Annals of Oncology 29 (Supplement 9): ix23–ix27, 2018 doi:10.1093/annonc/mdy430 DEVELOPMENTAL THERAPEUTICS 69O Larotrectinib efficacy and safety in TRK fusion cancer: An expanded clinical dataset showing consistency in an age and tumor agnostic approach D.S.W. Tan1, U.N. Lassen2, C.M. Albert3, S. Kummar4, C. van Tilburg5, S.G. Dubois6, B. Geoerger7, L. Mascarenhas8, N. Federman9, A. Basu-Mallick10, F. Doz11, J.D. Berlin12, D-Y. Oh13, S. Bielack14, R. McDermott15, S. Cruickshank16, N.C. Ku17, M.C. Cox17, A. Drilon18, D.S. Hong19 1 Division of Medical Oncology, National Cancer Center, Singapore, 2Finsen Center, Dept. of Oncology, Phase 1 Unit, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark, 3Department of Hematology-Oncology, Seattle Children’s Hospital, University of Washington, Seattle, WA, USA, 4Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA, 5Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg University Hospital and German Cancer Research Center (DKFZ), Heidelberg, Germany, 6Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, 7Department of Pediatric and Adolescent Oncology, Institut Gustave Roussy, Villejuif, France, 8Division of Hematology, Oncology, and Blood and Marrow Transplantation, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA, 9Pediatric Bone and Soft Tissue Sarcoma Program, University of California, Los Angeles, Los Angeles, CA, USA, 10Gynecologic Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA, 11SIREDO Oncology Centre, Institut Curie, Paris, France, 12Medicine, Vanderbilt Ingram Cancer Center, Nashville, TN, USA, 13Medical Oncology, Seoul National University Hospital, Seoul, Republic of Korea, 14Zentrum für Kinder-, Jugend- und Frauenmedizin P€adiatrie 5 (Onkologie, H€ amatologie, Immunologie), Klinikum Stuttgart – Olgahospital, Stuttgart, Germany, 15Department of Medical Oncology, St Vincent’s 16 University Hospital, Dublin, Ireland, Statistics, Loxo Oncology, Inc, South San Francisco, CA, USA, 17Clinical Development, Loxo Oncology, Inc, South San Francisco, CA, USA, 18Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, 19Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Background: TRK fusion cancer results from gene fusions involving NTRK1, NTRK2 or NTRK3. Larotrectinib, the first selective TRK inhibitor, has demonstrated an overall response rate (ORR) of 75% with a favorable safety profile in the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancer (Drilon et al., NEJM 2018). Here, we report the clinical activity of larotrectinib in an additional 35 TRK fusion patients and provide updated follow-up of the primary analysis set (PAS) of 55 patients as of 19th Feb 2018. Methods: Patients with TRK fusion cancer detected by molecular profiling from 3 larotrectinib clinical trials (NCT02122913, NCT02637687, and NCT02576431) were eligible. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed using RECIST version 1.1. Results: As of Feb 2018, by independent review, 6 PRs in the PAS deepened to CRs. The median DoR and progression-free survival in the PAS had still not been reached, with 12.9 months median follow-up. At 1 year, 69% of responses were ongoing, 58% of patients remained progression-free and 90% of patients were alive. An additional 19 children and 25 adults (age range, 0.1-78 years) with TRK fusion cancer were enrolled after the PAS, and included cancers of the salivary gland, thyroid, lung, colon, melanoma, sarcoma, GIST and congenital mesoblastic nephroma. In 35 evaluable patients, the ORR by investigator assessment was 74% (5 CR, 21 PR, 6 SD, 2 PD, 1 not determined). In these patients, with median follow-up of 5.5 months, median DoR had not yet been reached, and 88% of responses were ongoing at 6 months, consistent with the PAS. Adverse events (AEs) were predominantly grade 1, with dizziness, increased AST/ ALT, fatigue, nausea and constipation the most common AEs reported in  10% of patients. No AE of grade 3 or 4 related to larotrectinib occurred in more than 5% of patients. Conclusions: TRK fusion cancer is detected in a broad range of tumor types. Larotrectinib is an effective tumor-agnostic treatment for TRK fusion cancer with a favorable safety profile. Screening patients for NTRK gene fusions in solid tumors should be actively considered. Clinical trial identification: NCT02122913; NCT02637687; NCT02576431. Legal entity responsible for the study: Loxo Oncology Inc and Bayer AG. Funding: Loxo Oncology Inc; Bayer AG. Disclosure: S. Cruickshank, N.C. Ku, M.C. Cox: Employment: Loxo Oncology Inc. All other authors have declared no conflicts of interest. 70O Relationships between lenvatinib plasma concentration and toxicity in Japanese cancer patients R.A. Makihara1, S.N. Narita2, N. Yamamoto2, J. Sato3, S. Murakami4, Y. Goto2, S. Kanda2, Y. Fujiwara3, H. Horinouchi2, T. Tsukamoto5, H. Hashimoto1, Y. Makino1, Y. Ohe2, M. Yamaguchi1 1 Pharmacy, National Cancer Center Hospital, Tokyo, Japan, 2Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan, 3Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan, 4Thoracic Oncology, National Cancer Center Research Institiute, Tokyo, Japan, 5Grobal Apprication Center, Shimadzu Corporation, Kyoto, Japan Background: Lenvatinib is an oral, multi-targeting inhibitor for VEGFR, FGFR, PDGFR, KIT and RET. This agent has been approved for thyroid cancer with a recommended dosage of 24-mg QD and for hepato-cellular carcinoma with 8 or 12-mg QD. Although lenvatinib has substantial anti-tumor activity for thyroid cancer as well as other solid tumors including colorectal cancer and non-small cell lung cancer, dose modification is frequently required due to proteinuria, decreased weight, anorexia, hand-foot syndrome and some other gastro-intestinal toxicities. Dose individualization with close plasma concentration monitoring could contribute to address these issues in routine clinical practice. Methods: Patients, who received lenvatinib as practical treatment setting, were enrolled in our prospective pharmacokinetic individualized study. Plasma trough concentration as well as dried plasma spot (DPS) samples were obtained from all enrolled patients. Lenvatinib plasma concentrations were measured by in-house LC/MS/MS, and investigated with the correlation with toxicities by lenvatinib. The study protocol was approved by our institutional review board and informed consent was obtained from all patients. Results: From Jun 2017 to Jun 2018, 17 patients (13 thymic cancer, 1 thyroid cancer and 3 lung cancer with RET-fusion) were enrolled. At a dosage of 24-mg QD, the geometric mean plasma lenvatinib trough concentrations at steady state was averaged at 65.1 (range 39.3-105.4) ng/mL. All enrolled patients had required a dose reduction due to AEs, and final lenvatinib doses with acceptable tolerability were 20 mg in 3, 14 mg in 5, 10 mg in 4, 8 mg in 3, and 4 mg in 2 patients, respectively. The geometric mean plasma lenvatinib trough concentrations with final dosage was 52.6 (range 25.8-107.4) ng/mL. All DPS samples showed comparable concentrations to plasma samples. Conclusions: The plasma lenvatinib trough concentration with final dosage adjusted by AEs was < 60 ng/mL. Therapeutic drug monitoring of lenvatinib could minimize unacceptable AEs and contribute individualized dosing. Also, we firstly confirmed the feasibility of lenvatinib DPS assay with high compatibility with plasma concentrations. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: N. Yamamoto, Y. Fujiwara: Eisai Co., Ltd. All other authors have declared no conflicts of interest. 71O Phase I extension study of ETC-159 an oral PORCN inhibitor administered with bone protective treatment, in patients with advanced solid tumours D. Tan1, M. Ng2, V. Subbiah3, W. Messersmith4, V. Teneggi5, V. Diermayr5, K. Ethirajulu5, P. Yeo5, B.H. Gan5, L.H. Lee5, S. Blanchard5, R. Nellore5, M. Yasin5, D. Umrani5, M.A. Lee6, J. Hill6, B. Madan7, D. Virshup7, A. Matter6 1 Haematology - Oncology, National University Cancer Institute Singapore (NCIS), Singapore, 2Medical Oncology, National Cancer Center Singapore, Singapore, 3 Investigational Cancer Therapeutics (Phase 1 Program), MD Anderson Cancer Center, Huston, TX, USA, 4Cancer Center, University of Colorado, Denver, CO, USA, 5D3 (Drug Development and Discovery), A*STAR, Singapore, 6Experimental Therapeutics Centre, A*STAR, Singapore, 7Medical School, Duke-National University of Singapore (NUS), Singapore Background: Aberrant Wnt pathway signalling is seen in several cancers. ETC-159 is a selective small molecule inhibitor of porcupine. During dose escalation in patients (pts) with advanced solid tumours, the maximum tolerated dose (MTD) of ETC-159 was 30 mg every other day (qod) with dose-limiting toxicities (DLTs) of compression fractures and hyperbilirubinaemia, and toxicity of concern of elevated serum b-CTX (ASCO 2017, Abstract #2584). We report the interim results of ETC-159 dose escalation with prophylactic denosumab and biomarker analyses. Methods: Open-label, multi-centre study to assess safety, MTD, pharmacokinetics (PK) and pharmacodynamics (PD) of ETC-159 given orally, qod at the dose of 16 and 24 mg, with denosumab s.c. once every 28d during the first 2 cycles. Bone turnover was assessed in C European Society for Medical Oncology 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. V All rights reserved. For permissions, please email: journals.permissions@oup.com. abstracts serum and via radiology. PD was tested using Axin2 mRNA levels in hair follicles (HFs). Immune markers were analysed in pre- and post-dose biopsies. Dose escalation and DLT incidence assessment were assisted by a Bayesian approach, with a DLT period of 28d. Results: As of April 2018, 5 pts were treated at 16 mg and 3 at 24 mg. 50% were female, median age (range) 55.5 yr (47-71). There was one DLT (grade 2 dysgeusia). Adverse events (>20%) were: dysgeusia (62%), fatigue (37%), weight loss (37%), back pain (37%), headache (37%), vomiting (25%), nausea (25%) and abdominal pain (25%). At the dose of 16 mg ETC-159 showed inter-patient PK variability, with a mean t 1=2 of 15h (d1) and 37h (d15). Serum b-CTX reduction from pre-dose was seen in 6/8 pts. In 1 pt serum b-CTX increased to > 1000 pg/mL (with reduction of bone mineral density) and reduced after ETC-159 discontinuation; in 1 pt b-CTX was not assessed due to early discontinuation. 4 pts withdrew for progressive disease,1 pt for DLT, 1pt for consent withdrawal and 2 pts are ongoing. Decreased Axin2 mRNA was seen in HFs and a 2-fold increase of the ratio of tumour infiltrating CD8þ/FOXP3þ T-cells was seen in the tumour. Conclusions: ETC-159 with prophylactic denosumab is safe; there are no compression fractures and b-CTX decreases in most pts. ETC-159 has PD activity and increases immune infiltration. ETC-159 dosing is ongoing at 24 mg. Clinical trial identification: NCT02521844. Legal entity responsible for the study: A*STAR, D3 (Drug Discovery and Development), Singapore. Funding: A*STAR, D3 (Drug Discovery and Development), Singapore. Disclosure: V. Teneggi, V. Diermayr, K. Ethirajulu, P. Yeo, B.H. Gan, L.H. Lee, S. Blanchard, R. Nellore, M. Yasin, A. Matter, D. Umrani: Employment: D3, sponsor of the study. All other authors have declared no conflicts of interest. 72O Addition of durvalumab (Dur) upon progression to bevacizumab (Bev) maintenance in advanced HER2-negative (HERNEG) breast cancer (BC): Safety, efficacy and biomarkers M. Quintela-Fandino1, L.M. Manso Sanchez2, E. Holgado Martın3, M.C. Moreno4, S. Morales Murillo5, B. Bermejo De Las Heras6, D. Malon Gimenez7, R. Colomer Bosch8, noz1, S. Escudero4, R. Blanco4, L. Gonzalez Cortijo9, J. Hornedo9, S. Mouron1, M. Mu~ S. Ma~ nes4 1 Spanish National Cancer Research Centre, CNIO (Breast Cancer CR Unit), Spanish National Cancer Research Center, Madrid, Spain, 2Oncology, University Hospital 12 De Octubre, Madrid, Spain, 3Oncology, Hospital Ramon y Cajal, Madrid, Spain, 4Signaling Networks in Inflammation and Cancer, CNB, Madrid, Spain, 5Medical Oncology, Arnau de Vilanova, Lleida, Spain, 6Meical Oncology, Hospital Clinico Universitario de Valencia, Valencia, Spain, 7Medical Oncology, Hospital de Fuenlabrada, Fuenlabrada, Spain, 8 Medical Oncology, Hospital Universitario de La Princesa, Madrid, Spain, 9Medical Oncology, Hospital Quiron, Pozuelo De Alarc on, Spain Background: As opposed to other malignancies, immunotherapy has yielded limited efficacy in BC. We have found in animal models of HERNEG BC that chronic hypoxia secondary to prolonged Bev was associated to anti-tumor immune suppression and tumor PD-L1 upregulation. These events rendered HERNEG BC animal models sensitive to PD-L1 blockade in combination with Bev. We sought to explore this concept in the clinics in a pilot phase IB trial in HERNEG BC patients with disease progression (PD) on Bev maintenance by adding the anti-PD-L1 antibody Dur. Methods: HER2NEG metastatic patients with PD to Bev maintenance for a minimum of six weeks after first-line taxaneþBev were enrolled. Dur (10 mg/kg q14d) was added to maintenance Bev (10 mg/kg q14d). Patients were evaluated every 56 days (iRECIST). Before the first Dur dose and every 4 weeks until PD, peripheral-blood mononuclear cells (PBMCs) were phenotyped in order to monitor 24 lymphoid and non-neutrophil myeloid subpopulations. The primary endpoint was PFS time. Secondary endpoints were toxicity assessed with NCI CTC AE V. 4.03 and relative changes (%) in PBMCs subpopulations. Results: 24 patients were accrued. Median age was 56 and 12 (50%) patients were triple-negative. Median (range) Bev exposure during maintenance before entering trial was 11 (6-22) months. Grade 3 toxicity included pneumonitis (1 patient) and hypertension (2 patients), related to Dur and Bev respectively. Grade 1/ 2 toxicity was observed in 18 (66%) patients. Median PFS was 76 days; 8 patients (33%) are still in the trial. Four patients have not experienced PD yet after 100þ days. Best response was SD (9 patients, 38%). Sixty-two per cent of the patients reached the first evaluation with SD; all of them had a 1.2- to 3.5-fold increase in CD8 effector memory T-cells (CD8EM) in PBMCs after the first Dur dose. All but one patient that experienced PD in the first evaluation had no change or a decrease up to 3.2-fold in CD8EM in PBMCs. Conclusions: Bev maintenance could expand the therapeutic niche of immunotherapy in HERNEG BC, evidenced by the efficacy of Dur in this context at low toxicity cost in this phase 1B study. Patients experiencing benefit showed detectable changes in CD8EM in PBMCs. Clinical trial identification: NCT02802098. Legal entity responsible for the study: Fundacion CRIS Contra el Cancer. Funding: AstraZeneca. Disclosure: M. Quintela-Fandino: Research funds: AstraZeneca. All other authors have declared no conflicts of interest. ix24 | Developmental therapeutics Annals of Oncology 73P Ganoderic acids BT-01, a galectin-1 inhibitor, suppresses ovarian cancer growth in humanized mouse xenograft model C-P. Huang1, S-Y. Chen1, H-H. Lai1, Y-H. Lin1, C-T. Su1, S-J. Wu1, C-H. Chang1, C-C. Tsao1, Y-C. Chen1, S-C. Wang1, Y-H. Liu1, S-B. Lin2, T-H. Chen1 1 Biomedical Institute, Trineo Biotechnology Co., LTD, New Taipei, Taiwan, 2Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan Background: Ovarian cancer is the leading cause of death from gynaecological malignancies. Galectin-1 has been implicated in cancer progression and metastasis, and associated with poor prognosis in ovarian cancer. It is evidence that galectin-1 participates in tumor progression by evoking T cell anergy and contribute to cancer-immune escape. Ganoderma lucidum has been reported to exhibit anticancer properties. BT-01, a ganoderic acid composition, was purified from Ganoderma lucidum consisting of ganoderic acids P, Q, T, S, R, Me and ganodermic acid S. In this study, the potential role of BT-01 on inhibition of galectin-1 expression and tumor growth in ovarian was investigated. Methods: In vitro experiments were conducted to elucidate the effectiveness of BT-01 on galectin-1 expression, and in vivo studies were to evaluate the tumor growth and immune responses. The galectin-1 expression of ovarian cancer cells ES-2 treated with BT-01 was examined by real-time PCR and western blot. Peripheral blood mononuclear cells (PBMCs) isolated from healthy donors were injected intraperitoneally into mice to establish the humanized advanced immunodeficiency mice model (Hu-PBMCs-mice). Measurement of tumor volume was determined by CT imaging, expression levels of galectin-1 and T cell infiltration in tumor tissue were examined by immunohistochemical analysis. Results: A significant cytotoxic effect of BT-01 on ES-2 and its inhibition role on galectin-1 expression were detected in vitro. The tumor volume was decreased after treating with BT-01 in the immunodeficient mice, indicating the inhibition ability of BT-01 on tumor growth even with a defective immune system. Additionally, the tumor inhibition rate was increased in Hu-PBMCs-mice with BT-01 administration in comparison with non-humanized mice. Our findings suggested the tumor suppression effect of BT-01 which significantly decreased the expression level of galectin-1and enhanced T cell infiltration of tumor tissue in Hu-PBMCs-mice. Conclusions: The study showed that BT-01, a potential galectin-1 inhibitors, suppressed the tumor growth and induced immune response to trigger synergistic effects for anti-cancer. Legal entity responsible for the study: k Trineo Biotechnology Co., LTD. Funding: k Trineo Biotechnology Co., LTD. Disclosure: All authors have declared no conflicts of interest. 77P SMA-tDodSNO improves the potency of doxorubicin in breast cancer evidence for the involvement of oxidative stress H. Alimoradi1, A. Barzegarfallah1, K.F. Giresh2 Pharmacology and Toxicology, School of Medical Sciences; University of Otago, Dunedin, New Zealand, 2Aljawhara Center for Molecular Medicine, Arabian Gulf University, Bahrain 1 Background: When nitric oxide (NO) donor drugs combine with doxorubicin they potentiate doxorubicin, anticancer effects. However, limited NO payloads, too rapid NO release, and the lack of organ or tissue specificity have limited the clinical utility of currently available NO donors. Hence, there is a great need to design tuneable NO donors which can enhance the efficacy of currently available chemotherapeutic drugs such as doxorubicin. Methods: A highly stable NO-releasing compound was synthesized by nitrosation of hydrophobic and sterically hindered thiol to form tert-dodecane S-nitrosothiol (tDodSNO). It was then encapsulated in a polymer (SMA) to make stable and hydrophilic NO-releasing NPs (SMA-tDodSNO). The dose (1-100 lM) dependent cytotoxicity of SMA-tDodSNO alone or combined with doxorubicin on 4T1 (mouse breast cancer) cells were assessed by MTT and cell cycle analysis. In addition, the effect of SMA-tDodSNO and Dox were evaluated on mitochondrial oxidative stress, mitochondrial membrane potential, intracellular calcium level, and ERK1/2 activity. Results: Incubation of 4T1 cells with SMA-tDodSNO at lM concentrations showed a concentration-dependent decrease in cell survival. When the NPs were combined with doxorubicin they significantly (p<0.001) increased the doxorubicin cytotoxicity. In addition, the combination significantly enhanced mitochondrial oxidative stress and mitochondrial membrane permeabilization when compared to only doxorubicintreated cells. Evaluation of intracellular calcium level via calcium sensitive fluorophore (Indo-1) demonstrated that the SMA-tDodSNO caused a boost in the cytosolic calcium level and over-activation of ERK1/2 pathway and apoptosis. Conclusions: We designed a novel NO-releasing nanoparticle, SMA-tDodSNO, which showed controlled NO release and significant cytotoxicity in 4T1 cells. When combined with doxorubicin it increased the anticancer potency of doxorubicin via enhanced mitochondrial oxidative stress and elevation of cytosolic calcium level. Legal entity responsible for the study: University of Otago. Funding: University of Otago. Disclosure: All authors have declared no conflicts of interest. Volume 29 | Supplement 9 | November 2018