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Background: Preliminary data from the TATTON study (NCT02143466) suggested that savolitinib (AZD6094, HMPL-504, volitinib), a potent and highly selective MET-tyrosine kinase inhibitor (TKI), plus osimertinib, a third-generation, irreversible EGFR-TKI which selectively inhibits both EGFR-TKI sensitising and T790M resistance mutations, may overcome MET-driven resistance to EGFR-TKIs in non-small cell lung cancer. Methods: Patients were ≥18 years with locally advanced/metastatic, METpositive, EGFR mutation-positive non-small cell lung cancer, whose disease had progressed on a prior EGFR-TKI. In Part B, patients received osimertinib 80 mg plus savolitinib 600 mg orally once daily; after a protocol amendment, some patients received savolitinib at 300 mg through weight-based dosing. In Part D, patients had received no prior thirdgeneration EGFR-TKI and were EGFR T790M-negative, and received osimertinib plus savolitinib 300 mg, regardless of weight. Primary endpoints were safety and tolerability; secondary endpoints included objective response rate. Findings: In Part B, 138 patients received osimertinib plus savolitinib 600/300 mg. In Part D, 42 patients received osimertinib plus savolitinib 300 mg. In Parts B and D, 57% and 38% of patients experienced ≥Grade 3 adverse events (AEs), respectively. More patients in Part B had AEs possibly causally related to savolitinib (83% vs 60%), and serious AEs (45% vs 26%) vs Part D. Overall objective response rate (95% CI) was 48% (39-56) in Part B (30% [20-43] for patients with prior third-generation EGFR-TKI; 65% [50-78] and 67% [41-87] for patients with no prior thirdgeneration EGFR-TKI who were T790M-negative and T790M-positive, respectively). Objective response rate was 64% (46-79) in the T790Mnegative patients in Part D. Interpretation: This combination may address the unmet need for a targeted treatment option for patients with MET-driven resistance to EGFR-TKI treatment. Trial Registration: NCT02143466. Funding Statement: TATTON (NCT02143466) was funded by AstraZeneca, Cambridge, UK, manufacturers of savolitinib and osimertinib. Declaration of Interests: LVS has received research funding from AstraZeneca, Boehringer Ingelheim, Blueprint Medicines, Genentech, LOXO, Merrimack Pharmaceuticals, and Novartis; and received personal fees from AstraZeneca, Blueprint Medicines, Genentech, Janssen, and Merrimack Pharmceuticals. In addition, Dr. Sequist has a patent on treating EGFR-mutant cancer with osimertinib and BLU-667 pending. J-YH has received honoraria from MSD Oncology, Roche, AstraZeneca, and Takeda; received fees for consulting or advisory roles from Novartis, MSD Oncology, AstraZeneca, Lilly, and Takeda; and received research funding from Roche, Pfizer, and Ono Pharmaceutical. M-JA has received honoraria from AstraZeneca, Bristol-Myers Squibb, MSD, Ono Pharmaceutical, and Roche; and received fees for consulting or advisory roles for AstraZeneca, Bristol-Myers Squibb, Takeda, MSD, Ono Pharmaceutical, Roche, and Alpha Pharmaceutical. BCC has received research funding from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, and MSD; has received fees for consultancy from Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BristolMyers Squibb, Ono Pharmaceutical, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, and MSD; and has stock ownership in TheraCanVac Inc, Gencurix Inc, and Bridgebio Therapeutics. In addition, Dr. Cho has a patent with Champions Oncology with royalties paid. HY has received fees for consultancy from AstraZeneca; and received research funding from AstraZeneca, Lilly, Pfizer, Daiichi, Novartis, and Astellas. S-WK has recieved research funding and fees for consulting or advisory roles from AstraZeneca. JC-HY has received honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, MSD, Pfizer, Novartis, Bristol-Myers Squibb, and Ono Pharmaceuticals; and received honoraria for advisory boards from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, Bristol-Myers Squibb, Ono Pharmaceuticals, Daiichi Sankyo, Hansoh, Takeda, and Blueprint. JSL, W-CS, DK, and SO declare no competing interests. MC is an AstraZeneca contract employee and shareholder. RBV is an AstraZeneca employee and shareholder, and holds shares in Aduro Biotech. AM, PF are AstraZeneca employees and shareholders. XO is an AstraZeneca contract employee. GO has received honoraria from Chugai Pharma, Bio-Rad, Sysmex, Guardant Health, and Foundation Medicine; and received fees for consulting or advisory roles from AstraZeneca, Inviata, Takeda, LOXO, Ignyta, DropWorks, GRAIL, Illumina, and Janssen. In addition, Dr. Oxnard has a patent with DFCI pending. Ethics Approval Statement: The study was conducted in accordance with the Declaration of Helsinki Good Clinical Practice guidelines (as defined by the International Conference on Harmonisation), applicable regulatory requirements, and the policy on bioethics and human biological samples of the trial sponsor, AstraZeneca. All patients provided written informed consent.

// Robert E. Brown 1 , Jamie Buryanek 1 , Amanda M. Katz 2 , Keren Paz 2 , Johannes E. Wolff 3 1 Department of Pathology & Laboratory Medicine, UT Health, McGovern Medical School, Houston, TX 77025, USA 2 Scientific Operations, Champions Oncology, Baltimore, MD 21205, USA 3 Present address: Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA Correspondence to: Robert E. Brown, email: robert.brown@uth.tmc.edu Keywords: alveolar rhabdomyosarcoma, PAX3-FKHR subtype, morphoproteomics, xenograft testing, targeted therapy Received: April 08, 2016 Accepted: June 03, 2016 Published: June 15, 2016 ABSTRACT Alveolar rhabdomyosarcoma (ARMS) represents a block in differentiation of malignant myoblasts. Genomic events implicated in the pathogenesis of ARMS involve PAX3-FKHR (FOXO1) or PAX7-FKHR (FOXO1) translocation with corresponding fusion transcripts and fusion proteins. Commonalities in ARMS include uncontrollable proliferation and failure to differentiate. The genomic-molecular correlates contributing to the etiopathogenesis of ARMS incorporate PAX3-FKHR (FOXO1) fusion protein stimulation of the IGF-1R, c-Met and GSK3-β pathways. With sequential morphoproteomic profiling on such a case in conjunction with personalized tumor graft testing, we provide an expanded definition of the biology of PAX3-FKHR (FOXO1) ARMS that integrates genomics, proteomics and pharmacogenomics. Moreover, therapies that target the genomic and molecular biology and lead to tumoral regression and/or tumoral growth inhibition in a xenograft model of ARMS are identified. Significance: This case study could serve as a model for clinical trials using relatively low toxicity agents in both initial and maintenance therapies to induce remission and reduce the risk of recurrent disease in PAX3-FKHR (FOXO1) subtype of ARMS.

Background Pembrolizumab, a PD-1 inhibitor combined with platinum-based Ctx is standard therapy for eligible pts without a targetable mutation, stage IIIB/IV NSCLC. Currently, there is no data to guide treatment following progression on sequential/concomitant use of platinum-based Ctx and PD-1 inhibitors. Activation of inflammation and elevated baseline c-reactive protein (CRP) levels are associated with a lower response to immunotherapies. Canakinumab is a high-affinity anti-IL-1β monoclonal antibody that showed a significant reduction in the incidence of fatal and nonfatal lung cancer in myocardial infarction pts with increased CRP levels (CANTOS study). Trial design CANOPY-2 (NCT03626545) is a multicenter, phase 3 study evaluating the safety and efficacy of docetaxel ± canakinumab in pts with squamous/non-squamous, stage IIIB-IV NSCLC. This study includes a safety run-in part (part 1 – open-label) to confirm recommended phase 3 regimen (RP3R) to be used in the randomized phase 3 part (part 2 – double-blind, placebo-controlled). Key inclusion criteria: adult pts pretreated with one prior platinum-based Ctx and one prior PD-(L)1 inhibitor therapy for locally advanced or metastatic disease, either together/sequentially and then progressed; ECOG PS 0-1. In part 1, ∼9 pts will be enrolled to have at least 6 evaluable pts and ∼226 pts will be randomized (1:1, stratified by the number of prior lines of therapy and histology) in part 2 to docetaxel ± canakinumab. Primary objectives: to confirm RP3R of canakinumab + docetaxel, as determined by the incidence of dose-limiting toxicity in the first 42 days of administration (part 1) and overall survival (part 2). Secondary objectives: overall response rate, disease control rate, duration of response, time to response, progression-free survival by investigator (RECIST v1.1), safety, PK, immunogenicity of canakinumab, and patient-reported outcomes. Part 1 is completed and part 2 is ongoing after confirming canakinumab 300 mg Q3W as RP3R. Clinical trial identification ACZ885V2301/NCT03626545. Legal entity responsible for the study Novartis. Funding Novartis. Disclosure D. Lim: Advisory / Consultancy: MSD, Novartis, Astra-Zeneca, Boerhinger-Ingelheim; Honoraria (self): MSD, Novartis, Boehringer-Ingelheim. Y. Goto: Speaker Bureau / Expert testimony: AstraZeneca, Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer, MSD, Shionogi Pharma, Novartis; Advisory / Consultancy: Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Glaxo Smith Kline; Research grant / Funding (self): AbbVie, Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Pfizer, Novartis, Kyorin. B.C. Cho: Honoraria (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Advisory / Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD; Research grant / Funding (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Licensing / Royalties: Champions Oncology. H. Kaneda: Honoraria (self): Novartis; Advisory / Consultancy: Novartis. J-H. Kang: Honoraria (self): Roche, AZ, Merck ; Advisory / Consultancy: AZ, MSD, Takeda; Research grant / Funding (self): AZ, Yuhan, CKD, Astellas. S-W. Kim: Advisory / Consultancy: AstraZeneca; Research grant / Funding (self): AstraZeneca, Lilly, Boehringer Ingelheim. C-H. Chiu: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche. J.C-H. Yang: Honoraria (self): Novartis, personal fees from Boehringer Ingelheim, personal fees from Eli Lilly, personal fees from Roche/Genentech, personal fees from Chugai, personal fees from MSD, personal fees from Pfizer, personal fees from Novartis, personal fees from BMS, persona; Advisory / Consultancy: Novartis, personal fees from Boehringer Ingelheim, personal fees from Eli Lilly, personal fees from Bayer, personal fees from Roche/Genentech, personal fees from Astellas, personal fees from MSD, personal fees from Merck Serono, personal fees from Pfizer. W-C. Su: Travel / Accommodation / Expenses: BI, BMS. K. Obyrne: Advisory / Consultancy: Boehringer Ingelheim, Merck Sharpe and Dohme, Eli Lilly, AstraZeneca, Roche, Pfizer, Bristol-Myers Squibb, and Novartis. V. Papadimitrakopoulou: Advisory / Consultancy: Nektar Therapeutics, AstraZeneca, Arrys Therapeutics, Merck, LOXO Oncology, Araxes Pharma, F Hoffman-La Roche, Janssen Research Foundation, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, Novartis, Takeda, AbbVie, TRM Oncology, Tesaro, Exelixis, Gritsto; Honoraria (self): F Hoffman-La Roche; Research grant / Funding (self): Eli Lilly, Novartis, Merck, AstraZeneca, F Hoffman-La Roche, Nektar Therapeutics, Janssen, Bristol-Myers Squibb, Checkmate, Incyte (to institution). M. Reck: Speaker Bureau / Expert testimony: AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Advisory / Consultancy: AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Honoraria (self): AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Officer / Board of Directors: IASLC BOD, Member of Scientific Committee. I. Malet: Shareholder / Stockholder / Stock options: Novartis; Full / Part-time employment: Novartis. B. Mookerjee: Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: Novartis, Glaxo Smith Kine, Incyte, AstraZeneca. Z. Zewen: Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: Novartis. L. Paz-Ares Rodriguez: Advisory / Consultancy: Roche, Lilly, Novartis, Pfizer, BMS, MSD, Takeda, AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Celgene; Honoraria (self): Roche, Lilly, Novartis, Pfizer, BMS, MSD, Amgen, Merck, Sanofi, Takeda, AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, PharmaMar, Celgene.

Background Osimertinib is a 3rd-generation, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR-mutated (EGFRm) and EGFR T790M resistance mutations, and has demonstrated efficacy in NSCLC CNS metastases. In the phase III FLAURA study (NCT02296125), osimertinib resulted in significant progression-free survival (PFS) benefit (primary endpoint; datacut off [DCO] 12 June 2017) over comparator EGFR-TKI (HR 0.46, p Methods Eligible patients (pts): ≥18 years (Japan: ≥20), treatment-naive with Ex19del/L858R EGFRm advanced NSCLC; WHO performance status 0–1. Pts with stable CNS metastases not requiring steroids for ≥2 weeks were allowed. Pts were randomised 1:1 to osimertinib 80 mg once daily (qd) orally (po) or comparator EGFR-TKI (gefitinib 250 mg qd/erlotinib 150 mg qd po), stratified by mutation status (Ex19del/L858R) and race (Asian/non-Asian). Crossover was allowed for pts in the comparator EGFR-TKI arm upon central confirmation of progression and T790M positivity. Primary endpoint: PFS by RECIST v1.1, per investigator. OS was a secondary endpoint. DCO 25 June 2019. Results Globally, 556 pts were randomised to osimertinib (n = 279) or comparator EGFR-TKI (n = 277). Per study protocol, 70 (25%) pts crossed over from comparator EGFR-TKI to osimertinib. Osimertinib significantly improved OS vs comparator EGFR-TKI. All causality AEs, per investigator: osimertinib, 98% (grade ≥3, 42%); comparator EGFR-TKI, 98% (grade ≥3, 47%). AEs leading to discontinuation: osimertinib, 15%; comparator EGFR-TKI, 18%. The safety profile appears consistent with previously reported data. Table . LBA5_PR Efficacy output Osimertinib n = 279 Comparator EGFR-TKI n = 277 OS hazard ratio 0.799 (0.641, 0.997); p = 0.0462 (95.05% confidence interval) Median OS, months 38.6 31.8 (95% confidence interval) (34.5, 41.8) (26.6, 36.0) Deaths, total pts (%) 155 (56) 166 (60) Median follow-up for OS in all pts, months 35.8 27.0 Median follow-up for OS in censored* pts, months 43.1 43.1 12-month survival rate, % 89 83 (95% confidence interval) (85, 92) (77, 87) 24-month survival rate, % 74 59 (95% confidence interval) (69, 79) (53, 65) 36-month survival rate, % 54 44 (95% confidence interval) (48, 60) (38, 50) OS for patients in the full analysis set was analysed using a log rank test (stratified by race and mutation type) for generation of the p-value and using the Breslow approach for handling ties. The median OS with 95% confidence intervals were calculated by Kaplan Meier technique. For statistical significance, a 2-sided p-value of less than 0.0495, as determined by the O’Brien-Fleming approach was required due the previous interim analysis.*Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Conclusions Osimertinib provided a statistically significant and clinically meaningful improvement in OS vs comparator EGFR-TKI in first-line pts with EGFRm advanced NSCLC. Clinical trial identification NCT02296125. Editorial acknowledgement Natalie Griffiths, PhD, from iMed Comms, an Ashfield Company; funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure S.S. Ramalingam: Honoraria (self), Advisory / Consultancy: AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, Tesaro; Research grant / Funding (institution): AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Tesaro, Advaxis, Takeda. J.E. Gray: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Takeda; Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Celgene, Takeda; Research grant / Funding (institution): Array, Merck, AstraZeneca, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb. Y. Ohe: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca, Chugai, Dainippon Lilly, Ono, BMS Japan, Daiichi Sankyo, BI, Bayer, Ignyta, Pfizer, MSD, Taiho, Novartis, Kyorin, Kyowa Hakko Kirin, Takeda, Celltrion, Kissei, Amgen, Janssen, ROXO. B.C. Cho: Honoraria (institution), Advisory / Consultancy: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Eli Lilly, Takeda; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (institution): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Licensing / Royalties: Champions Oncology; Shareholder / Stockholder / Stock options: TheraCanVac Inc.. J. Vansteenkiste: Research grant / Funding (institution): MSD; Advisory / Consultancy: Apotex, AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Roche; Speaker Bureau / Expert testimony: AstraZeneca, BMS, MSD, Roche. C. Zhou: Honoraria (self): Roche, Eli Lilly, Boehringer Ingelheim, Merck, Hengrui and Qiru. B. Chewaskulyong: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca. R. Shah: Honoraria (self), Travel / Accommodation / Expenses: Boehringer Ingelheim, Roche, AstraZeneca. P. Cheema: Honoraria (self), Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Merck, Takeda, Novartis, Genomic Health, Pfizer. M. Tiseo: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, Takeda; Research grant / Funding (institution): AstraZeneca. T. John: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZeneca, Takeda, Boehringer Ingelheim, Pfizer. F. Imamura: Honoraria (self), Research grant / Funding (institution): AstraZeneca. R. Hodge: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. Y. Rukazenkov: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Soria: Advisory / Consultancy: AstraZeneca, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen, and Takeda; Shareholder / Stockholder / Stock options: AstraZeneca, Gritstone; Full / Part-time employment: AstraZeneca. D. Planchard: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, MedImmune, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, AbbVie, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; Travel / Accommodation / Expenses: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim , Roche, Merck,Novartis, prIME Oncology, Pfizer. All other authors have declared no conflicts of interest.

Background Overexpression of interleukin (IL)-1β has been described in solid tumors, including lung. IL-1β can promote angiogenesis, tumor invasiveness, and induces tumor-associated immunosuppression through myeloid-derived suppressor cell (MDSC) accumulation in tumors. Pre-clinical data has shown that IL-1β inhibition reduced tumor growth, by limiting pro-tumorigenic inflammation and polarization of MDSCs into M1 phenotype. Canakinumab is a human monoclonal antibody with high affinity and specificity for IL-1β. Recently, it was found that canakinumab was associated with a significant and dose-dependent reduction in incidence and mortality from lung cancer based on CANTOS study. Trial design CANOPY-A (NCT03447769) is a phase III, randomized, double-blind, placebo-controlled study designed to evaluate efficacy and safety of adjuvant canakinumab vs placebo in pts with surgically resected NSCLC. This trial will enroll adult pts, with completely resected (R0) AJCC/UICC v.8 stages II-IIIA and IIIB (T > 5 cm and N2) NSCLC, who have completed standard-of-care adjuvant treatments, including cisplatin-based chemotherapy and mediastinal radiation therapy (if applicable). Prior treatment with neoadjuvant chemotherapy or neoadjuvant radiotherapy is not permitted. Approximately 1500 pts will be randomized 1:1 to receive canakinumab (200 mg Q3W, s.c) or placebo (Q3W, s.c.) for 18 cycles or until disease recurrence, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or pt, death, or loss to follow-up. Randomization will be stratified by AJCC/UICC v.8 stage, tumor histology, and region. In the amended protocol, a sub-study was included to determine the biomarker levels in the blood at pre- and post-surgery, and to establish their association with canakinumab efficacy. The primary objective is disease-free survival (per investigator assessment). Secondary objectives include overall survival (key secondary objective), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and pt-reported outcomes. Enrollment is ongoing. Clinical trial identification CACZ885T2301. Legal entity responsible for the study Novartis. Funding Novartis. Disclosure B.C. Cho: Honoraria (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Advisory / Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD; Research grant / Funding (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Licensing / Royalties: Champions Oncology. G-C. Chang: Honoraria (self): F. Hoffmann–La Roche, Ltd, Eli Lilly and Company Oncology, AstraZeneca, Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, and Merck Sharp & Dohme. Y-C. Kim: Honoraria (self): AstraZeneca, Roche, Boehringer Ingelheim; Research grant / Funding (self): AstraZeneca, Roche, Boehringer Ingelheim. S. Geater: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Roche; Advisory / Consultancy: Boehringer Ingelheim; Research grant / Funding (institution): AstraZeneca, Boehringer Ingelheim, Roche, MSD; Travel / Accommodation / Expenses: AstraZeneca, Boehringer Ingelheim, Roche. S. Saeteng: Honoraria (self): AstraZeneca, Novartis : Speaker. Y. Goto: Speaker Bureau / Expert testimony: AstraZeneca, Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer, MSD, Shionogi Pharma, Novartis; Advisory / Consultancy: Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Glaxo Smith Kline; Research grant / Funding (self): AbbVie, Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Pfizer, Novartis, Kyorin. S. Lu: Research grant / Funding (self): AstraZeneca, Hutchison, Roche; Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Hutchison MediPharma, Simcere, Roche; Honoraria (self): AstraZeneca, Roche. A. Ardizzoni: Advisory / Consultancy: MDS, Roche; Honoraria (self): MSD, BMS, Pfizer, Lilly; Research grant / Funding (self): BMS, Celgene, Roche; Leadership role: Member Educational Committee. F. Barlesi: Honoraria (self): AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology,. P. De Marchi: Advisory / Consultancy: Roche, Bayer, Msd, BMS, Pfizer, AstraZeneca; Speaker Bureau / Expert Testimony: Roche, Bayer, MSD, BMS, Pfizer, AstraZeneca; Travel / Accommodation / Expenses: Roche, MSD, BMS, AstraZeneca. L. Paz-Ares: Advisory / Consultancy: Roche, Lilly, Novartis, Pfizer, BMS, MSD, Takeda, AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, Celgene; Honoraria (self): Roche, Lilly, Novartis, Pfizer, BMS, MSD, Amgen, Merck, Sanofi, Takeda, AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, PharmaMar, Celgene. D.R. Spigel: Advisory / Consultancy: AbbVie (Inst); Amgen (Inst); AstraZeneca (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); Evelo Therapeutics (Inst); Foundation Medicine (Inst); Genentech/Roche (Inst); GlaxoSmithKline (Inst); Illumina (Inst); Lilly (Inst); Research grant / Funding (institution): AbbVie (Inst); Acerta Pharma (Inst); Aeglea Biotherapeutics (Inst); Amgen (Inst); ARMO BioSciences (Inst); Astellas Pharma (Inst); AstraZeneca (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); Celldex (Inst); Clovis Oncolog; Travel / Accommodation / Expenses: AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; EMD Serono; Genentech; Genzyme; Intuitive Surgical; Lilly; Merck; Pfizer; Purdue Pharma; Spectrum Pharmaceuticals; Sysmex. M. Thomas: Advisory / Consultancy: Novartis, Lilly, Pfizer, Bristol-Myers Squibb, Roche, AstraZeneca, Boehringer Ingelheim, MSD; Honoraria (self): Roche, Bristol-Myers Squibb, Lilly, AstraZeneca, Novartis, Pfizer, Boehringer Ingelheim, MSD; Research grant / Funding (self): Roche, BMS, MSD, AstraZeneca, Takeda. E.B. Garon: Advisory / Consultancy: Dracen, EMD Serono; Research grant / Funding (self): AstraZeneca, BMS, Eli Lilly, Genentech, Merck, Novartis, Neon, Iovance, Dynavax, Mirati. M. Leung: Shareholder / Stockholder / Stock options: Novartis; Full / Part-time employment: Novartis. J. Baum: Shareholder / Stockholder / Stock options: Novartis stock; Full / Part-time employment: Novartis. Spouse (Lauren Baum) – Abbot Laboratories. Z. Zewen: Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: Novartis. B. Mookerjee: Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: Novartis, GlaxoSmithKline, Incyte, AstraZeneca. J.C-H. Yang: Advisory / Consultancy: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai Pharmaceutical, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceuticals, Daiichi-Sankyo, Hansoh Pharmaceuticals, Takeda Pharmaceuticals, Bluep; Honoraria (self): Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai Pharmaceutical, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceuticals, Daiichi-Sankyo, Hansoh Pharmaceuticals, Takeda Pharmaceuticals, Bluep; Leadership role: IASLC CME activity: Author/Board of Directors/Presenter/Reviewer. All other authors have declared no conflicts of interest.

Background Preliminary data from TATTON (NCT02143466, a multi-arm, multi-drug combination study) suggested that adding savolitinib (AZD6094, HMPL-504, volitinib), a potent and highly selective MET TKI, to osimertinib, a 3rd generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), which selectively inhibits EGFR TKI sensitising (EGFRm) and T790M resistance mutations, may overcome MET-driven resistance to EGFR TKIs. We present updated data from TATTON Part B and data from Part D, for the first time. Methods Pts were ≥18 years (Japan ≥20 years), mainly Asian, with locally advanced/metastatic, MET-positive, EGFRm NSCLC and disease progression on prior therapy. Pts enrolled based on MET status by local fluorescent in-situ hybridisation (MET gene copy ≥5 or MET/CEP7 ratio ≥2), next-generation sequencing or immunohistochemistry (+3 in ≥ 50% of tumour cells), with retrospective central confirmation. Pts in Part B received osimertinib 80 mg + savolitinib 600 mg or 300 mg orally (PO) once daily (QD). Pts in Part D received osimertinib 80 mg + savolitinib 300 mg PO QD, were T790M negative and had received no prior 3rd generation EGFR TKI. Primary endpoints: safety and tolerability; secondary endpoints included objective response rate and progression-free survival. Results In Parts B (N = 138) and D (N = 42); Grade ≥3 AEs reported by 57% and 38%, respectively; serious AEs reported by 45% and 26%, respectively. AEs possibly related to treatment, led to discontinuation of savolitinib in 38 (28%) vs 9 (21%) and osimertinib in 14 (10%) vs 2 (5%), for Parts B and D, respectively. Efficacy data: Table. Table . LBA2 Efficacy endpoints Part B Part D Endpoint Previously treated with a 3G EGFR TKI No prior 3G EGFR TKI, T790M-negative No prior 3G EGFR TKI, T790M-positive Total No prior 3G EGFR TKI, T790M-negative Best response n = 69 n = 51 n = 18 n = 138 n = 36 * ORR † , n (%) [95% CI] 21 (30) [20–43] 33 (65) [50–78] 12 (67) [41–87] 66 (48) [39–56] 23 (64) [46–79] PFS n = 69 n = 51 n = 18 n = 138 n = 42 Median PFS, months 5·4 9·0 11·0 7·6 9·1 [95% CI] [4·1–8·0] [5·5–11·9] [4·0–NR] [5·5–9·2] [5·4–12·9] Total events, n (%) 43 (62) 33 (65) 10 (56) 86 (62) 17 (40) * Best response data are for patients who had an opportunity to have two follow-up scans. † All confirmed responses were partial response. Conclusions Our results support that osimertinib + savolitinib may overcome MET-driven resistance to EGFR TKIs, and warrant further exploration of the osimertinib 80 mg + savolitinib 300 mg combination in the SAVANNAH (NCT03778229) and ORCHARD (NCT03944772) studies. Clinical trial identification NCT02143466. Editorial acknowledgement Laura Crocker, BMedSci, of iMed Comms, an Ashfield Company, funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure J. Han: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Research grant / Funding (self): ONO; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Takeda. L.V. Sequist: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Janssen; Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Merrimack Pharmaceuticals; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): LOXO; Honoraria (self), Research grant / Funding (institution): Blueprint Medicines; Honoraria (self), Research grant / Funding (institution): Genentech. M. Ahn: Honoraria (self), Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD, Ono Pharmaceutical, Roche; Advisory / Consultancy: Takeda, Alpha Pharmaceutical. B.C. Cho: Research grant / Funding (institution): Novartis, Bayer, AstraZeneca, Mogam Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, MSD; Advisory / Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Ono Pharmaceutical, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, and MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc, Gencurix Inc, Bridgebio Therapeutics; Licensing / Royalties, Patent with royalties paid: Champions Oncology. H. Yu: Advisory / Consultancy: AstraZeneca; Research grant / Funding (institution): AstraZeneca, Lilly, Pfizer, Daiichi, Novartis, Astellas. S. Kim: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. J.C. Yang: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, MSD, Pfizer, Novartis, Bristol-Myers Squibb, Ono Pharmaceuticals; Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, Bristol-Myers Squibb, Ono Pharmaceuticals, Daiichi Sankyo, Hansoh, Takeda, Blueprint. M. Cantarini: Shareholder / Stockholder / Stock options, Full / Part-time employment, Full time Contractor: AstraZeneca. R.B. Verheijen: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options: Aduro Biotech. A. Mellemgaard: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P. Frewer: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. X. Ou: Full / Part-time employment, Full time Contractor: AstraZeneca. G. Oxnard: Honoraria (self): Chugai Pharma, Bio-Rad, Sysmex, Guardant Health, Foundation Medicine; Advisory / Consultancy: AstraZeneca, Inviata, Takeda, Loxo, Ignyta, DropWorks, GRAIL, Illumina, Janssen; Licensing / Royalties, Patent pending: DFCI.

Background In the phase III FLAURA study (NCT02296125), the 3rd-generation EGFR-TKI osimertinib showed superior efficacy to comparator EGFR-TKIs in previously untreated EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC). Here we report results from an exploratory analysis of ctDNA for the early detection of disease progression (PD) in FLAURA. Methods Treatment-naive patients (pts) with EGFRm (ex19del/L858R) locally advanced/metastatic NSCLC (n = 556) were randomised 1:1 (osimertinib 80 mg qd: comparator [gefitinib 250 mg qd/erlotinib 150 mg qd]). Plasma samples were collected on Days 1, 8 and 15, then every 21 days for weeks (W) 3–18, then every 6W thereafter. In pts who had a plasma sample on PD and/or discontinuation, ctDNA droplet digital PCR (ddPCR; Biodesix) for EGFRm (ex19del/L858R/T790M) was performed at all available time points and C797S for post-W6 time points. C797S and T790M were the only resistance mutations assayed. ctDNA progression was defined with respect to the nadir ctDNA result and its proximity to the ddPCR detection and quantification limits. Results The ctDNA progression analysis included 122/556 (22%) pts with valid longitudinal monitoring ddPCR data and RECIST PD by DCO1 (12 June 2017). Across both arms, ctDNA progression preceded or co-occurred with PD in 80/122 (66%) pts with 2.7 months (mo) median lead time; 9.5 mo median progression-free survival (mPFS; n = 80). Acquired C797S or T790M was detected in 57/122 (47%) pts with ctDNA progression (osimertinib 4/50 [8%] C797S, comparator 53/72 [74%] T790M); median time to detection was 16.7 and 8.4 mo for the osimertinib and comparator arms, respectively, mirroring overall mPFS. In pts with ctDNA progression and PD (n = 106), acquired T790M and C797S were detected either at the same time as, or earlier than PD in 41/106 (38%) pts (osimertinib 2/39 [5%], comparator 39/67 [58%]); median lead time was 1.4 mo. Conclusions ctDNA monitoring may allow for earlier identification of pts who progress on first-line EGFR-TKI therapy and the detection of EGFR-mediated resistance mechanisms in advance of PD in EGFRm NSCLC. Future work aims to explore early detection of non-EGFR-mediated resistance. Clinical trial identification NCT02296125. Editorial acknowledgement Donna Tillotson, PhD, of iMed Comms, Macclesfield, UK, an Ashfield Company, part of UDG Healthcare plc, funded by AstraZeneca in accordance with Good Publications Practice (GPP3) guidelines. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure J.E. Gray: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Array; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Takeda. A. Markovets: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. N. Nogami: Honoraria (self): Pfizer Inc., Chugai Pharmaceutical Co. Ltd, Eli Lilly, Taiho Pharmaceutical Co. Ltd., AstraZeneca, Kyowa Hakko Kirin, Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb, MSD. B.C. Cho: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, MSD; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Licensing / Royalties: Champions Oncology; Honoraria (institution), Advisory / Consultancy: Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Eli Lilly, Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc. B. Chewaskulyong: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca. M. Majem: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Tesaro; Speaker Bureau / Expert testimony: Hellsin; Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Speaker Bureau / Expert testimony: Amgen. N. Peled: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Pfizer, Roche, Takeda; Advisory / Consultancy: Eli Lilly; Honoraria (self): Foundation Medicine; Shareholder / Stockholder / Stock options: Novellus Dx; Honoraria (self): Guardant360. K. Vishwanathan: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. A. Todd: Full / Part-time employment: AstraZeneca. Y. Rukazenkov: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. M. Johnson: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C. Barrett: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Chmielecki: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. R. Hartmaier: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca; Shareholder / Stockholder / Stock options, Licensing / Royalties, Nfe2l2 exon 2 ano/or exon 3 loss from work conducted at Foundation Medicine; provisional patent filed: Foundation Medicine. S.S. Ramalingam: Advisory / Consultancy, Research grant / Funding (self): Amgen, AstraZeneca, Bristol-Myers Squibb, Merck; Advisory / Consultancy: AbbVie, Celgene, Genentech, Lilly, Loxo, Takeda; Research grant / Funding (self): Tesaro.

Background The first-in-human, ongoing phase I study of PF-06801591, a humanized IgG4 antibody to programmed cell death 1 (PD-1) receptor, consisted of a Part 1 dose escalation and Part 2 dose expansion. In Part 1, PF-06801591 was administered intravenously or SC with an acceptable safety profile and antitumor activity in several solid tumor types. Herein, we report on Part 2 where we further evaluated SC PF-06801591 in patients (pts) with NSCLC and UC. Methods Anti-PD-1/L1-naive pts with NSCLC (n = 68) and UC (n = 38) received SC PF-06801591 300 mg q4w. NSCLC pts had ≤1 prior line of chemotherapy (CT) ± ≥1 ALK/EGFR mutation-directed therapies (if applicable) and UC pts had ≤2 lines of prior CT. Tumors were evaluated q8w by RECIST 1.1. Blood samples were collected for pharmacokinetic (PK) and immunogenicity assessments. Archival or baseline biopsies were evaluated by immunohistochemistry for PD-L1, RNA-seq, and whole exome sequencing. Results As of 27Dec2018, with median duration of treatment of 2.8 mos. in all 106 treated pts (55 still receiving treatment), 50.9% had treatment-related AEs (TRAEs) with 8.5% grade 3 or higher. Most common TRAEs were hyperthyroidism (9.4%), pruritus (6.6%), and increased amylase/lipase, anemia, hypothyroidism, pneumonitis, and rash (4.7% each). Treatment-emergent anti-drug antibodies were detected in 3 pts. With median follow-up of 5.1 mos. in 67 modified intent to treat (mITT) NSCLC pts, 11 (16.4%) pts achieved a partial response (PR) and 26 (38.8%) had stable disease (SD); the objective response rate (ORR) was 16.4% with 95% confidence interval (CI) 8.5-27.5% (25% in pts with ≥1% tumor cell PD-L1 expression). With median follow-up of 3.0 mos. in 37 mITT UC pts, 6 (16.2%) pts had a PR and 13 (35.1%) had SD; ORR was 16.2% (95% CI 6.2-32.0%). PK and biomarker data will be presented. Conclusions SC PF-06801591 given monthly was well tolerated, with minimal rates of injection site reactions and low incidence of immunogenicity. SC PF-06801591 demonstrated antitumor activity in NSCLC and UC pts at an early time point. The study is ongoing to further assess the durability of responses and long-term safety profile. Clinical trial identification NCT02573259. Editorial acknowledgement S. Mariani MD PhD of Engage Scientific Solutions, Southport, CT, funded by Pfizer and L. Chen. Legal entity responsible for the study Pfizer Inc. Funding Pfizer Inc. Disclosure B.C. Cho: Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): MOGAM Institute; Research grant / Funding (institution): Dong-A ST; Research grant / Funding (institution), Licensing / Royalties: Champions Oncology; Advisory / Consultancy, Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Yuhan; Advisory / Consultancy, Research grant / Funding (institution): Ono; Research grant / Funding (institution): Dizal Pharma; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Shareholder / Stockholder / Stock options: Gencurix Inc; Shareholder / Stockholder / Stock options: Bridgebio Therapeutics. K. Penkov: Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Prestige Biopharma; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Tanvex. M. Korozan: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Regeneron. Y. Kulyaba: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Azaya Therapeutics; Research grant / Funding (institution): Celltrion; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Synta Pharmaceuticals; Research grant / Funding (institution): Tanvex. H.K. Ahn: Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Eisai; Honoraria (self): Ono; Honoraria (self): Roche. S. Odintsova: Full / Part-time employment: Complete Medical Technologies. J. Davda: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. A. Forgie: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. X. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. R. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. I.A. Jacobs: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. F. Kazazi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. J. Chou: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. M.L. Johnson: Honoraria (institution), Research grant / Funding (institution): AstraZeneca; Honoraria (institution), Research grant / Funding (institution): Genentech/Roche; Honoraria (institution), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (institution), Research grant / Funding (institution): Loxo; Honoraria (institution), Research grant / Funding (institution): Merck; Honoraria (institution), Research grant / Funding (institution): Mirati; Honoraria (institution), Research grant / Funding (institution): Sanofi; Honoraria (institution): Calithera; Honoraria (institution): Celgene; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): GenMab; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): StemCentrix; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Apexigen; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): BerGenBio; Research grant / Funding (institution): Birdie; Research grant / Funding (institution): Checkpoint Therapeutics; Research grant / Funding (institution): Corvus; Research grant / Funding (institution): Cytomx; Research grant / Funding (institution): Daiichi–Sankyo; Research grant / Funding (institution): Dynavax; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Genocea; Research grant / Funding (institution): Gritstone; Research grant / Funding (institution): Hengrui Therapeutics; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Neovia; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Tarveda; Spouse / Financial dependant, contract lobbyist : Astellas; Spouse / Financial dependant, contract lobbyist : Otsuka Pharmaceuticals. All other authors have declared no conflicts of interest.

Background Chemotherapy (CT) for advanced ESCC offers poor long-term survival. We report the final analysis from the phase III ATTRACTION-3 study of the programmed death (PD)-1 inhibitor nivolumab (NIVO) versus CT in patients (pts) with unresectable advanced or recurrent ESCC refractory or intolerant to 1 prior fluoropyrimidine/platinum-based CT. Methods Pts were enrolled regardless of PD-ligand 1 (PD-L1) expression and randomized 1:1 to either NIVO (240 mg Q2W) or investigator’s choice of paclitaxel or docetaxel. Primary endpoint was overall survival (OS). Results 419 pts were randomized (NIVO = 210, CT = 209). At a minimum follow-up of 17.6 months (mo; time from randomization of the last pt to data cutoff), NIVO showed a statistically significant improvement in OS vs CT (HR for death 0.77 [95% CI, 0.62–0.96; P = 0.02]; median OS, 10.9 vs 8.4 mo; Table). The proportion of pts alive at 18 mo was numerically larger with NIVO vs CT (31% vs 21%; Table). HRs for the risk of death favored NIVO over CT across tumor PD-L1 expression levels (PD-L1 ≥1%, HR 0.69 [95% CI, 0.51 to 0.94]; PD-L1 Table . LBA11 Efficacy (all randomized pts) NIVO N = 210 CT N = 209 Median OS, mo (95% CI) 10.9 (9.2–13.3) 8.4 (7.2–9.9) HR (95% CI; P-value) 0.77 (0.62–0.96; P = 0.02) 12-mo rate, % (95% CI) 47 (40–54) 34 (28–41) 18-mo rate, % (95% CI) 31 (24–37) 21 (15–27) ORR, n (%) a 33 (19) 34 (22) 95% CI 14–26 15–29 Median DOR, b mo (95% CI) 6.9 (5.4–11.1) 3.9 (2.8–4.2) Median PFS, mo (95% CI) 1.7 (1.5–2.7) 3.4 (3.0–4.2) HR (95% CI) 1.08 (0.87–1.34) 6-mo rate, % (95% CI) 24 (19–30) 17 (12–23) 12-mo rate, % (95% CI) 12 (8–17) 7 (4–12) Safety (all treated pts) N = 209 N = 208 Pts with TRAEs, n (%) 137 (66) 198 (95) Grade 3–4 TRAEs, n (%) 38 (18) 131 (63) Pts with serious TRAEs, n (%) 33 c (16) 47 (23) Pts with TRAEs leading to discontinuation, n (%) 18 (9) 19 (9) a Assessed in randomized pts who had target lesion measurements at baseline: NIVO, N = 171; CT, N = 158. b Time from date of first response to date of first documented tumor progression or death. c One grade 4 serious TRAE was not reported before the database lock and is not captured here. Conclusions NIVO demonstrated superior OS and a favorable safety profile vs CT in pts with previously treated advanced ESCC, with survival benefit observed regardless of tumor PD-L1 expression. NIVO may represent a new standard second-line treatment option for pts with advanced ESCC. Clinical trial identification NCT02569242. Editorial acknowledgement Professional medical writing assistance and editorial assistance were provided by Jennifer Granit, PhD, and Christine Craig of Parexel, funded by Bristol-Myers Squibb. Legal entity responsible for the study Ono Pharmaceutical Co, Bristol-Myers Squibb. Funding Ono Pharmaceutical Co, Bristol-Myers Squibb. Disclosure B.C. Cho: Research grant / Funding (self): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD ; Licensing / Royalties: Champions Oncology; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Honoraria (self): Novatis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Advisory / Consultancy: Novatis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takega, MSD; Speaker Bureau / Expert testimony: Novartis. K. Kato: Advisory / Consultancy: Ono Pharmaceutical, BeiGene, MSD, Oncolys BioPharma; Research grant / Funding (institution): Ono Pharmaceutical, Shionogi, MSD, Beigene. M. Takahashi: Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony: Ono Pharmaceutical, Brystol-Myers Squibb, Daichi-Sankyo. M. Okada: Speaker Bureau / Expert testimony: Tahio Pharmaceutical, Johnson & Johnson, Coviden, Lilly, Chugai Pharma; Research grant / Funding (institution): Taiho Pharmaceutical, Nippon Kayaku, Chugai Pharma, Coviden, Johnson & Johnson, Daiichi Sanko, Yakult Honsha, Lilly Japan, Nihon Medi-Physics, Pfizer, Mochida Pharmaceuticals Co. Ltd, Shionogi. S. Kadowaki: Research grant / Funding (institution): Ono Pharmaceutical, Lilly Japan, Taiho Pharmaceutical, Boehringer Ingelheim, Bristol-Myers Squibb. Y. Doki: Speaker Bureau / Expert testimony: Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Daiichi Sankyo, Yakult Honsha, Takeda Pharmaceutical, Kaken Pharmaceutical, Abbott Japan; Research grant / Funding (self): Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Eli Lilly, MSD, Daiichi Sankyo, Yakult Honsha, Takeda Pharmaceutical, Kaken Pharmaceutical, Abbott Japan, Eisai, Shionogi . C. Yen: Honoraria (self): Lilly, Merck Sharp & Dohme, Amgen, Eisai; Advisory / Consultancy: Lilly, Merck Sharp & Dohme; Speaker Bureau / Expert testimony: Lilly, Ono Pharmaceutical, Eisai, Effective Pharmaceuticals. S. Kim: Research grant / Funding (institution): Novartis, Genzyme, Dongkook Pharma. C. Hsu: Advisory / Consultancy: Ono Pharmaceutical, Lilly, MSD, Novartis; Honoraria (self): Bristol-Myers Squibb, Ono Pharmaceutical, Merck Sharp & Dohme; Research grant / Funding (institution): Ono Pharmaceutical, AstraZeneca, MSD, Genentech. I. Xynos: Shareholder / Stockholder / Stock options: Bristol-Myers Squibb. M. Kodani: Shareholder / Stockholder / Stock options: Ono Pharmaceutical Co. Ltd. Y. Kitagawa: Honoraria (self): Ethicon, Olympus, Ono Pharmaceutical, Tahi Pharmaceutical, Chugai Pharma, Nippon Kayaku, Asahi Kasei; Research grant / Funding (institution): Astellas, Otsuka, Kaken Pharmaceutical, Kyowa Hakko Kirin, Kowa, CSL Behring, Shionogi, Saiichi Sankyo, Taiho Pharmaceutical, Takeda, Chugai Pharma, Tsumura & Co., Teijin Pharma, Medtronic, Boehringer Ingelheim, Merck Serono, Novartis, Ajinomoto, Asahi Ka. All other authors have declared no conflicts of interest.

Background Dense stroma is a hallmark of hard-to-treat cancers such as pancreatic adenocarcinoma. VCN-01 oncolytic adenovirus is designed to replicate in cancer cells with dysfunctional RB1 pathway, improve tumor targeting and express hyaluronidase to enhance virus intratumor spreading and facilitate drug extravasation into the tumor. Methods The mechanisms of action of VCN-01 were tested in pancreatic xenograft models after both intravenous and intratumor administration. In a proof of concept phase I clinical trial study (8 patients), VCN-01 was escalated up to 1E+11vp per Endoscopic Ultrasound (EUS)-guided intratumor injection (3x) combined with the standard of care, SoC (gemcitabine or nab-paclitaxel/gemcitabine) in patients with advanced pancreatic adenocarcinoma. Results VCN-01 alone showed antitumor efficacy in preclinical models and further increased its efficacy when combined with SoC chemotherapy. VCN-01 replicated within injected tumors regardless of chemotherapy. Hyaluronidase expression by VCN-01 facilitated tumor extravasation and increased uptake of chemotherapy agents and antibodies. Data obtained from a phase 1 clinical trial of VCN-01 administered by repeated intratumor injection showed that the combination treatment was generally well-tolerated although dose limiting toxicity was found at highest dose. When combined with chemotherapy, VCN-01 stabilized the injected lesion in all patients, with a patient showing long progression free survival of 134 weeks. VCN-01 was detected as secondary peaks in blood several days after injection and in tumors at day 20-28, indicating virus replication. Hyaluronidase PH20 presence in sera was confirmed for all patients injected at 1E+11vp. Elastography of VCN-01-treated tumors evidenced reduction in tumor stiffness regardless of nab-paclitaxel co-administration. Conclusions VCN-01 replicates and expresses hyaluronidase after intratumor injection both in preclinical models and in patients with pancreatic cancer. Enhanced chemotherapy access and reduction of tumor stiffness favours local control of pancreatic tumours treated with VCN-01 + standard of care. Clinical trial identification EudraCT: 2012-005556-42. Legal entity responsible for the study VCN Biosciences. Funding VCN Biosciences. Disclosure M. Hidalgo: Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): EMD; Speaker Bureau / Expert testimony: Ipsem; Speaker Bureau / Expert testimony: Shire; Advisory / Consultancy: SOBI; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Champions Oncology; Advisory / Consultancy: Agenus; Advisory / Consultancy: Erytech; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Pharmacyte; Advisory / Consultancy: Bioline; Advisory / Consultancy, Shareholder / Stockholder / Stock options: BioOncotech; Advisory / Consultancy, Research grant / Funding (institution): Oncomatrix; Advisory / Consultancy: VCN Biosciences; Advisory / Consultancy: Bayer; Advisory / Consultancy: BMS; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Nelum; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Eng T Cells. M. Bazan-Peregrino: Full / Part-time employment: VCN Biosciences. B. Laquente: Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy: Servier; Research grant / Funding (institution): Mylan. R. Alvarez Gallego: Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (institution): Shire. A. Mato-Berciano: Full / Part-time employment: VCN Biosciences. M. Gimenez-Alejandre: Full / Part-time employment: VCN Biosciences. V. Maliandi: Full / Part-time employment: VCN Biosciences. M.C. Riesco Martinez: Speaker Bureau / Expert testimony: Merck. M. Perez-Carreras: Advisory / Consultancy: Intercept; Research grant / Funding (institution): GENFIT. G. Capella: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: VCN Biosciences. R. Alemany: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: VCN Biosciences; Research grant / Funding (institution): Lokon Pharma; Research grant / Funding (institution): Mologen. R. Salazar: Advisory / Consultancy, Research grant / Funding (institution): VCN Biosciences; Advisory / Consultancy: Agendia; Advisory / Consultancy: Guardant Health; Advisory / Consultancy, Research grant / Funding (institution): Roche Diagnostics; Advisory / Consultancy: Ferrer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Roche Farma; Advisory / Consultancy: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: AZD; Speaker Bureau / Expert testimony: Celgene; Leadership role, Shareholder / Stockholder / Stock options: Sace MedHealth; Research grant / Funding (institution): PsiOxus; Research grant / Funding (institution): Mologen. E. Blasi: Full / Part-time employment: VCN Biosciences. C. Blasco: Full / Part-time employment: VCN Biosciences. M. Cascallo: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: VCN Biosciences. R. Garcia-Carbonero: Advisory / Consultancy: AAA; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: PharmaMar; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Servier; Research grant / Funding (institution): ARMO; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): VCN Biosciences. All other authors have declared no conflicts of interest.

Background Interleukin-1β (IL-1β) inhibition with canakinumab was associated with a significant reduction in the incidence of lung cancer and lung cancer mortality in pts with atherosclerosis in CANTOS trial. Inhibition of IL-1β driven inflammation may lead to a tumor microenvironment more susceptible to anti-PD-(L)1 therapies. Recent studies have shown that low levels of CRP at baseline or decreased levels over time correlated with improved responses to anti-PD-(L)1 agents, providing rationale for combining canakinumab and PEM. Trial design CANOPY-1 (NCT03631199) is a double-blind, randomized, placebo (Pb)-controlled, phase III trial to determine efficacy and safety of PEM + platinum-based Ctx ± canakinumab in untreated stage IIIB/IIIC-IV squamous and non-squamous NSCLC pts. It is a 2 part study- In part 1 (open-label safety run-in with 3 cohorts of ∼9 pts each), pts received canakinumab 200 mg s.c (Q3W) + PEM 200 mg i.v (Q3W) + platinum-based Ctx [Cohort A (non-squamous), carboplatin (CBCDA) + pemetrexed (PTX); Cohort B (non-squamous), cisplatin + PTX; Cohort C (squamous or non-squamous), CBCDA + paclitaxel]. In part 2 (with ∼600 pts), pts will be randomize to receive canakinumab/Pb + PEM + platinum-based Ctx (non-squamous, CBCDA or cisplatin + PTX; squamous, CBCDA + paclitaxel or nab-paclitaxel). PEM and platinum-based Ctx will be administered at their approved doses. Randomization (1:1) will be stratified by PD-L1 status, region, and histology. In both parts, pts will receive 4 cycles of induction therapy (canakinumab/Pb + PEM + Ctx) followed by maintenance therapy (PEM + canakinumab/Pb +/- PTX) until progressive disease. Primary objectives: confirm recommended phase 3 (RP3R) for canakinumab combination (part 1), compare PFS and OS between treatment arms (part 2). Secondary objectives (part 1 and 2): ORR, DCR, safety, PK and DOR. Part 1 is completed and part 2 is ongoing based on the confirmation of canakinumab 200 mg Q3W + PEM and platinum-doublet Ctx as RP3R. Clinical trial identification CACZ885U2301/NCT03631199. Legal entity responsible for the study Novartis. Funding Novartis. Disclosure D.S.W. Tan: Advisory / Consultancy: Novartis, Pfizer, AstraZeneca; Research grant / Funding (self): Novartis ; Advisory / Consultancy: Novartis; Research grant / Funding (self): Pfizer, AstraZeneca. T.M. Kim: Advisory / Consultancy: AstraZeneca, Novartis, Takeda, Sanofi, and Bayer ; Research grant / Funding (self): AstraZeneca-KHIDI outside this work. B.J. Solomon: Advisory / Consultancy: Roche/Genentech; AstraZeneca; Novartis; Pfizer; Merck; Bristol-Myers Squibb; Loxo Oncology; Gritstone Oncology; Honoraria (self): Roche/Genentech; AstraZeneca; Novartis; Pfizer; Merck; Bristol-Myers Squibb; Loxo Oncology; Gritstone Oncology. W.L. Tan: Travel / Accommodation / Expenses: Boehringer Ingelheim for WCLC in Toronto Sept 2018. S. Geater: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Roche; Advisory / Consultancy: Boehringer Ingelheim; Research grant / Funding (institution): AstraZeneca, Boehringer Ingelheim, Roche, MSD; Travel / Accommodation / Expenses: AstraZeneca, Boehringer Ingelheim, Roche. G. De Castro Jr.: Honoraria (self): Bristol-Myers Squibb; Merck Serono Serbia; MSD; Advisory / Consultancy: Bristol-Myers Squibb; MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Merck Serono Serbia; MSD; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Merck Serono Serbia; MSD. A. Greystoke: Speaker Bureau / Expert testimony: Novartis, AstraZeneca, Boehringer Ingelheim, BMS, MSD, Takeda, Pfizer; Advisory / Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, BMS, MSD, Takeda, Pfizer. E. Felip: Advisory / Consultancy: AbbVie; AstraZeneca; Blueprint Medicines; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; Guardant Health; Lilly; Merck KGaA; Merck Sharp & Dohme; Novartis; Pfizer; Roche; Takeda; Speaker Bureau / Expert testimony: AbbVie; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Lilly; Merck KGaA; Merck Sharp & Dohme; Novartis; Pfizer; Roche; Takeda; Research grant / Funding (self): EMD Serono (Inst); Fundacion Merck Salud (Inst). B.E. Johnson: Advisory / Consultancy: Novartis Steering Committee and Array Biopharma Steering Committee; Research grant / Funding (self): Research Grants from Novartis and Cannon Medical Imaging. A-L. Louveau: Full / Part-time employment: Novartis. V.Q. Passos: Full / Part-time employment: Novartis. B.C. Cho: Shareholder / Stockholder / Stock options: TheraCanVac Inc; Honoraria (self): AstraZeneca; Bayer; Champions Oncology; Dizal Pharma; Dong-A ST; Janssen; MOGAM Institute; MSD; Novartis; Ono Pharmaceutical; Yuhan; Advisory / Consultancy: AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Janssen; Lilly; MSD; Novartis; Ono Pharmaceutical; Pfizer; Roche; Takeda; Yuhan; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (self): AstraZeneca; Bayer; Champions Oncology; Dizal Pharma; Dong-A ST; Janssen; MOGAM Institute; MSD; Novartis; Ono Pharmaceutical; Yuhan; Licensing / Royalties: Champions Oncology. All other authors have declared no conflicts of interest.

Background Approximately 20%–30% of patients (pts) with EGFR mutation-positive NSCLC present with CNS metastases at the time of diagnosis of advanced disease. CNS metastases are associated with a poor prognosis. Osimertinib is a third-generation, irreversible, oral EGFR-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitising (EGFRm) and EGFR T790M mutations and in clinical trials has demonstrated efficacy in NSCLC CNS metastases. ASTRIS is the largest ongoing, international, real-world study of osimertinib in EGFR T790M positive advanced NSCLC (NCT02474355). We report a subset analysis of pts with CNS metastases. Methods Eligible pts with stage IIIB/IV EGFR T790M positive NSCLC previously treated with an EGFR-TKI received osimertinib 80 mg once-daily. Investigator-assessed (IA) progression-free survival (PFS), clinical response and time to treatment discontinuation (TTD) were analysed in a subset of pts with CNS (leptomeningeal and/or brain) metastases at baseline (BL). Follow-up brain imaging was not mandatory. Results From 18 September 2015 to 15 October 2018, 3015 pts across 16 countries had received ≥1 dose of osimertinib (full analysis set [FAS]); 882 (29%) pts presented with CNS metastases at BL. BL demographics were similar between this subset and the FAS (female: 63%/64%; Asian: 69%/69%; median age (range): 61 (27–88) years/62 (27–92); WHO performance status 2: 15%/11%). IA response rates were consistent across the two groups, while median PFS and TTD appeared to be slightly lower in the CNS subset (Table). Overall survival data are immature. Conclusions In a real-world setting, over half of pts with EGFR T790M positive advanced NSCLC and CNS metastases responded to treatment with osimertinib 80 mg. These findings support previous clinical research showing clinically meaningful CNS efficacy with osimertinib in advanced NSCLC. Table . 1521P Clinical outcomes for pts with EGFR T790M advanced NSCLC and CNS metastases at BL Clinical outcomes FAS Osimertinib 80 mg (N = 3015) CNS subset Osimertinib 80 mg (N = 882) Response rate * , % (95% CI) 57 (55, 59) 59 (55, 62) Best overall response†, n (%) Responding Stable disease Progressive disease Unknown 1655 (55) 1043 (35) 202 (7) 115 (4) 485 (55) 274 (31) 66 (7) 57 (6) Median PFS, months (95% CI) 11.1 (11.0, 12.0) 9.7 (9.2, 10.5) Median TTD, months (95% CI) 13.5 (12.6, 13.9) 11.1 (10.1, 12.1) CI, confidence interval * Response rate is defined as the percentage of pts with a best response of ’Responding’ by investigator assessment, based on pts with ≥1 documented response assessment. 95% CI is defined by Clopper-Pearson method †Best overall response is defined as the best response by investigator assessment. Pts with no assessments were considered as ’Unknown’ Clinical trial identification NCT02474355. Editorial acknowledgement Bernadette Tynan, MSc, of iMed Comms, Macclesfield, UK, an Ashfield Company, part of UDG Healthcare plc, funded by AstraZeneca. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure M. Provencio: Advisory / Consultancy: BMS, MSD, AstraZeneca, BI; Travel / Accommodation / Expenses: MSD, AstraZeneca. D. Kim: Research grant / Funding (institution): Alpha Biopharma, AstraZeneca/MedImmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan. B.C. Cho: Honoraria (institution): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, Boehringer Ingelheim, Roche, BMS, Pfizer, Eli Lilly, Takeda, TheraCanVac Inc.; Advisory / Consultancy: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, Boehringer Ingelheim, Roche, BMS, Pfizer, Eli Lilly, Takeda, TheraCanVac Inc.; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (institution): Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc.; Licensing / Royalties: Champions Oncology. K. Park: Advisory / Consultancy: AMGEN, AstraZeneca, Astellas, BluePrint, Eli Lilly, Hanmi, KHK, MSD, Boehringer Ingelheim, Roche, Merck KGaA, Ono; Speaker Bureau / Expert testimony: Boehringer Ingelheim; Research grant / Funding (self): AstraZeneca. R. Migliorino: Advisory / Consultancy: AstraZeneca, MSD, BI, Pfizer, Roche, BMS; Speaker Bureau / Expert testimony: AstraZeneca, MSD, BI, Pfizer, Roche, BMS; Travel / Accommodation / Expenses: AstraZeneca, MSD, BI, Pfizer, Roche, BMS. M. Tiseo: Advisory / Consultancy: AstraZeneca, BMS, MSD, Boehringer Ingelheim, Takeda; Research grant / Funding (institution): AstraZeneca. Q. Zhou: Honoraria (self): AstraZeneca, Roche. A. Santo: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca, Roche. A. Ardizzoni: Honoraria (self): MSD, BMS, Pfizer, Eli Lilly; Advisory / Consultancy: MSD, Roche; Research grant / Funding (institution): BMS, Celgene, Roche. Y. Wu: Honoraria (self): AstraZeneca, Roche, Eli Lilly, Pfizer, MSD, BMS, Boehringer Ingelheim; Advisory / Consultancy: AstraZeneca, Roche, Boehringer Ingelheim; Research grant / Funding (institution): AstraZeneca, Roche. S. Kim: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. M. Miranda: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca PLC. A. Fernandes: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. F. de Marinis: Honoraria (self), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Roche, Celgene, MSD, BMS, AstraZeneca, Takeda, Pfizer; Research grant / Funding (self): Boehringer Ingelheim, MSD. All other authors have declared no conflicts of interest.

Background Repotrectinib is a next-generation ROS1/TRK/ALK TKI with >90-fold potency versus crizotinib against ROS1 and >100-fold potency versus larotrectinib against TRK in engineered Ba/F3 cell proliferation assays. Preclinical studies demonstrate robust activity against all known ROS1/TRK resistance mutations, including the most common solvent-front mutations (SFM) ROS1 G2032R, TRKA G595R, and TRKC G623R/E. Methods In the ongoing phase 1 study (NCT03093116), TKI-naive and TKI-pretreated (≥1 TKI) pts with advanced ROS1, TRK, or ALK fusion+ solid tumors received repotrectinib. Endpoints include safety, PK, and confirmed overall response (cORR). Results As of 4-March-2019, 83 pts were treated with repotrectinib (dose levels from 40 mg QD to 200 mg BID under fasted/fed conditions). Most AEs were manageable and grade (gr) 1-2. The most common treatment-emergent AEs (found in > 30% of pts) were dizziness (57%), dysgeusia (51%), dyspnea (30%), and fatigue (30%). Four DLTs occurred and were manageable with dose modifications: gr3 dyspnea/hypoxia (n = 1); gr2 (n = 1) and gr3 (n = 1) dizziness at 160 mg BID, and gr3 dizziness (n = 1) at 240 mg QD. In ROS1+ NSCLC, the median number of prior TKIs was 1 (0-3); all TKI-naive and 77% of TKI-pretreated pts received prior chemotherapy. In 11 evaluable TKI-naive ROS1+ NSCLC pts, cORR by Blinded Central Review (BCR) was 82% (95% CI 48 - 98); median duration of response was not reached ((range 5.6 - 17.7+ months (mos)). In 18 ROS1+ NSCLC pts pretreated with 1 prior TKI, cORR by BCR was 39% (95% CI 17 – 64), and in 11 pts with 1 prior TKI at doses of 160 mg QD or above cORR was 55% (95% CI 23 - 83). All pts with ROS1 G2032R had tumor regression [cORR of 40% (n = 2/5)]. In 1 TKI-pretreated pt with ETV6-NTRK3+ and an acquired TRKC G623E-mutant salivary gland tumor, a cPR of 9.8 mos was achieved; the patient was treated for 17.9 mos. Enrollment continues. Updated data in ∼10 additional ROS1+ NSCLC and TRK+ solid tumor pts will be presented. Conclusions Repotrectinib was well tolerated and demonstrated encouraging overall clinical activity in pts with ROS1 fusion-positive NSCLC and TRK fusion-positive solid tumors. Clinical trial identification NCT03093116. Legal entity responsible for the study Turning Point Therapeutics Inc, San Diego, CA, USA. Funding Turning Point Therapeutics Inc, San Diego, CA, USA. Disclosure A. Drilon: Honoraria (self), Advisory / Consultancy: Ignyta/Genentech/Roche; Honoraria (self), Advisory / Consultancy: Loxo Oncology/Bayer/Lilly; Honoraria (self), Advisory / Consultancy: TP Therapeutics Inc; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Blueprint Medicines; Honoraria (institution), Advisory / Consultancy: Takeda/Ariad/Milenium; Honoraria (self), Advisory / Consultancy: Helsinn; Honoraria (institution), Advisory / Consultancy: Beigene; Honoraria (self), Advisory / Consultancy: BergenBio; Honoraria (self), Advisory / Consultancy: Hengrui Therapeutics; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Honoraria (self), Advisory / Consultancy: Tyra Biosciences; Research grant / Funding (institution): Foundation Medicine; Licensing / Royalties: Wolters Kluwer; Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy: MORE Health; Honoraria (self), Advisory / Consultancy: Verastem; Travel / Accommodation / Expenses: Puma; Research grant / Funding (institution): Teva; Research grant / Funding (institution): GlaxoSmithKlein. B.C. Cho: Shareholder / Stockholder / Stock options: heraCanVac Inc; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self), Research grant / Funding (institution): AtraZeneca; Honoraria (self), Research grant / Funding (institution): MOGAM Institute; Honoraria (self): Dong-A ST; Licensing / Royalties: Champions Oncology. J.J. Lin: Speaker Bureau / Expert testimony: TP Therapeutics Inc; Honoraria (institution): Chugai; Honoraria (institution): Boehringer-Ingelheim. V. Zhu: Shareholder / Stockholder / Stock options: TP Therapeutics Inc; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astra Zeneka; Honoraria (institution), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Takeda; Honoraria (self): Biocept; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche/Genentech. R.D. Camidge: Research grant / Funding (self): Takeda. S. Stopatschinskaja: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: TP Therapeutics Inc. J..J. Cui: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: TP Therapeutics Inc. D.M. Hyman: Advisory / Consultancy, Travel / Accommodation / Expenses: Chugai; Advisory / Consultancy: CytomX Therapeutics; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Research grant / Funding (self): Puma Biotechnology; Research grant / Funding (self): Loxo. S. Ou: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: TP Therapeutics Inc; Shareholder / Stockholder / Stock options: Ignyta; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ariad; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech/Roche; Honoraria (self), Research grant / Funding (institution): Ignyta; Honoraria (self): Novartis; Research grant / Funding (institution): Blueprint Medicine. A.T. Shaw: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Honoraria (self): Foundation Medicine; Honoraria (self): Guardant Health; Advisory / Consultancy, Research grant / Funding (institution): Ariad; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Advisory / Consultancy: Blueprint Medicine; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy: EDM Serono; Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: KSQ Therapeutics; Advisory / Consultancy: Natera; Advisory / Consultancy: Loxo; Advisory / Consultancy: Takeda; Advisory / Consultancy: Bayer; Advisory / Consultancy: Chugai Pharm; Research grant / Funding (institution): TP Therapeutics. R.C. Doebele: Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Licensing / Royalties: Ignyta; Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Genentech; Shareholder / Stockholder / Stock options: Roche; Research grant / Funding (institution), Licensing / Royalties: Rain Therapeutics; Licensing / Royalties: Abbott Molecular. All other authors have declared no conflicts of interest.

Background PD-L1 expression determined by immunohistochemistry (IHC) can be a useful biomarker to assess the likelihood of benefit with anti-PD-1/PD-L1 therapies in pts with mNSCLC. Understanding the impact of sample type (primary tumour or metastatic) on predictivity of benefit will inform the suitability of such samples for clinical testing. MYSTIC (NCT02453282) was an open-label, phase III study of durvalumab (D) ± tremelimumab vs chemotherapy (CT) as first-line treatment for mNSCLC; stratification factors for randomisation included tumour cell (TC) PD-L1 expression (≥25% vs Methods All pts enrolled in MYSTIC were assessed centrally for TC staining for PD-L1 from tissue samples acquired Results Of 1118 pts randomised, 716 (64.0%) provided a primary tumour sample and 402 (36.0%) provided a metastatic sample. The prevalence of PD-L1 TC ≥25% assessed using primary vs metastatic samples was 43.0% vs 44.8% (p = 0.569). Outcomes in pts with TC ≥ 25% determined using samples of each type are shown. Table . 1491P Primary tumour sample PD-L1 TC ≥25% Metastatic sample PD-L1 TC ≥25% Durvalumab (n = 104) Chemotherapy (n = 100) Durvalumab (n = 59) Chemotherapy (n = 62) Median OS, months 15.8 13.0 20.5 12.9 HR for OS vs CT (95% CI) 0.81 (0.59–1.11) - 0.65 (0.41–1.01) - 24-month OS, % 33.4 19.1 46.9 28.6 ORR, % 30.8 37.0 44.1 38.7 Median DoR, months Not reached 4.4 Not reached 4.1 Conclusions In MYSTIC, PD-L1 TC ≥25% prevalence was similar using primary or metastatic samples. Favourable HRs for OS with D vs CT were seen in pts with TC ≥ 25% expression as determined in either the primary tumour or a metastatic site. Results should be interpreted with caution given the retrospective nature of the analysis. Clinical trial identification NCT02453282 (release date: 25 May 2015). Editorial acknowledgement Samantha Holmes, PhD, of Cirrus Communications (Macclesfield, UK), an Ashfield company, funded by AstraZeneca and in accordance with Good Publication Practice (GPP3) guidelines. Legal entity responsible for the study AstraZeneca PLC. Funding AstraZeneca. Disclosure N. Reinmuth: Honoraria (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Bohringer Ingelheim; Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: MSD; Honoraria (self), Travel / Accommodation / Expenses: Takeda; Honoraria (self): Pfizer. A. Boothman: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. B.C. Cho: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (self): Ono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Yuhan; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Janssen; Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy: MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self), Research grant / Funding (self): MOGAM Institute; Honoraria (self), Research grant / Funding (self): Dong-A ST; Honoraria (self), Research grant / Funding (self), Licensing / Royalties: Champions Oncology; Honoraria (self), Research grant / Funding (self): Dizal Pharma; Honoraria (self), Research grant / Funding (self): MSD. K.H. Lee: Research grant / Funding (institution): AstraZeneca. M. Ahn: Advisory / Consultancy, Research grant / Funding (institution), Spouse / Financial dependant: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Research grant / Funding (institution): BIND Biosciences; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer. M. Scott: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Whiteley: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. J. Walker: Full / Part-time employment: AstraZeneca. V. Karwe: Full / Part-time employment: AstraZeneca. P. Mukhopadhyay: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P. Thiyagarajah: Full / Part-time employment: AstraZeneca. U. Scheuring: Full / Part-time employment: AstraZeneca. N. Rizvi: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Lilly; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Merck KGaA; Advisory / Consultancy: Regeneron; Shareholder / Stockholder / Stock options: Gritstone Oncology; Shareholder / Stockholder / Stock options: ARMO Biosciences. All other authors have declared no conflicts of interest.

Background The overall benefit from systemic treatments in advanced STS remains modest despite advances in cancer therapies. PDX models may help as avatars in guiding individualized drug use decisions. Methods In this prospective single center trial, fresh tumors from patients (pts) with suspected or recently diagnosed STS were engrafted into immunodeficient mice avatars (TumorGraft; Champions Oncology) and tested against a number of standard or non-licensed agents. PDX drug sensitivity profiles were then compared with real-life treatment outcomes. Results Of 18 patients enrolled, 3 patients were excluded (consent withdrawal/non-sarcomas). Patient baseline characteristics are summarized in the table. Rate of engraftment was 40% (6/15 pts), while the median time from biopsy to availability of drug sensitivity profile was 379 days (186 – 421). In patients with available drug sensitivity profile (9 different drugs involving 6 pts), the mouse avatar correctly predicted the drug efficacy or lack thereof of drugs in 7 of 9 drug selection time-points (78%) and in 5 of 6 patients (83%). Table . 1718P Patient baseline characteristics Item Eligible patients (n = 15) Engrafted patients (n = 6) Median age (range) 57 (23-76) 57 (45-69) Gender (M:F) 8:7 3:3 Subtype - Liposarcoma - Leiomyosarcoma -UPS -Others 5 3 1 6 2 2 1 1 Conclusions PDX avatars can accurately predict drug response in STS pts. The rate of engraftment and time taken to produce drug sensitivity profiles are limitations for using this platform in guiding treatment for individual patients in real time. Nonetheless, the high degree of clinical predictability of this PDX platform may offer therapeutic value for personalized oncology approaches. Legal entity responsible for the study Albiruni Razak. Funding Mount Sinai Sarcoma Foundation. Disclosure G. Paris: Full / Part-time employment: champions oncology. M. Mancini: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Champions Oncology. A.R.R. Albiruni: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (self): Lilly; Advisory / Consultancy, Research grant / Funding (self): Merck; Research grant / Funding (self): CASI Pharmaceuticals; Research grant / Funding (self): Novartis; Research grant / Funding (self): Deciphera; Research grant / Funding (self): Kayopharm Therapeutics; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Roche/ Genentech; Research grant / Funding (self): Boston Biomedical; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): MedImmune; Research grant / Funding (self): Amgen; Research grant / Funding (self): GlaxoSmithKline; Research grant / Funding (self): Blueprint Medicines; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Adaptimmune. All other authors have declared no conflicts of interest.

Background Limited data are available on effectiveness and safety of systemic therapies for treatment of advanced (unresectable and/or metastatic) epithelioid sarcoma (ES). This natural history study collected real-world (rw) data on outcomes of ES patients (pts) receiving at least first-line (1L) or 2 or more lines (2L+) of systemic therapies. Methods Retrospective chart review was conducted in pts with advanced ES who initiated systemic therapy between 2000-2017 at 5 US cancer centers. Due to unavailability of RECIST assessment, rw overall response rate (rwORR) was assessed by review of radiology reports. rw disease control rate (rwDCR) was defined as percent of pts with response of any duration or stable disease ≥32 wks. Median rw duration of response (rwDOR), rw progression-free survival (rwPFS) and overall survival (OS) were estimated from start of therapy by Kaplan-Meier method. The index date for time-to-event endpoints was the start of first-line treatment. Adverse events (AEs) resulting in treatment modification, discontinuation, hospitalization, permanent sequelae or death, were abstracted. Results Of 74 eligible pts, 53 (71.6%) were male, and 63 (85.1%) had metastatic ES. INI1/BAF47 was not expressed in 90.2% of 41 tumors tested. Mean age at advanced ES diagnosis was 36.4 years. Anthracycline-based (54.1%) and gemcitabine-based (24.3%) regimens were most common in 1L. Median (range) number of lines of therapy received was 2 (1-7). 1L rwORR was 14.9%, rwDCR was 20.3%, rwDOR was 14.5 wks, and median OS was 66.3 wks. The table shows 1L and 2L+ results. Over 50% of pts had an AE; most frequently febrile neutropenia (13.5%), pain (9.5%), anemia, dyspnea, fever, thrombocytopenia and transaminitis (5.4% each). Conclusions Currently available systemic therapies are not specific for advanced ES, have a limited response durability and low tolerability. This is the largest US-based rw study that provides benchmarking treatment efficacy and safety data for development of standard of care therapies for ES. Table . 1687P Real-world outcomes by line of therapy 1L N = 74 2L+ N = 46 rwORR (95% CI), % 14.9 (7.7-25.0) 9.4 (4.4-17.1) Median rwDOR (95% CI), wks 14.5 (9.1-22.6) 19.6 (3.1-24.3) rwDCR (95% CI), % 20.3 (11.8-31.2) 19.8 (12.4-29.2) Median rwPFS (95% CI), wks 11.0 (7.3-29.9) 26.0 (13.9-32.0) Median OS (95% CI), wks 66.3 (49.6-94.1) 43.3 (33.6-78.3) Legal entity responsible for the study Epizyme, Inc. Funding Epizyme, Inc. Disclosure M.M. Gounder: Advisory / Consultancy, Travel / Accommodation / Expenses: Epizyme; Honoraria (self), Advisory / Consultancy: Karyopharm; Honoraria (self), Advisory / Consultancy: Daiichi; Honoraria (self): TRACON; Honoraria (self): Amgen. P. Merriam: Advisory / Consultancy: Lilly. S.R. Patel: Advisory / Consultancy, Research grant / Funding (self): Janssen; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: MJ Hennessey/Onc Live; Advisory / Consultancy: Novartis; Advisory / Consultancy: Immune D; Research grant / Funding (self): Eisai; Research grant / Funding (self): Blueprint Medicines; Research grant / Funding (self): Bavarian Nordic. R. Chugh: Advisory / Consultancy: Epizyme, Janssen ,EMD Serono; Research grant / Funding (institution): AADi (Institution), Novartis (Institution), Lilly (Institution), Medivation (Institution), Advenchen (Institution), Epizyme (Institution), Plexiconn (Institution), Pfizer (Institution); Research grant / Funding (self): Portoia Pharmaceuticals. M. Thorton: Research grant / Funding (self): Epizyme; Advisory / Consultancy: Biologics Consulting Group; Shareholder / Stockholder / Stock options: Ziopharm, Novavax, Zogenix. B.A. Van Tine: Advisory / Consultancy, Research grant / Funding (institution): Epizyme. A.H. Abdelhamid: Research grant / Funding (institution): Dubai Harvard Foundation. P. Joshi: Full / Part-time employment: Epizyme. J. Whalen: Full / Part-time employment: Epizyme. J. Yang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Epizyme. A. Rajarethinam: Shareholder / Stockholder / Stock options, Full / Part-time employment: Epizyme. M.S. Duh: Research grant / Funding (self): Epizyme, Novartis, GlaxoSmithKline, Janssen, Pfizer, Bayer, Taiho Pharmaceutical; Speaker Bureau / Expert testimony: AbbVie. P.J. Bobbili: Research grant / Funding (self): Epizyme, Novartis, AstraZeneca, GlaxoSmithKline. C.L. Cavanaugh: Research grant / Funding (institution): Epizyme, GlaxoSmithKline, NovoNordisk, Merck, Eisai, AstraZeneca. L. Huynh: Research grant / Funding (institution): Epizyme, Novartis, Pfizer, Taiho Pharmaceutical; Travel / Accommodation / Expenses: Novartis. T. Totev: Research grant / Funding (institution): Epizyme, Novartis, Takeda (formerly Shire). G. Demetri: Shareholder / Stockholder / Stock options: Blueprint Medicines, Merrimack G1 Therapeutics; Caris Life Sciences; Chapions Oncology; Besson Phramceuticals; Advisory / Consultancy: Novartis, Pfizer, EMD Serono, Jannsen, Ignyta, Loxo, Mirati Therapeutics, Epizyme, PharmaMar, Daiichi Sankyo, WIRB-copernicus group, Ziopharm Oncology, Polaris, Bluprint Medicines, Merrimack, G1 Therapeutics, Caris Life Sciences, Champions Oncology, Besso; Research grant / Funding (institution): Bayer, Novartis, Pfizer, Jannsen, Ignyta, Loxo, AbbVie, Epizyme, AdaptImmune.; Licensing / Royalties: Novartis. All other authors have declared no conflicts of interest.

Background Entrectinib is a systemic and CNS-active, potent inhibitor of TRKA/B/C and ROS1. Primary data from integrated efficacy and safety analyses (6 months’ follow-up) from entrectinib clinical trials have shown that entrectinib is a promising option for patients (pts) with NTRK fusion-positive (NTRK+) solid tumors: blinded independent central review (BICR) objective response rate (ORR) was 57.4% (95% CI 43.2–70.8). We show longer follow-up data from this integrated analysis. Methods Pts with locally advanced/metastatic NTRK+ solid tumors confirmed by nucleic acid-based methods and enrolled in global (>150 sites, 15 countries) phase 1/2 entrectinib trials (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267) were included. Tumors were assessed after 4 wks (Cycle 1) then every 8 wks. Scans underwent BICR using RECIST v1.1. Primary endpoints were ORR and duration of response (DOR) by BICR. Secondary endpoints included overall survival (OS); ORR and DOR in pts with and without baseline CNS disease; intracranial (IC) ORR and DOR in pts with baseline CNS disease; safety. Results The efficacy-evaluable population comprises 54 adult pts with advanced/metastatic NTRK+ solid tumors, including pts with baseline CNS metastases. As of 30 Oct 2018 (additional 5 months’ follow-up), BICR ORR was 59.3% (95% CI 45.0–72.4); complete responses n = 4 (7.4%). Median BICR DOR was 12.9 mo (95% CI 7.9–not estimable [NE]), median OS was 23.9 mo (95% CI 16.8–NE). Per baseline CNS status, BICR ORR was 58.3% (95% CI 27.7–84.8) and 59.5% (95% CI 43.3–74.4) and median DOR was NE (4.2–NE) and 12.9 mo (7.9–NE) for pts with (n = 12) and without (n = 42) CNS disease, respectively. IC ORR was 54.5% (95% CI 23.4–83.3) and median IC DOR by BICR was NE (6.7–NE). Entrectinib was well tolerated with a safety profile consistent with that previously reported; there were no new or unexpected safety findings. Conclusions In line with the primary data, these results at an additional 5 months of follow-up show that entrectinib induced clinically meaningful, durable systemic and intracranial responses in pts with NTRK+ solid tumors. Clinical trial identification ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267. Editorial acknowledgement Medical Writing support was provided by Laura Vergoz and Charlotte Kennerley, PhD of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche. Legal entity responsible for the study F. Hoffman-La Roche. Funding F. Hoffman-La Roche. Disclosure C. Rolfo: Speaker Bureau / Expert testimony: MSD, GuardantHealth, Mylan; Research grant / Funding (institution): Novartis, Sanofi; Non-remunerated activity/ies: Oncompass Steering scientific committee; OncoDNA: Research collaboration no renumerated for Exosomes (2017); GuarantHealth research collaboration (2019); Leadership role: IALSC, Educational Committee Member; ISLB, Vice President; Educational Chair, OLA Oncology Latin American Association; Scientific Committee Member at ESO; Membership Committee Officer, ESMO. R. Dziadziuszko: Advisory / Consultancy, Officer / Board of Directors: Roche, Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Novartis; Research grant / Funding (institution): Roche, Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Novartis, Boehringer Ingelheim, Clovis; Travel / Accommodation / Expenses: Roche, AstraZeneca. R.C. Doebele: Shareholder / Stockholder / Stock options: Rain Therapeutics; Advisory / Consultancy: Chair of Scientific Advisory Board for Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer, Trovagene, Ariad, Takeda, AstraZeneca, Genentech/Roche, Ignyta, Loxo, Rain.; Research grant / Funding (institution): Ignyta, Loxo, Mirati; Licensing / Royalties: Abbott Molecular, Rain Therapeutics, GVKbio, Chugai, Loxo, Ignyta, Genentech, Ariad, Foundation Medicine, Black Diamond. G. Demetri: Research grant / Funding (institution): Bayer, Novartis, Pfizer, Janssen Oncology, Ignyta (now Roche), Roche/Genentech, Loxo Oncology, AbbVie, Epizyme, Adaptimmune, GlaxoSmithKline; Advisory / Consultancy: Novartis, Pfizer, EMD-Serono, Sanofi Oncology, Janssen Oncology, Ignyta (now Roche), Roche/Genentech, Loxo Oncology, Mirati Therapeutics, Epizyme, PharmaMar, Daiichi-Sankyo, WIRB Copernicus Group/ Arsenal Capital, ZioPharm, Polaris Pharmaceuticals, M.J.; Licensing / Royalties: Novartis; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: c ICON plc; Advisory / Consultancy, Officer / Board of Directors: Blueprint Medicines; Officer / Board of Directors: Merrimack Pharmaceuticals; Shareholder / Stockholder / Stock options: G1 Therapeutics, Caris Life Sciences, Champions Oncology, Bessor Pharmaceuticals, Erasca Pharmaceuticals. B. Simmons: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche (Genentech). A. Aziez: Full / Part-time employment: Roche. X. Huang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech. S. Osborne: Full / Part-time employment: Roche. L. Paz-Ares: Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly, MSD, BMS, Roche, PharmaMar, Merck, Astra-Zeneca, Novartis, Boehringer Ingelheim, Celgene, Servier, Sysmex, Celgene, Amgen, Incyte, Pfizer; Officer / Board of Directors: Genomica; Research grant / Funding (institution): Astra-Zeneca, BMS, MSD; Non-remunerated activity/ies: Scientific Chair and Member of the Board of Asociacion Espanola Contra el Cancer (AECC; Majoir Spanish Anti-Cancer Charity); Spouse / Financial dependant: My wife (Rocio Garcia-Carbonero): - She has been EMA SAG member untill June 2017 - She has received honoraria from July 2017 onwards from Ipsen, Novartis, Pfizer, Servier, Sanofi, Roche, Amgen and Merck.

Background Tumor stroma represents 20-60% of solid tumor mass and plays a key role in promotion, invasiveness and metastasis. FAP-expressing CAFs, the predominant stroma cell type, are involved in tumor immune response. A novel antibody-drug conjugate, OMTX705, was generated through CYS-based conjugation of a new anti-FAP humanized antibody to a novel cytolysin using an optimized vcPABA linker. Methods In vivo studies were performed in patient-derived xenograft models for NSCL cancer in humanized mice. Tumor volume and animal weight were monitored over 4-week treatment with OMTX705 administered intravenously at different doses, alone or combined with Pembrolizumab. FACS and IHC analysis of markers for immune cells, CAFs, and cell proliferation or apoptosis, were performed on tumor samples to study OMTX705 effect on tumor stroma and elucidate its mechanism of action. In vitro assays were performed to support in vivo data. OMTX705 stability in blood was determined after i.v administration in CD1 mice. Results OMTX705 showed 100% tumor growth inhibition and higher activity than Pembrolizumab in the humanized PDX model for NSCL cancer without weight loss. Full tumor regression was found in 10% of mice treated with OMTX705 alone and 20% in combination with Pembrolizumab. A significant delay in tumor recurrence was observed. OMTX705 was 100% stable in bloodstream after 7 days. FACS analysis evidenced a significant increase in CD8(+) T cell tumor infiltration. Results from in vitro studies and IHC analysis of tumors identified CAFs as highly specific reservoir cells for OMTX705 from which the high potent cytolysin payload is released to induce apoptosis of adjacent tumor cells and CD8(+) T cell immunomodulation. Conclusions OMTX705 alone induces tumor shrinkage, and full regression with Pembrolizumab, through highly specific, CAF-dependent and long-lasting modulation of tumor stroma. This novel mechanism of action makes OMTX705 a potent and innovative strategy for NSCL cancer treatment. Considering FAP is expressed in a wide array of carcinomas, OMTX705 represents a highly promising and well-tolerated candidate to treat solid tumors with low response to anti-PD1 immunotherapies. Legal entity responsible for the study Oncomatryx Biopharma, S.L. Funding Oncomatryx Biopharma, S.L. Disclosure M. Fabre: Full / Part-time employment: Oncomatryx Biopharma, S.L. C. Ferrer: Full / Part-time employment: Oncomatryx Biopharma, S.L. S. Dominguez-Hormaetxe: Full / Part-time employment: Oncomatryx Biopharma, S.L. R. Kontermann: Advisory / Consultancy: Oncomatryx Biopharma, S.L.; Advisory / Consultancy: SunRock Biopharma, S.L.; Advisory / Consultancy: Roche. K. Pfizenmaier: Advisory / Consultancy: Oncomatryx Biopharma, S.L.; Advisory / Consultancy: SunRock Biopharma, S.L. O. Seifer: Research grant / Funding (institution): Oncomatryx Biopharma, S.L. M.D. Vivanco: Research grant / Funding (institution): Oncomatryx Biopharma, S.L. S. Lee: Research grant / Funding (institution): Oncomatryx Biopharma, S.L. P. Lopez-Casas: Full / Part-time employment: Bioncotech Therapeutics, S.L. M. Abbas: Full / Part-time employment: Tube Pharmaceuticals GmBH. W. Richter: Advisory / Consultancy: Oncomatryx Biopharma, S.L.; Shareholder / Stockholder / Stock options, Full / Part-time employment: Tube Pharmaceuticals GmBH. L. Simon: Honoraria (self), Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment, Patents: Oncomatryx Biopharma, S.L.; Honoraria (self), Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment, Patents: Patia Biopharma, SA de CV; Honoraria (self), Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Patia Europe, S.L.; Shareholder / Stockholder / Stock options, Full / Part-time employment: PatiaCan, SA de CV; Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Permedika Entrepeneurs; Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: SunRock Biopharma, S.L.; Licensing / Royalties, Patents: Quimatryx, S.L.; Shareholder / Stockholder / Stock options: Stemcell Therapeutics, S.L.; Shareholder / Stockholder / Stock options: Helenes Ventures, S.L.; Shareholder / Stockholder / Stock options: Nellum Corp. M. Hidalgo: Advisory / Consultancy: Oncomatryx Biopharma, S.L.; Honoraria (self), Advisory / Consultancy, Shareholder / Stockholder / Stock options: Champions Oncology; Honoraria (self), Advisory / Consultancy, Shareholder / Stockholder / Stock options: Pharmacite Biotech; Shareholder / Stockholder / Stock options: BioOncotech; Shareholder / Stockholder / Stock options: Nelum; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self): MSD Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: BiolineRX; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Advisory / Consultancy: SOBI; Honoraria (self), Advisory / Consultancy: Agenus; Honoraria (self), Advisory / Consultancy: Erytech Pharma; Advisory / Consultancy: Merck; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune; Advisory / Consultancy, Travel / Accommodation / Expenses: Menarini; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Research grant / Funding (self): Bicycle Therapeutics; Research grant / Funding (self): Asana Biosciences.

Champions Oncology is a biotech company pushing the limits of biology: It9s selling personalized mouse models to cancer patients. The company creates "avatar" mice with samples of a patient9s tumor and some normal tissue, building a cohort of animals in which to test drugs. The hope is that any therapies that help the mice will also help that particular patient. Champions is drawing praise and criticism, and sparking debate about whether avatar mice are ready for patient use and whether it9s appropriate for families to pay thousands of dollars for a strategy that is still experimental. At the same time, others say the mice have so far shown they can predict responses to drugs in people, and that patients with few options should have the right to try them. There are many hurdles along the way. They include coaxing tumor to engraft in a mouse, and the several months it usually takes to build the animals and test the drugs. Many patients have little time to wait.

Background: Neoadjuvant chemotherapy (NACT) is standard of care in operable breast cancer (BC). There are no therapies that have demonstrated benefit in patients who failed to achieve a pathologic complete response (pCR). There remains an unmet need to identify appropriate targets in which to direct therapy in this high-risk population to decrease BC mortality. Computational approaches to reverse engineering of cell signaling networks from patient tumor-specific RNA expression data can identify key molecular dependencies that result in the malignant phenotype, i.e. MRs. These approaches out-perform traditional methods, such as identifying mutated or over-expressed genes, in determining true tumor dependencies. Successful targeting of MRs may be a means for rational selection of targeted drugs in the operable BC setting. Trial Design: A single center pilot study that will accrue 35 subjects with BC who will have received standard NACT and at least 1.5 cm of residual disease. At the time of definitive surgery, resected tissue will be assessed for residual disease and then allocated. After reserving required tissue for pathologic diagnosis, 0.5 cm3 will be procured for xenografting and 0.5 cm3 will be flash frozen for RNA extraction. Tissue for xenografting is immediately sent to a Champions Oncology site for implantation. We will use fresh frozen tissue to perform RNA-seq. Previously validated computational algorithms at our center, including MARINa and VIPER, will be used to interrogate the expression data and identify the top MRs in individual tumors. Upon maturation of a Champions Oncology Tumor Graft model, the second generation expansion group will be divided into four cohorts. We plan to test two drugs that target tumor-specific MRs, one vehicle control, and one negative control (paclitaxel, as these tumors have demonstrated paclitaxel resistance) in each model. Eligibility Criteria 1. Patients ≥18 years with newly diagnosed BC, deemed candidates for definitive surgery. 2. Subjects must have received standard NACT with taxane (paclitaxel or docetaxel; herceptin +/- pertuzumab if HER2+) and/or adriamycin/cytoxan. 3. Clinical or radiographic evidence of ≥1.5 cm of residual BC. 4. ECOG PS ≤2 Specific Aims: 1) To computationally infer MRs in individual patient tumors resistant to NACT 2) To determine if targeting MRs results in superior tumor growth inhibition in PDX models Statistical Methods: In the PDX model, pre- and post-treatment tumor volume (TV) is calculated: TV= width2 x length x 0.52, and is standardized as a tumor growth inhibition (TGI) percentage compared to the vehicle control. Since we anticipate the MR-directed arms will demonstrate a TGI (80%) twice that of the paclitaxel arm (40%), we have 80% power to detect a difference in 18 patients (one-sided alpha, 0.05). We assume a xenograft take-rate of 50% in the post-NACT setting and thus aim for an N of 35. Final data analysis will be adjusted using ANOVA. Present and Target Accrual: 35 patients, projected to accrue in 18-24 months. Estimate based on number of locally advanced BC patients seen, competing studies, and likelihood of participation. The study will open in Fall 2014. Citation Format: Kevin Kalinsky, Prabhjot Mundi, Dawn L Hershman, Eileen Connolly, Katherine D Crew, Hanina Hibshoosh, Andrea Calfiano, Matthew Maurer. Master regulator (MR)-directed therapy in residual breast cancer patient derived xenografts (PDXs) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-08.

Cachexia is present in the majority of patients with advanced cancer progression and is not reversible through nutritional supplementation, leading to loss of skeletal muscle and adipose tissue. There are a lack of quality pre-clinical models for cachexia research. Previously, Champions Oncology reported a mouse cachexia model derived from a primary human renal cell carcinoma tumor implanted in immunocompromised mice. This model, CTG-0804, was developed using the innovative Champions TumorGraft™ platform, which preserves the biological properties of the original human tumor. The Champions TumorGraft platform demonstrated dramatic weight loss in these mice as the tumor grew. Plasma from these mice also showed elevated levels of human IL-6. We have now further characterized this TumorGraft model by evaluating standard of care (SOC) agents for renal cell carcinoma and anti-IL-6 compounds to determine the mechanism of cachexia. The SOC evaluation revealed that sorafenib, sunitinib, temsirolimus and bevacizumab as single agents provided a survival advantage by inhibiting tumor growth and preventing weight loss in these mice. Blockade of human IL-6 with tocilizumab or ALD518 did not inhibit tumor growth and weight loss still occurred, demonstrating the possibility of other pathways involved in the cachexia mechanism. In addition, the SOC data for sunitinib showed significant tumor growth inhibition, but no regression at the study end point. This correlated with the clinical profile, where sunitinib could not prevent metastasis and the patient eventually progressed. The TumorGraft model was molecularly characterized and mutation analysis revealed a KIT V530I mutation. This mutation has been reported in extra-abdominal aggressive fibromatosis (desmoid tumor) and acute myeloid leukemia patients that have responded to c-kit targeting therapies, such as imatanib and dasatinib. Further characterization of this TumorGraft is ongoing to include additional bioinformatics using gene expression and mutation pathway analyses. In summary, we have continued development of this cachexia model using the Champions TumorGraft platform, along with molecular evaluation, to produce a robust and well-characterized approach for cachexia investigation which can also be applied to other areas of drug development and cancer research. Citation Format: Nathan Anderson, Tin Khor, Andrew Feldhaus, Andreya Gatling, Katie Olson, John Latham, David Sidransky, Elizabeth M. Bruckheimer. Development of a spontaneous in vivo cachexia model using the Champions TumorGraft™ platform. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1217. doi:10.1158/1538-7445.AM2014-1217

The blockade of immune checkpoints with monoclonal antibodies (mAbs) is a promising therapeutic avenue, with durable objective responses observed in patients with solid tumors, particularly melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma. Preclinical models that recapitulate a functional human immune system will therefore be essential tools for the continued investigation of immunotherapy approaches. Champions Oncology is engaged in advanced personalized solutions and our TumorGraft models have been developed and extensively characterized as a platform for use in personalizing cancer patient care, as well as pharmaceutical development. However, because TumorGrafts are established by engrafting patient tumors into immune-deficient mice, the therapeutic efficacy of immune-modulatory drugs cannot be directly examined. To circumvent this limitation, we reconstituted the human immune system by engrafting human hematopoietic cells (HLA-A2; CD34+) into immune-compromised mice (PrkdcscidIl2rgtm1Sug) carrying the scid mutation and a targeted mutation of the Il2r-gamma gene. Ten to twelve weeks later, mature CD45+ human T cells could be detected in these mice, at which time TumorGrafts were established, followed by drug-sensitivity testing with various mAbs targeting the immune system. Fifty six well-established melanoma, colorectal, breast and lung TumorGraft models were characterized and selected with regard to their HLA type and other molecular characteristics such as BRAF mutation status (in melanoma) and KRAS mutation status (in colorectal and lung cancer) as well as expression of PD-L1. With the present study, we demonstrated the potential of combining the humanized mouse with Champions TumorGraft to generate a preclinical platform for assessing the therapeutic value of mAbs targeting immune checkpoints in various solid tumors. Citation Format: Gilson S. Baia, David Vasquez, Daniel Ciznadija, Brandy Wilkinson, David Sidransky, Amanda Katz, Keren Paz. Humanized mouse models for personalized preclinical testing of monoclonal antibodies targeting immune checkpoints. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1674. doi:10.1158/1538-7445.AM2014-1674

Aim: The inability to distinguish patient populations that are most likely to respond to different treatments is a continuing challenge for medical oncologists. Technologies that can be broadly applied to all patients, which enable multiple therapeutic regimens to be evaluated simultaneously to identify the ones most likely to be clinically beneficial, are needed. Drug sensitivity screening in patient-derived xenografts (PDXs) is a viable solution. In this study we examined the capacity of PDXs to replicate patient outcomes across a variety of solid tumors and treatments and report performance metrics highlighting the clinical utility of this tool. Methods: Tumor tissue from 495 cancer patients was engrafted into immunodeficient mice to generate PDX models. Of these, 65 were screened against the treatments received by the corresponding patient. Patient clinical responses and model drug responses were assessed and correlated using RECIST criteria, with parameters, including sensitivity, specificity, and predictive values, calculated to determine the capacity of PDX responses to capture patient responses. Results: Positive (complete and partial response as well as stable disease) and negative (progressive disease) patient outcomes to treatment were accurately replicated by PDXs, regardless of tumor type or treatment. Based on 96 correlations in 65 patients, we calculated a sensitivity of 99% (72/73 correlations) and specificity of 70% (16/23 correlations) for our PDX drug screens, as well as predictive values of 91% (72/79 correlations) and 94% (16/17 correlations). Despite patient exposure to first-line regimens, PDX models generated from the first resection retained the ability to reproduce outcomes to treatments used for recurrent disease. Conclusions: PDXs accurately reflect clinical responses and have strong potential to correctly guide an oncologist to treatments most likely to yield a favorable patient response, whilst avoiding those that would not. Integration of PDX technology into routine cancer care will re-shape clinical decision-making paradigms in oncology, generating better patient outcomes and eventually help cancer be managed as a chronic disease. Disclosure: M. Hidalgo: I am on the Scientific Advisory Board of Champions Oncology; A. Davies: I am an employee of Champions Oncology and I own stock in the company; D. Vasquez-Dunddel: I am an employee of Champions Oncology and I own stock in the company; D. Ciznadija: I am an employee of Champions Oncology and own shares in the company; A. Katz: I am an employee of Champions Oncology and I own stock in the company; D. Sidransky: I am on the Board of Directors for Champions Oncology and I own stock in the company; K. Paz: I am an employee of Champions Oncology and I own stock in the company. All other authors have declared no conflicts of interest.

The oncogenic receptor tyrosine kinases (RTK) AXL and c-Met are over-expressed and constitutively activated in a variety of human cancers. Activation of these receptors contributes to multiple steps in tumor progression, including the epithelial-mesenchymal transition (EMT) by which cancer cells escape to form metastases and frequently develop resistance to a variety of agents, most notably to epidermal growth factor receptor (EGFR) targeted therapies. CEP-40783 is an orally-active, nanomolar potent and highly kinase-selective Type II inhibitor of the AXL and c-Met RTK in drug development. In the current study, five Champions human TumorGraft™ models of NSCLC expressing constitutively activated AXL and/or c-Met were used to determine the anti-tumor efficacy of single agent CEP-40783 compared to paclitaxel and the EGFR inhibitor, erlotinib (Genentech-Roche; OSI Pharmaceuticals). Champions Oncology has developed an innovative platform that utilizes the implantation of primary human tumors in immune-deficient mice in a manner that preserves the biological properties of the original human tumor and results in more rigorous and clinically relevant models for drug discovery. Previous reports have shown the correlation between responsiveness observed in Champions TumorGraft™ models and clinical responses of the patients from which the models were derived. Mice bearing established Champions TumorGrafts™ were treated orally with 10 mg/kg and 30 mg/kg qd of CEP-40783 for 10 to 34 days (until control tumors achieved >1000 mm3 volume) and anti-tumor efficacy and tolerability were evaluated. In 3/5 (60%) of the tumor models, CEP-40783 showed in vivo efficacy, including tumor regressions, significantly superior to that achieved with an optimal regimen of paclitaxel. In 4/4 (100%) of the erlotinib-insensitive tumor models, CEP-40783 demonstrated significant efficacy (66 to 118% TGI) compared to the control group at the 30 mg/kg dose. Additionally, CEP-40783 in combination with erlotinib demonstrated superior anti-tumor efficacy compared to CEP-40783 and erlotinib single agents in the one erlotinib-sensitive model evaluated. CEP-40783 as a single agent and in combination with erlotinib was well tolerated. Retrospective bioinformatics analyses are planned to determine potential signatures of response and resistance to CEP-40783. These results demonstrate that CEP-40783 shows superior efficacy alone and in combination with erlotinib in Champions TumorGraft™ models of NSCLC compared to SOC agents and supports the development of CEP-40783 for the treatment of erlotinib-resistant NSCLC. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C272. Citation Format: Jay A. Friedman, Rodney Donaldson, Sheila Miknyoczki, Mangeng Cheng, Robert Hudkins, Bruce Dorsey, Mark Ator, Thelma Angeles, Bruce Ruggeri, Elizabeth Bruckheimer. Antitumor activity of the dual AXL/c-Met inhibitor CEP-40783 in Champions primary TumorGraft™ models of human non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C272.

Glioblastoma (GBM) is characterized by recurrence and resistance to conventional treatments such as chemotherapy and radiation. Therefore alternative therapeutic approaches are needed. TRAIL, a promising anti-tumor agent, induces apoptosis in cancer cells but not in normal cells. However, its short half-life and lack of efficient administration modes are serious impediments to its therapeutic efficacy. Nanoparticles (NP) have been used as effective delivery tools for various anticancer drugs. In the current study, TRAIL was covalently conjugated to the surface of iron oxide NP via its primary amine groups. The efficacy of TRAIL conjugated NP (NP-TRAIL), temozolomide (TMZ), and NP-TRAIL + TMZ was evaluated in vivo in three human TumorGraft models representing human GBM from Champions Oncology or START, ST108, CTG-0667 and ST146. Champions Oncology has developed an innovative platform that utilizes the implantation of primary human tumors in immune-deficient mice in a manner that preserves the biological properties of the original human tumor and results in more rigorous and clinically relevant models for drug discovery. Previous reports have shown the correlation between responsiveness observed in Champions TumorGraft™ models and clinical responses of the patients from which the models were derived. Results demonstrated significant tumor growth inhibition (TGI) following treatment with either TMZ alone or the combination of NP-TRAIL + TMZ. In TumorGraft model ST108 the combination demonstrated superior anti-tumor activity, 109% TGI, compared to TMZ alone, 53% TGI. Interestingly, in addition to tumor growth inhibition, the combination also demonstrated 2 partial responses whereas TMZ alone demonstrated none. The MGMT methylation status of the specimens, which is known to be correlated to the degree of response to TMZ, was evaluated and results were found to be low indicative of an unmethylated status. In conclusion, our innovative compound NP-TRAIL was tested in vivo on three different TumorGraft models, each representing a GBM patient with unmethylated MGMT. The combination treatment of NPT+TMZ was found to be effective and superior to treatment with either NPT or TMZ as single agents and suggests that NP-TRAIL, in combination with TMZ, may be an effective treatment of GBM. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A84. Citation Format: Jay A. Friedman, Michael Wick, Lizette Gamez, Rodger Chaves, Elizabeth Bruckheimer, Shifra Kleinman, Benny Perlstein. Nanoparticles-TRAIL demonstrated superior anti-tumor activity in champions and START tumor graft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A84.

Phosphatidylinositol 3-kinase (PI3K) is an important intracellular signal transducer that is involved in many cellular functions such as cell growth, proliferation, and differentiation. PI3K is a heterodimeric molecule composed of a regulatory and a catalytic subunit. PIK3CA, which encodes the p110α catalytic subunit, is often mutated in a range of human cancers, such as colorectal and non-small-cell lung cancers. Increasing our understanding of the biological implications of these mutations and the role of PI3K pathway in cancer proliferation or survival may lead to potential new therapeutic opportunities targeting PI3K signaling. Champions Oncology focuses on the development of TumorGraft models derived from the direct implantation of patient tumors into immunocompromised mice. Compared to traditional cell line-based xenograft models, the patient derived Champions TumorGraft™ models maintain stable gene-expression patterns and mutational status and correlate to clinical predictability. Through extensively characterization, Champions has identified 19 TumorGraft models with PIK3CA mutations. Out of these 19 models, there are 11 colorectal cancers, 3 non-small cell lung cancers, 3 pancreatic cancers, 1 gastric cancer and 1 melanoma. Genomics analyses using the Ampliseq platform identified the majority of PIK3CA mutations in exon 9 and 20. Mutations in these regions of PIK3CA are known to confer resistance to some anti-cancer agents, such as HER2 antibodies. Additionally, it has been reported that PIK3CA mutations frequently coexist with RAS and BRAF mutations in patients with advanced cancers. Upon further analysis, we identified the same pattern in Champions TumorGraft models where∼70% (13 out of 19) of the PIK3CA mutant models possess either concurrent RAS or BRAF mutations. Notably, PI3K activates the downstream kinase AKT which ultimately triggers the mTOR pathway. Mutations in cancer often result in constitutive activation of this pathway. Given the role of the PI3K/AKT signaling in cancer and the presence of these specific mutations in the Champions TumorGraft bank, utilization of Champions’ TumorGraft models in oncology drug development allows for greater insight into new therapeutic opportunities targeting the inhibition of PI3K/AKT signaling and offers new promise for patients with these activated pathways. Citation Format: Tin Oo Khor, Dhanrajan Tiruchinapalli, Jay Friedman, Nathan Anderson, David Sidransky, Elizabeth M. Bruckheimer. Champions TumorGraft™ models possess PIK3CA mutations - A great tool to explore the PI3K/AKT pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2781. doi:10.1158/1538-7445.AM2013-2781

Cachexia, defined as a loss of adipose tissue and skeletal muscle mass not reversible by nutritional support, is present in the majority of patients with advanced cancer progression. This reduces the patient's quality of life and impacts their ability to function normally and undergo treatments. Reversing cachexia has been problematic due to a lack of quality pre-clinical models. Traditional xenograft models using cell lines are limited due to their inability to accurately replicate the whole body response to cancer. Champions Oncology overcomes this challenge through the use of its innovative Champions TumorGraft™ platform, where primary human tumors are implanted into immunocompromised mice in a manner that preserves the biological properties of the original human tumor. Champions has identified a panel of three TumorGraft models which spontaneously induce cachexia when implanted subcutaneously into nude mice: 1) CTG-0282, a pancreatic cancer model, 2) CTG-0765, a NSCLC model, and 3) CTG-0804, a renal cell carcinoma model. All three models have shown a greater than 90% cachexia rate, as demonstrated by lost body weight, over multiple passages. In addition, loss of body weight correlates with an increase in tumor volume size. Mice that have little or no tumor growth show no loss of body weight. Past studies have indicated a function for pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin 1 (IL-1), interleukin 6 (IL-6) and interferon gamma (IFNγ), in the cachexia process. Champions is currently investigating the roles of these possible tumor-mediated factors in the aforementioned models. Principle among these factors is IL-6, which has been shown to be required in the regulation of cachexia in tumor-bearing mice and is correlated with weight loss and survival in patients. Preliminary results from our studies suggest a correlation between IL-6 levels and spontaneous cachexia in Champions TumorGraft models. In summary, we demonstrate that the Champions TumorGraft platform preserves the biological properties of the original human tumor, including spontaneous cachexia behavior in these models, and is therefore ideal for oncology drug development programs focused on the inhibition of cachexia. Citation Format: Nathan Anderson, Tin Oo Khor, Andrew Feldhaus, Katie Olson, John Latham, David Sidransky, Elizabeth M. Bruckheimer. Characterization of spontaneous in vivo cachexia models in Champions TumorGraft™ models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2792. doi:10.1158/1538-7445.AM2013-2792

One of the challenges in oncology drug development is the inability of traditional in vivo models to predict clinical responses. Champions Oncology overcomes this challenge through the use of its innovative Champions TumorGraft™ platform, where primary human tumors are implanted into immunocompromised mice in a manner that preserves the biological properties of the original human tumor. The current study evaluated the molecular and demographic characteristics of the Champions TumorGraft™ bank to demonstrate that these models closely resemble cancer patients that pharmaceutical companies encounter in clinical trials during the development of innovative and targeted oncology compounds. In particular, the relative frequency of ethnicity, age, and geographic location in the Champions TumorGraft™ bank closely aligns with patients enrolled in oncology clinical trials. For instance, greater than half of the models in Champions TumorGraft bank are derived from patients with advanced disease, who failed several previous lines of therapy. This is extremely important for accurate translational research, as most patients enrolling in critical mid-stage oncology clinical trials often have advanced disease and have failed multiple lines of therapy. Additionally, in recent years, clinical trials have progressed to designs where there are specific enrichments in patient populations/sub-populations based on the incorporation of companion diagnostics. Molecular evaluation of the Champions TumorGraft™ bank identifies models that possess genomic signatures or pathway expressions which can be used to identify and validate potential enrichment strategies. For example, 40% of Champions’ NSCLC models possess p53 mutations and 36% of all NSCLC clinical cases also possess p53 mutations according to the COSMIC database. Additionally, 50% of Champions colorectal TumorGraft models possess K-ras mutations, whereas 36% the clinical colorectal cancer population possesses this mutation. These cases, as well as other mutations observed across several tumor types, demonstrate that the TumorGraft mutation prevalence is representative of the prevalence in cancer patients. Together, these results demonstrate that Champions TumorGraft™ models represent a unique preclinical in vivo platform that correlate to oncology clinical trial populations. Overall, these results suggest that Champions TumorGraft™ models are capable of predicting the clinical effectiveness of drug candidates and can accelerate and enhance oncology drug development. Citation Format: Tin Oo Khor, Jay Friedman, Dhanrajan Tiruchinapalli, Nathan Anderson, David Sidransky, Elizabeth M. Bruckheimer. Champions TumorGraft™ models represent oncology clinical trial populations. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2798. doi:10.1158/1538-7445.AM2013-2798

Prostate cancer (PCa)is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males, with the highest incidence rates recorded in developed countries such as those in North America (Jemal et al., 2011). While the five year-survival rate for PCa patients with localized disease is 100%, it is only 30.6% once the cancer metastasizes (Vishnu et al., 2010). One of the biggest challenges for finding a better treatment for metastatic PCa is the lack of predictable and accurate preclinical models that closely recapitulate different stages of the pathogenesis of human PCa. Champions Oncology focuses on the development of Champions TumorGraft™ models derived from the direct implantation of patient tumors into immunocompromised mice. Compared to traditional cell line-based xenograft models, the patient-derived TumorGraft models maintain stable gene-expression patterns and mutational status and correlate to clinical predictability. To overcome the challenge for PCa, Champions Oncology has utilized its TumorGraft technology to establish and characterize a new androgen-dependent prostate cancer TumorGraft model, CTG-0488. This involved the implantation of a primary human prostate tumor in immunocompromised mice in a manner that preserves the biological properties of the original human tumor. In this preliminary work, the characteristics of Champion TumorGraft™ model CTG-0488 are showcased, including tumor histology, mutational status, and chemosensitivity profiles to several standard of care compounds. Overall the development of an androgen-dependent prostate cancer Champions TumorGraft™ model will significantly aid in the development of oncology compounds focused on androgen-dependent prostate cancer. Citation Format: Tin Oo Khor, Keren Paz, Dhanrajan Tiruchinapalli, David Sidransky, Elizabeth M. Bruckheimer. Development of an androgen-dependent prostate Champions TumorGraft™ cancer model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2793. doi:10.1158/1538-7445.AM2013-2793

Breast cancer is the most common cancer among women with over 280,000 new annual cases and 40,000 deaths in the US alone. While hormonal-dependent breast cancer is correlated with good prognosis, an adequate solution for hormonal-independent tumors remains an unmet medical need, largely due to a significant heterogeneity within tumors and their makeover. Various personalized oncology approaches aim at tailoring the optimal regimen for these patients by better understanding their tumor distinctiveness. Champions Oncology focuses on personalizing cancer treatment through the generation of TumorGraft™ models form the patient's own tumor. The current study is focused on the attempt to identify a personalized solution for a patient with HER2-amplified metastatic breast cancer whose disease progressed on Trastuzimab (Herceptin). Using Champions novel and cutting-edge TumorGraft™ technology, the challenge was confronted empirically by preforming a personalized clinical trial in vivo. Tumor fragments, obtained from both the primary breast tumor and lung metastasis, were implanted in immune-deficient mice in a manner that preserves the biological properties of the original tumor and its supporting stroma. Once the TumorGraft™ models were established, panel of drugs and drug combinations were evaluated to help identify treatment regimens that are likely to be most effective for the patient clinically. The drug study encompassed 7 different treatment groups including FDA-approved, as well as investigational agents. Of the 7 treatment arms, 3 demonstrated a significant anti-tumor response with tumor growth inhibition values of 80, 93 and 97% for Lapatinib+Capecitabine, Gemcitabine+Carboplatin and Ixabepilone+Capecitabine, respectively. Molecular analysis of the tumor revealed a truncated HER2 (p95) and a robust HER2 translocation to the nucleus. Additional molecular characterization is ongoing to determine other potential signatures of response. Results from the TumorGraft™ study were recommended to the patient and her medical oncologist and new lines of treatment were commenced subsequently. Herein, we describe the data from the TumorGraft™ drug study, the molecular exploration and the pathway analysis of the primary and the metastatic tumor and the consequences correlation to the clinical outcome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5252. doi:1538-7445.AM2012-5252

One of the challenges in oncology drug development is the lack of in vivo models that demonstrate the spontaneous metastatic process. Standard subcutaneous implantation of cell-line based xenografts models seldom results in the generation of spontaneous metastatic lesions. In general, experimental metastatic models are utilized which requires the intravenous injection of cells or orthotopic implantation of tumors cells to replicate metastases. These methods fail to capture the full process of metastases and only capture seeding in the distant location. Champions Oncology utilizes its innovative Champions Tumorgraft™ platform where primary human tumors are implanted into immunocompromised mice in a manner that preserves the biological properties of the original human tumor. As part of its extensive characterization, Champions has recently observed an increasing number of Champions Tumorgraft™ models demonstrating spontaneous metastatic lesions following subcutaneous (s.c.) implantation. The tumor types demonstrating spontaneous metastasis include breast, melanoma, colorectal, esophageal adenocarcinoma, and head and neck squamous cell carcinoma. Two Champions Tumorgraft models highlighted in this report are CTG-0033, a breast cancer model, and CTG-0213, a melanoma model. These Champions Tumorgraft models demonstrate frequent metastases to the liver and spleen following s.c. implantation. For model CTG-0033, metastases were seen in greater than 75% of the animals following implantation. The metastatic behavior of this Tumorgraft model also parallels the clinical disease progression. For instance, CTG-0033 was derived from a breast cancer patient who, following the development of the Tumorgraft model, developed extensive metastases. Given that treatment failures clinically are often due to recurrence of the tumor at metastatic locations, there is significant need for in vivo models that replicate the spontaneous metastatic process. Overall, numerous Champions Tumorgraft models implanted s.c. exhibit spontaneous metastatic behavior and are therefore ideal models for oncology drug development focused on inhibition of metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B18.