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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.

7024 Background: The eicosanoid pathway is altered in NSCLC. Pharmacological activators of peroxisome proliferator-activated receptor-gamma (PPARγ) have been shown to inhibit lung tumors in vitro. LY293111 inhibits the eicosanoid pathway, is a PPARγ agonist and modulates adipophilin and adiponectin expression levels in vitro. LY293111 is well tolerated and can be administered with cisplatin/gemcitabine. A randomized phase II study in NSCLC was undertaken. Methods: Pts with stage IIIB/IV NSCLC were randomized to two doses of LY293111 (200 mg BID (Arm A) or 600 mg BID (Arm B) or placebo (Arm C) alone for 7 days followed by concurrent cisplatin (75 mg/m2;d1) and gemcitabine (1250 mg/m2;d1,8) q21 days. Treatment was continued until disease progression or toxicity. Primary endpoint was PFS with 75% power to detect 33% improvement compared to placebo (5 months). Calculated sample size was 65 pts/arm (195 total) with a one sided type I error of 0.2. Changes in adipophilin mRNA expression and adiponectin serum levels were assessed at baseline and day 7. Results: Between 09/03 and 07/04, 201 pts were randomized and 195 treated. Demographics (all pts): M:F (65%:35%); median age 61 (range 27–87); stage IIIB/IV (15%:85%); ECOG PS (0:36%;1:64%). Demographics were well balanced between the 3 arms. Most common CTC grade 3/4 toxicities were nausea (8%), vomiting (7%), fatigue (6%) and diarrhea (6%) with only diarrhea related to dose of LY293111 (p=0.03). Response rates (CR+PR) were similar in all 3 arms (A:20%; B:27%; C:21%). There was no significant difference in median PFS (95% CI) between the arms (A: 4.6 months (3.2–5.0); B:6.0 months (4.6–7.2); C:6.0 months (5.2–7.0)). Median survival (95% CI) was similar in all 3 arms (A: 7.3 months (6.2–9.4); B:7.9 months (7.2–9.7); C: 9.0 months (7.7–12.5). Median change in serum adiponectin levels at d7 were significantly higher in arm B vs. placebo (p < 0.05). Adipophilin expression at d7 was increased in a dose dependent manner (p=NS) in arms A and B vs. placebo. Conclusions: LY293111 in combination with cisplatin/gemcitabine did not increase median PFS compared to placebo in pts with NSCLC. Pharmacodynamic modulation was observed but did not impact efficacy. [Table: see text]