patients beyond progression-free survival observed with taxanes and platinum-containing anticancer drugs alone, including treating Asian patients with a combination of motesanib, taxane, and platinum-containing anticancer drugs Use of motesanib in the manufacture of a drug to effectively prolong progression-free survival related to

  6). 6. Use according to claim 5, wherein the medicament prolongs progression-free survival compared to treatment with paclitaxel and carboplatin.

  7). Use of motesanib in the manufacture of a medicament for effectively improving overall survival associated with non-squamous non-small cell lung cancer in Asian patients, including treating Asian patients with motesanib, taxanes, and platinum-containing anticancer agents .

  8). The use according to claim 1, wherein motesanib is administered in combination with one or more chemotherapeutic agents, provided that the chemotherapeutic agent is not panitumumab.

  9. The use according to claim 1, wherein the taxane is paclitaxel and the platinum-containing anticancer agent is carboplatin.

10. Paclitaxel is administered at 200 mg / ^{m 2,} use according to claim 9.

  11. 10. Use according to claim 9, wherein carboplatin is administered at AUC 6 mg / mL / min.

  12 The use according to claim 1, 5 or 7, wherein the non-squamous non-small cell lung cancer is an adenocarcinoma.

  13. 8. Use according to claim 1, 5 or 7, wherein the treatment is a first line treatment.

  14 8. Use according to claim 1, 5 or 7, wherein motesanib is administered in a daily dose of 100 mg or 125 mg.

  15. 8. Use according to claim 1, 5 or 7, wherein motesanib is administered in a daily dose of 125 mg.

  16. The use according to claim 1, 5 or 7, wherein the Asian patient is a patient of Japanese, Korean, Taiwan, Chinese, Hong Kong, Filipino or Singaporean ethnicity.

  17. The use according to claim 1, 5 or 7, wherein the Asian patient is a patient of Korean, Taiwan, Chinese, Hong Kong, Filipino or Singaporean ethnicity.

  18. The use according to claim 1, 5 or 7, wherein the Asian patient is Japanese.

  19. Use of motesanib in the manufacture of a medicament for first line treatment of non-squamous non-small cell lung cancer in a patient, wherein the patient is not non-Asian.

  Currently, standard treatment of primary tumors is surgical excision followed by radiation or IV dose chemotherapy. Typical chemotherapy regimens consist of DNA alkylating agents, DNA intercalating agents, CDK inhibitors, or microtubule poisons. The dose of chemotherapy used is just below the maximum tolerated dose, and thus dose limiting toxicity typically includes nausea, vomiting, diarrhea, hair loss, neutropenia and the like.

  There are a number of anti-neoplastic agents available for commercial use, clinical evaluation and preclinical development and are selected for the treatment of neoplasms with combination drug chemotherapy. Such antineoplastic drugs fall into several major categories: antibiotic-type drugs, alkylating agents, antimetabolites, hormonal drugs, immune drugs, interferon-type drugs and other drug categories .

  The first family of antineoplastic agents that can be used in combination with the compounds of the present invention consists of antimetabolite / thymidylate synthase inhibitor antineoplastic agents. Suitable antimetabolite anti-neoplastic agents include, but are not limited to, 5-FU, fibrinogen, acantiphoric acid, aminothiadiazole, brequinal sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine Complex, Lilly DATHF, Merrel Dow DDFC, Dezaguanine, dideoxycytidine, dideoxyguanosine, zidox, Yoshitomi DMDC, doxyfluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N- (2'-furanidyl) -5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolidine, Lilly LY-188011, Lilly LY-2646 (Methobenzaprim), methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin h , Takeda TAC-788, Thiog Nin, tiazofurin, Erbamont TIF, trimetrexate, tyrosine kinase inhibitors may be selected from the group consisting of Taiho UFT and uricytin (uricytin).

  A second family of antineoplastic agents that can be used in combination with the compounds of the present invention consists of alkylated antineoplastic agents. Suitable alkylated anti-neoplastic agents include, but are not limited to, Shionogi 254-S, aldo-phosphamide analogs, altretamine, anaxylone, Boehringer Mannheim BBR-2207, vestlabcil, bud titanium, Wakunaga CA-102, carboplatin , Carmustine, Chinoin-139, Chinoin-153, Chlorambucil, Cisplatin, Cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, Cyplatate, Degussa D-19-384, SumitomoMDA Diphenylspiromustine, diplatinum cell growth inhibitor, Erba distamycin derivative, Chu ai DWA-2114R, ITI E09, Elmustine, Erbamont FCE-24517, Estramustine sodium phosphate, Fotemustine, Unimed G-6-M, Chinoin GYKI-17230, Hepsulfam, Ifosfamide p, Ropromitol p, Ropromitol p NK-121, NCI NSC-264395, NCI NSC-342215, Oxaliplatin, Upjohn PCNU, Predonimustine, Proter PTT-119, Ranimustine, Semustine, SmithKline SK & F-101727, Yakult HonsT Tauromustine Temozolomide, teroxirone, can be selected from the group consisting of tetraplatin and trimelamol.

  A third family of antineoplastic agents that can be used in combination with the compounds of the present invention consists of antibiotic type antineoplastic agents. Suitable antibiotic anti-neoplastic agents include, but are not limited to, Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aeropricinin derivative, Ajinomoto AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycin, anthracycline, azinomycin-A, biscaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25ol, B66-Bol-Mol-Bol-Moli Myers BMY-27557, Bristol-Myers BMY-28438, sulfuric acid Rheomycin, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin, Kyowa Hako DC-102, Kyowa Hako DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1 DC92-B, ditrisarrubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, elvstatin, esorubicin, esperamicin-A1, esperamicin-Alb, ErFCEm 19t Fujisawa FK-973, Host Liesin, Fujisawa F R-900482, Glidobactin, Greggatin-A, Grincamycin, Herbimycin, Idarubicin, Irdin, Kazusamycin, Quesarolidin, Kyowa Hakko KM-5539, Kirin Brekley KRN-8602, Kyowa Hak Tak 5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME2303, Menogalil, Mitomycin, Mitoxantrone, SmithKline M-TAG, NeoNectin, Nippon KayK C-357704, Oxalicin, Oxaunomycin, Pepromycin, Pyratin, Pirarubicin, Polosuramicin, Pyrindamycin A, Tobishi RA-I, Rapamycin, Rhizoxin, Rodolubicin, Shivanomicin, Siwenmycin, Sumitomo SM-5877, Snow Brand SN -706, Snow Brand SN-07, Sorangisin-A, Sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, Steffimycin B, Taiho 4181-2K Talymy TA , Terpenthesin, sorazine, triclozarin A, Upjohn It can be selected from the group consisting of U-73975, Kyowa Hako UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024, and Zorubicin.

  A fourth family of anti-neoplastic agents that can be used in combination with the compounds of the present invention includes, but is not limited to, α-carotene, α-difluoromethyl-arginine, acitretin, Biotec AD-5, Kyorin AHC-52, alstonine , Amonafide, amphetinyl, amsacrine, angiostat, ankinomycin, antineoplaston A10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, aphidicolin glycinate, asparaginase Avarol, baccaroline, butracillin, benfluron, benzotrypto, Ipsen-Beaufour BIM-23015, bisantren, Bristol-Myers BMY-40481, Vestar Boron-10, Bromophosphamide, Wellcome BW-502, Wellcome BW-773, Caracemide, carmethizole hydrochloride, Ajinomoto CDAF, Chlorsulfakinoxalon, CH-205 CHM -100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, Cranfenull, claviridone, ICN compound 1259, ICN compound 4711, Contrac-1 PT , Crisnatol, Cu Curderm, cytochalasin B, cytarabine, cytosine, Merz D-609, DABIS maleate, dacarbazine, dateliptinium, didemnin-B, dihematoporphyrin ether, dihydrolenperone, dinamycin, toyomah 341, Toyo Pharma DM-75, Daiichi Seiyaku DN-9693, Docetaxel Elipravin, Elliptinium acetate, Tsumura EPMTC, Epothilone, Ergotamine, Etoposide, Etretatin, FenRawa 70G Glaxo GR-63178, Gryho NMF-5N, hexadecylphosphocholine, Green Cross HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, ilmofosin, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuka K-76COONa , Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, Leukoregulin, Lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) M Merrel Dow MDL-27048, Medco MEDR-340, Melvalon, Merocyanine invitation Body, methylanilinoacridine, Molecular Genetics MGI-136, minactivin, mitonafide, mitokidone, mopidamol, motretinide, Zenyaku Kogyo MST-16, N- (retinoyl) amino acid, NisshinMl NilMinFl Dehydroalanine, Nafazatrom, Taisho NCU-190, Nocodazole derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, octreotide, Ono-Ozuzin (oquozine) 10172, paclitaxel, pancratis Chin, Pazeliptin, Warner-Lambert PD-11707, Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, pyroxanthrone, polyhematoporic p, polyhematoporphylic p Efamol porphyrin, probiman, procarbazine, proglumide, Invitron protease nexin I, Tobishi RA-700, razoxane, Saporo Breweries RBS, restrictin-P, retelliptin, retinoic acid, Rhone-Poulen RPonc RP-4956R ine SK & F-104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10094, Spartol, Spirocyclopropane Derivatives, Spirogermanium, Unimed, SS Pharmaceutical SS-554, StripoldinSnStySolP Oxido dismutase, Toyama T-506, Toyama T-680, Taxol, Teijin TEI-0303, Teniposide, Salivlastine, Eastman Kodak TJB-29, Tocotrienol, Topotecan, Topostin, Te82K Selected from kko UCN-01, Kyowa Hako UCN-1028, Ukrain, Eastman Kodak USB-006, Vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintryn, and vinolidine Consisting of a diverse family of anti-neoplastic agents including tubulin interactors, topoisomerase II inhibitors, topoisomerase I inhibitors and hormonal agents.

  Alternatively, the compounds of the present invention can also be acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine, sermoleukin, cetrorelix, cladribine, clotrimazole, cytarabine ocphosphate, DA3030 (Dong-A), daclizumab, denileukin diftitox, desloreloxin, dexrazoxandi , Docetaxel, docosanol, doxel calciferol, doxyfluridine, doxorubicin, Mocriptine, carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alpha, daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emiteflu, epirubicin, epoetin beta, etoposide zoline tefidomeste Fludarabine phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gemtuzumabzogamycin, combination of gimeracil / oteracil / tegafur, glycopin, goserelin, heptaplatin, human chorionic gonadotropin, human fetal alpha fetoprotein, ibandron Acid, idarubicin, (imiquimod, interferon alpha, inter -Ferron α, natural type, interferon α-2, interferon α-2a, interferon α-2b, interferon α-N1, interferon α-n3, interferon alphacon-1, interferon α, natural type, interferon β, interferon β-1a , Interferon β-1b, interferon γ, natural interferon γ-1a, interferon γ-1b, interleukin-1β, iobenguan, irinotecan, irsogladine, lanreotide, LC9018 (Yakult), leflunomide, lenograstim, lentinan sulfate, letrozole, leukocytes alpha interferon, leuprorelin, levamisole + fluorouracil, riarosol, lovaplatin, lonidamine, lovastatin, masoploco , Melalsoprol, metoclopramide, mifepristone, miltefosine, mirimostim, mismatched double-stranded RNA, mitoguazone, mitractol, mitoxantrone, morgramostim, nafarelin, naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, new erythrocytes Production-promoting protein, NSC631570 octreotide, oprelbequin, osateron, oxaliplatin, paclitaxel, pamidronic acid, pegase pargase, peginterferon α-2b, pentosan polysulfate sodium, pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, polyethylene glycol Interferon α-2a, porfimer sodium, raloxifene, ralchito Xedo, rasburicase, rhenium Re186 etidronate, RII retinamide, rituximab, romultide, samarium (153Sm) lexidronam, sargramostim, schizophyllan, sobuzoxan, sonermine, strontium chloride-89, suramin, tasonomoteportemotezotetemotemol Decaoxide, thalidomide, simulfacin, thyrotropin alpha, topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex, bladder cancer vaccine , Maruyama vaccine, melanoma lysate vaccine, valrubicin, verteporf In, vinorelbine, VIRULIZIN, dinostatin stimamarer or zoledronic acid; abarelix; AE941 (Aeterna), ambermustine, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglu Tetimide, diaziquan, EL532 (Elan), EM800 (Endorecherche), eniluracil, etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant, garocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), granule Sphere macrophage colony-stimulating factor, histamine dihydrochloride, ibritumomab tiuxetan, ilomastert, IM862 Cytran), interleukin-2, iproxyfen, LDI200 (Milkhaus), relidistim, lintuzumab, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and FcMAb (Medarex) C, idiotype C7 ), Idiotype CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone), polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogalil, mitsumomab, motexafingadolinium, MX6 (Galderma), nelabin Noratrexed, P30 protein, pegvisomant Pemetrexed, porphyromycin, purinomastert, RL0903 (Shire), rubitecan, satraplatin, sodium phenylacetate, sparphos acid, SRL172 (SR Pharma), SU5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, talbupotin, thrombopotin , Ethyl etiopurpurins, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), melanoma tumor decay product vaccine (New York Medical Collage), viral melanoma Cell lysate vaccine (Royal Newcastle Hospital), or It can be used in concurrent therapy with other antineoplastic agents such as Valspodal.

  Taxanes are a group of drugs including paclitaxel (Taxol®) and docetaxel (Taxotere®).

  Platinum-containing anticancer agents include cisplatin (Platinol®, Bristol-Myers Squibb), carboplatin (Paraplatin®, Bristol-Myers Squibb), and oxaliplatin (Eloxatin®-Sanoth), Sanoth. It is done.

  Alternatively, motesanib is combined with pemetrexed and a platinum-containing anticancer agent.

Definitions An “Asian patient” is a person whose ancestor is one who originally lived in the Far East or Southeast Asia, including, for example, Cambodia, China, Japan, Korea, Malaysia, Philippines, Thailand and Vietnam.

  A “Caucasian patient” is a person whose ancestor is one who originally lived in Europe, the Middle East, or North Africa.

  A “non-Asian patient” is an ancestor of any person who originally lived in North America, Central America, or South America, and maintains a racial affiliation or community; any of the African black racial groups Someone with ancestors: Pacific Islanders; or people with ancestry in India.

  Tyrosine kinase inhibitors are small molecule inhibitors of tyrosine kinases, including VEGFR inhibitors.

  A VEGFR inhibitor is a small molecule inhibitor of VEGFR, including motesanib and its pharmaceutically acceptable salts. Motesanib is also known as AMG 706 and N- (3,3-dimethyl-2,3-dihydro-1H-indol-6-yl) -2-((4-pyridinylmethyl) amino) -3-pyridinecarboxamide .

  The term “OS” includes overall survival.

  The term “PFS” includes progression free survival.

  The term “PR” is defined as a partial response.

  The term “CR” is defined as a complete response.

  When used in the context of the present invention, the terms “treat” or “treatment” etc. should be taken broader. These should not be taken to mean that the animals are treated until they have fully recovered. Thus, these terms include improving the symptoms or severity of a particular condition, or preventing or otherwise reducing the risk of further progression of a particular condition.

  The term “first line therapy” or “first line therapy” means that the patient has not previously received treatment for lung cancer, including chemotherapy.

  The term “comprising” is not limiting and includes the indicated components, but does not exclude other elements.

  The phrase “therapeutically effective” limits the amount of each drug that achieves the goal of improving the severity and frequency of disability in the treatment of each drug alone, while avoiding the harmful side effects normally associated with alternative therapies . For example, effective neoplastic therapeutics prolong patient survival or prevent rapidly proliferating cell proliferation associated with neoplasia or regress neoplasia.

  It should be understood that the methods of the invention may be applicable to humans.

  As used herein, the compounds of the present invention include those pharmaceutically acceptable derivatives.

  Where the plural form is used for compounds, salts, and the like, this also means a single compound, salt, and the like.

  As used herein, the terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by dysregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, sarcoma, blastoma and leukemia. More detailed examples of such cancers include squamous cell carcinoma, lung cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, thyroid cancer and head and neck cancer.

  By lung cancer is meant non-small cell lung cancer, including non-squamous non-small cell lung cancer and adenocarcinoma.

  The term “pharmaceutically acceptable salts” includes salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic or organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Suitable organic acids can be selected from the classes of aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic acids of organic acids, examples of which include formic acid, acetic acid, Adipic acid, butyric acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, Anthranilic acid, mesylic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, benzenesulfonic acid, pantothenic acid, 2-hydroxyethanesulfonic acid , Toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, camphoric acid Camphorsulfonic acid, digluconic acid, cyclopentanepropionic acid, dodecylsulfonic acid, glucoheptanoic acid, glycerophosphoric acid, heptanoic acid, hexanoic acid, 2-hydroxy-ethanesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, palmo Acid (palmoic acid), pectinic acid, persulfuric acid, 2-phenylpropionic acid, picric acid, pivalic acid, propionic acid, succinic acid, tartaric acid, thiocyanic acid, mesylic acid, undecanoic acid, stearic acid, argenic acid , Β-hydroxybutyric acid, salicylic acid, galactaric acid and galacturonic acid. Suitable pharmaceutically acceptable base addition salts include metal salts such as those made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or primary, secondary and tertiary amines, cyclic Organics including substituted amines including amines such as caffeine, arginine, diethylamine, N-ethylpiperidine, aisitidine, glucamine, isopropylamine, lysine, morpholine, N-ethylmorpholine, piperazine, piperidine, triethylamine, trimethylamine And salts made from bases. All of these salts can be prepared from the corresponding compound of the present invention by conventional means, for example by reacting the appropriate acid or base with the compound of the present invention. When basic and acidic groups are present in the same molecule, the compounds of the present invention can also form inner salts.

Formulations One or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants (collectively referred to herein as “carrier” materials), as well as other A class of pharmaceutical compositions comprising an active VEGFR inhibitor together with the active ingredient is also encompassed within the present invention. The active compounds of the invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition compatible with such a route, and in a dose effective for the intended treatment. The compounds and compositions of the invention can be formulated, for example, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles, orally, mucosally, topically, rectally, pulmonarily ( For example, by inhalation spray.) Or can be administered parenterally including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, intrasternal and infusion methods.

  The pharmaceutically active compounds of the present invention can be processed according to conventional methods of pharmacy to produce medicaments for administration to patients, including humans and other mammals.

  For oral administration, the pharmaceutical composition can be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a specific amount of the active ingredient. An example of such a dosage unit is a tablet or capsule. For example, they can contain the active ingredient in an amount of about 1 to 2000 mg, preferably about 1 to 500 mg. Suitable daily doses for humans or other mammals can vary widely depending on the condition of the patient and other factors, but again can be determined using routine methods. For example, a dosage of about 10 mg to about 150 mg, or about 25 to about 125 mg can be used. The therapeutically effective amount of the VEGFR inhibitor in the composition can be selected to be about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg. A therapeutically effective amount of a VEGFR inhibitor in the composition is a dosage of about 50 mg twice a day, or a dosage of about 75 mg twice a day, or a dosage of about 100 mg twice a day, or about 100 mg once a day. Dosage, or a dosage of about 125 mg once a day can be selected.

  The amount of compound to be administered, as well as the dosing regimen for treating a condition with the compounds and / or compositions of the present invention, includes the age, weight, sex and medical condition of the subject, the type of illness, the severity of the disease, It depends on a variety of factors including the route and frequency, and the particular compound used. Thus, dosage regimens can vary widely, but can be determined routinely using standard methods. A daily dose of between about 0.01 and 500 mg / kg, preferably between about 0.01 and about 50 mg / kg, more preferably between about 0.01 and about 30 mg / kg body weight may be appropriate. The daily dose is administered in 1 to 4 doses per day.

  For therapeutic purposes, the active compounds of the invention are usually combined with one or more adjuvants appropriate to the indicated route of administration. When administered orally, the compound comprises lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, It can be mixed with gum arabic, sodium alginate, polyvinyl pyrrolidone and / or polyvinyl alcohol and then into tablets or capsules for convenient administration. Such capsules or tablets can contain a controlled release formulation as can be given in dispersion of the active compound in hydroxypropylmethylcellulose.

  Formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions use one or more of the carriers or diluents described above for use in formulations for oral administration, or use other suitable dispersing or wetting agents and suspending agents. Can be prepared from sterile powders or granules. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum and / or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient can also be a composition with a suitable carrier including saline, dextrose or water, or a cyclodextrin (ie Captisol), a cosolvent solubilizer (ie polypyrene glycol) or a micelle solubilizer. (Ie, Tween 80) can also be administered by injection as a composition.

  The invention will now be further described with reference to the following non-limiting examples.

Example 1-NSCLC
Eligible patients (18 years of age and older) have advanced non-squamous NSCLC (unresectable stage IIIB with malignant exudate, or stage IV), 1 or less Eastern Cooperative Oncology Group (ECOG) performance status, REIST guidelines (Response) Diseases measurable according to Evaluation Criteria in Solid Tumors (RECIST)), and a life expectancy of more than 3 months were confirmed histologically or cytologically. Patients have a history of central nervous system metastases; pulmonary hemorrhage or hemoptysis; hemorrhagic predisposition or non-pulmonary hemorrhage within 6 months of randomization; uncontrolled hypertension (> 150/90 mmHg); Liver, blood or kidney dysfunction; within 52 weeks of randomization, experience with chemotherapy or advanced chemotherapy for advanced NSCLC; experience with targeted therapy; anticoagulation within 7 days of randomization; local Experience of chemoradiotherapy for stage III that has progressed progressively; central radiation therapy within 28 days of randomization; or other radiation therapy within 14 days of randomization Patients were excluded. The study method was approved by each ethics committee at each location. All patients submitted written consent. This was an international, multicenter, open-label, randomized phase 3 study conducted at over 200 institutions.

Did this study improve overall survival (OS) compared to placebo and carboplatin / paclitaxel in patients with advanced non-squamous non-NSCLC and a subset of patients with adenocarcinoma, with motesanib plus carboplatin / paclitaxel I evaluated it. The patient suffered from stage IIIB / IV or recurrent non-squamous NSCLC and had never received systemic therapy for advanced NSCLC. This study initially enrolled all histology but modified it to exclude patients with squamous NSCLC because of the high rate of hemoptysis. Patients were randomized 1: 1 and with carboplatin (AUC 6 mg / mL / min) and paclitaxel (200 mg / m ² ), motesanib 125 mg (once a day) (Arm A) or placebo (once a day) (Arm B ) Was given orally continuously in a 3 week cycle up to 6 times. The primary endpoint was OS, and secondary endpoints included progression-free survival (PFS), adverse events (AE), and associations between placental growth factor (PLGF) changes and OS . OS was assessed using a stratified Cox model and a two-sided log rank test (α = 0.03 for patients with non-squamous epithelium, α = 0.02 for a subset of adenocarcinoma). The demographic and baseline characteristics were balanced between the two groups (Table 1). 1090 patients with advanced non-squamous NSCLC were randomized (Arm A n = 541; Arm B n = 549); 890 patients had adenocarcinoma (n = 448/442). 61% were male, the median age was 60 years (range 21-87 years) and 83% had stage IV disease.

  At the time of analysis, 753 patients died (608 patients have adenocarcinoma). The median follow-up period was 10.6 months. OS and PFS did not significantly improve in motesanib Arm A compared to placebo Arm B (Table 2). In Arm A / B, the incidence of grade 3 or higher was 73/59%. Grade 3 or higher AEs that occur more frequently in Arm A than Arm B include neutropenia (22% vs 15%), diarrhea (9% vs 1%), hypertension (7% vs 1%) and Cholecystitis (3% vs. 0%) was mentioned. The incidence of grade 5AE was 14% / 9% in Arm A / B.

  Response was not significantly improved with motesanib Arm A compared to placebo Arm B (Table 3).

  A Kaplan-Meier plot generated by the proportion of patients surviving treatment with motesanib and the base days of survival indicates that overall survival is extended. [FIG. 1]. Cox proportional hazard-P = 0.137; hazard ratio = 0.897; (95% CI: 0.776, 1.035).

  A Kaplan-Meier plot generated by the proportion of patients surviving treatment with motesanib and progression-free survival days shows that progression-free survival has been extended. [FIG. 2] Cox proportional hazard-P = 0.006; hazard ratio = 0.785; (95% CI: 0.684, 0.901).

  In patients with advanced non-squamous NSCLC, treatment with motesanib and carboplatin / paclitaxel did not significantly improve OS compared to carboplatin / paclitaxel alone.

Example 2—Efficacy Results and Baseline Distribution for Asian Subgroup The Asian subgroup (N = 219) included patients from Japan, Korea, Singapore, Philippines, Taiwan and China (Hong Kong). Japan provided 107 patients and Korea had 63 patients. The demographic and baseline characteristics were balanced between the two groups (Table 4).

  At the time of analysis, 132 Asian patients died. OS, PFS and response were significantly improved in motesanib Arm A compared to placebo Arm B (Table 5-7).

  A Kaplan-Meier plot generated by the proportion of patients surviving treatment with motesanib and the base days of survival indicates that overall survival is extended. [FIG. 3]. The median was 20.9 months vs 15.5 months (for placebo). Cox proportional hazard-P = 0.017; hazard ratio = 0.657; (95% CI: 0.465, 0.929).

  A Kaplan-Meier plot generated by the proportion of patients surviving treatment with motesanib and progression-free survival days shows that progression-free survival has been extended. [FIG. 4] The median was 7 months versus 4.5 months. Cox proportional hazard-P = 0.0003; hazard ratio = 0.58; (95% CI: 0.430, 0.782).

  In a subset of Asian patients with advanced non-squamous NSCLC, treatment with motesanib and carboplatin / paclitaxel significantly improved OS, PFS, and response compared to carboplatin / paclitaxel alone.

[Example 3] -Efficacy results and baseline distribution for non-Asian subgroups Non-Asian subgroups (N = 871) are ethnic groups from Japan, Korea, Singapore, Philippines, Taiwan and China (Hong Kong). Includes patients who do not have it. At the time of analysis, 621 non-Asian patients died. OS, PFS and response were improved in motesanib Arm A compared to placebo Arm B (Table 8-10).

  A Kaplan-Meier plot generated by the proportion of patients surviving treatment with motesanib and the base days of survival indicates that overall survival is extended. [FIG. 5] For placebo, the median was 10.9 months vs. 10.7 months. Cox proportional hazard-P = 0.774; hazard ratio = 0.977; (95% CI: 0.835, 1.144).

  A Kaplan-Meier plot generated by the proportion of patients surviving treatment with motesanib and progression-free survival days shows that progression-free survival has been extended. [FIG. 6] The median was 5.5 months vs. 5.4 months. Cox proportional hazard-P = 0.03; hazard ratio = 0.847; (95% CI: 0.727, 0.987).

  In non-Asian patients with advanced non-squamous NSCLC, treatment with motesanib and carboplatin / paclitaxel did not significantly improve OS, PFS or response compared to carboplatin / paclitaxel alone.

Example 4-Correction of clinical data While reviewing the initial clinical data later, it was discovered that 8 patients were misclassified. All analyzes were redone and the correct results are shown below and in FIGS. 7-10.

  Patient ethnicity was based on clinical location. Other countries (eg, the United States) may have Asian patients, but they are not captured in this analysis.

  An unexpected finding is that Asian patients (as defined herein) responded better to treatment with motesanib than non-Asian patients. This study confirms ethnic differences in the effects of motesanib on overall survival of cancer patients. Clear evidence of ethnic differences was not seen with carboplatin / paclitaxel treatment.

  The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes apparent to those skilled in the art are intended to be within the scope and nature of the invention as defined by the appended claims.

  From the foregoing description, those skilled in the art can readily ascertain the essential features of the present invention and to adapt the features to various uses and conditions without departing from the spirit and scope of the present invention. Various changes and modifications can be made.

  The references, patents, patent applications and publications mentioned above are hereby incorporated by reference in their entirety as if they had been written herein.

Claims (19)

  Beyond the overall survival observed with taxanes and platinum-containing anticancer drugs alone, including treating Asian patients with a combination of motesanib, taxane, and platinum-containing anticancer drugs, for non-squamous non-small cell lung cancer in Asian patients Use of motesanib in the manufacture of a drug to effectively prolong the associated overall survival.   Use according to claim 1, wherein the medicament extends overall survival compared to treatment with paclitaxel and carboplatin.   Use according to claim 1, wherein the non-squamous non-small cell lung cancer is progressive.   Use according to claim 1, wherein the non-squamous non-small cell lung cancer is stage IIIB, stage IV or recurrent.   Non-squamous non-small cell lung cancer in Asian patients beyond progression-free survival observed with taxanes and platinum-containing anticancer agents alone, including treating Asian patients with a combination of motesanib, taxane, and platinum-containing anticancer agents Use of motesanib in the manufacture of a drug to effectively prolong progression-free survival related to   6. Use according to claim 5, wherein the medicament prolongs progression-free survival compared to treatment with paclitaxel and carboplatin.   Use of motesanib in the manufacture of a medicament for effectively improving overall survival associated with non-squamous non-small cell lung cancer in Asian patients, including treating Asian patients with motesanib, taxanes, and platinum-containing anticancer agents .   The use according to claim 1, wherein motesanib is administered in combination with one or more chemotherapeutic agents, and the chemotherapeutic agent is not panitumumab.   The use according to claim 1, wherein the taxane is paclitaxel and the platinum-containing anticancer agent is carboplatin. Paclitaxel is administered at 200 mg / ^{m 2,} use according to claim 9.   10. Use according to claim 9, wherein carboplatin is administered at AUC 6 mg / mL / min.   The use according to claim 1, 5 or 7, wherein the non-squamous non-small cell lung cancer is an adenocarcinoma.   8. Use according to claim 1, 5 or 7, wherein the treatment is a first line treatment.   8. Use according to claim 1, 5 or 7, wherein motesanib is administered in a daily dose of 100 mg or 125 mg.   8. Use according to claim 1, 5 or 7, wherein motesanib is administered in a daily dose of 125 mg.   The use according to claim 1, 5 or 7, wherein the Asian patient is a patient of Japanese, Korean, Taiwan, Chinese, Hong Kong, Filipino or Singaporean ethnicity.   The use according to claim 1, 5 or 7, wherein the Asian patient is a patient of Korean, Taiwan, Chinese, Hong Kong, Filipino or Singaporean ethnicity.   The use according to claim 1, 5 or 7, wherein the Asian patient is Japanese.   Use of motesanib in the manufacture of a medicament for first line treatment of non-squamous non-small cell lung cancer in a patient, wherein the patient is not non-Asian.

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