A randomized phase 3 study evaluating the efficacy and safety of first-line pembrolizumab plus lenvatinib plus chemotherapy compared with chemotherapy in patients with advanced/metastatic gastroesophageal adenocarcinoma: LEAP-015

Background Combination chemotherapy with fluoropyrimidine and platinum is recommended by the National Comprehensive Cancer Network as a first-line treatment option for patients with locally advanced recurrent and/or metastatic gastric cancer; however, there is a need for more effective therapies. PD-1 inhibitor pembrolizumab in combination with the RTK inhibitor lenvatinib previously demonstrated antitumor activity and acceptable safety in advanced gastroesophageal adenocarcinoma. Pembrolizumab plus lenvatinib plus platinum-doublet chemotherapy also showed acceptable safety in metastatic non–small cell lung cancer in the phase 3 LEAP-006 study. Here we describe the LEAP-015 (NCT04662710) study, a randomized, two-part, phase 3 trial evaluating the efficacy and safety of pembrolizumab plus lenvatinib plus chemotherapy as first-line therapy in advanced/metastatic gastroesophageal adenocarcinoma. Trial design Eligible patients have histologically and/or cytologically confirmed diagnoses of previously untreated locally advanced unresectable or metastatic gastroesophageal adenocarcinoma that is not HER2-positive, measurable disease per RECIST v1.1, Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1, and a tumor tissue sample for biomarker analysis. Part 1, safety run-in: ≥12 patients will be treated for induction with intravenous pembrolizumab 400 mg Q6W (×2) plus oral lenvatinib 8 mg QD plus investigator’s choice of chemotherapy (CAPOX Q3W ×4 [oral capecitabine 1000 mg/m2 twice daily for 14 days and intravenous infusion oxaliplatin 130 mg/m2] or mFOLFOX6 Q2W ×6 [bolus intravenous infusion 5-fluorouracil 400 mg/m2 or continuous intravenous infusion 5-fluorourcail 2400 mg/m2, intravenous infusion leucovorin 400 mg/m2 or levoleucovorin 200 mg/m2, and intravenous infusion oxaliplatin 85 mg/m2 ]) and for consolidation with pembrolizumab 400 mg Q6W for ≤16 doses plus lenvatinib 20 mg QD; dose-limiting toxicities will be evaluated for 21 days after the last patient is enrolled. Part 2, main study: patients will be randomly assigned 1:1 to induction with pembrolizumab plus lenvatinib plus chemotherapy (CAPOX or mFOLFOX6) followed by consolidation with pembrolizumab plus lenvatinib using the same dosing schedule as in part 1 or chemotherapy alone (CAPOX or mFOLFOX6 for maximum cycles allowed per local standards). Randomization will be stratified by region (East Asia vs North America and Western Europe vs rest of world), ECOG PS (0 vs 1), and intended chemotherapy (CAPOX vs mFOLFOX6). Treatment will continue until confirmed disease progression, unacceptable toxicity, intercurrent illness that prevents further administration of treatment, patient/physician decision to withdraw, or noncompliance. The first tumor imaging assessment will be performed at 6 weeks from the date of randomization, then Q6W or more frequently if clinically indicated. In part 1, the primary objective is to evaluate the safety and tolerability of treatment in all patients. In part 2, the dual primary objectives are to compare overall survival and progression-free survival (per RECIST v1.1 assessed by BICR) between treatment groups in patients with PD-L1 combined positive score (CPS) ≥1 and all patients; secondary objectives include comparing objective response rate and duration of response (per RECIST v1.1 assessed by BICR) between treatment groups in patients with PD-L1 CPS ≥1 and in all patients and to evaluate the safety and tolerability of treatment in all patients. Recruitment is ongoing. Clinical trial identification ClinicalTrials.gov, NCT04662710. Editorial acknowledgement Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc., Woodcliff Lake, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Eisai Inc., Woodcliff Lake, NJ, USA. Disclosure J. Tabernero: Honoraria (self): educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER); Advisory / Consultancy: Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics and TheraMyc. E. Van Cutsem: Advisory / Consultancy: Array, Astellas, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex, Taiho; Research grant / Funding (institution): Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. Y. Janjigian: Advisory / Consultancy: Bristol-Myers Squibb, Merck Serono, RGENIX, Eli Lilly, Daiichi-Sankyo, Pfizer, Bayer, Imugene, Merck, Zymeworks, Seattle Genetics, Basilea Pharmaceutica, AstraZeneca; Research grant / Funding (institution): NCI, Department of Defense, Cycle for Survival, Fred's Team, RGENIX, Bayer, Genetech/Roche, Bristol-Myers Squibb, Eli Lilly, Merck. Y. Bang: Advisory / Consultancy: AstraZeneca, Novarits, Genetech/Roche, Merck Serano, MSD, BMS, Daiichi-Sankyo, Astellas, BeiGene, GreenCross, Samyang Biopharm, Hanmi; Research grant / Funding (institution): MSD, Merck Serano, GreenCross, AstraZeneca, Novartis, Genetech/Roche, Bayer, BMS, GSK, Pfizer, Eli Lilly, Curis, Taiho, Takeda, Ono, Daiichi-Sankyo, Astellas, BeiGene, Genexine. A. Wang: Travel / Accommodation / Expenses: Merck; Shareholder / Stockholder / Stock options: Merck; Full / Part-time employment: Merck. C. Shih: Shareholder / Stockholder / Stock options: Merck & Co.; Full / Part-time employment: Merck & Co. P. Bhagia: Full / Part-time employment: Merck & Co., Inc. K. Shitara: Honoraria (self): Novartis, AbbVie Inc, Yakult; Advisory / Consultancy: Astellas Pharma; Bristol-Myers Squibb; Novartis; Taiho Pharmaceutical; Merck Pharmaceutical, Eli Lilly and Company; Pfizer Inc; AbbVie Inc; GlaxoSmithKline; Amgen, Takeda Pharmaceuticals; Ono Pharmaceutical; Daiichi Sankyo; Boehringer Ingelheim; Research grant / Funding (institution): Astellas Pharma; Daiichi Sankyo; Merck Pharmaceutical; Medi Science, Ono Pharmaceutical; Taiho Pharmaceutical, Dainippon Sumitomo Pharma; Chugai Pharma; Eisai. All other authors have declared no conflicts of interest.