An open label phase II study of lenvatinib with pembrolizumab and FLOT in the neoadjuvant and adjuvant treatment for patients with gastric and gastroesophageal junction adenocarcinoma (EPOC2001)

BackgroundWe previously reported anti-tumor activity of lenvatinib plus pembrolizumab for metastatic gastric cancer (Kawazoe A, et al. Lancet Oncol. 2020), leading to the phase 3 LEAP-015 trial. The objective of this study is to evaluate anti-tumor activity of lenvatinib with pembrolizumab and FLOT as neoadjuvant and adjuvant treatment for patients (pts) with locally advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma.MethodsEligible pts are with previously untreated gastric and GEJ adenocarcinoma as defined by cT2-4 and/or cN+ without evidence of metastatic disease. Dose-limiting toxicity (DLT) was assessed in the first 3 pts, and then additional 29 pts were enrolled. Pts will receive 8 mg oral lenvatinib daily with 200 mg intravenous pembrolizumab every 3 weeks for 3 infusions in combination with 4 cycles of FLOT as the neoadjuvant treatment followed by surgery. Same cycles of combination therapies followed by 11 cycles of pembrolizumab monotherapy were given as the adjuvant treatment. The primary endpoint was major pathological response (MPR) rate by central assessment (threshold 30%, expected 50%, α = 0.10, β = 0.20). We also conducted biomarker research using paired samples from repeated tumor biopsies and blood collections.ResultsA total of 32 pts were enrolled from Nov. 2022 to Sep. 2023. The primary sites were gastric (22 pts) and GEJ (10 pts). Clinical stages ranged from II/III/IVa: 10/20/2 pts. Six pts had dMMR tumors. No DLTs were observed in the safety lead-in period. Of the cohort, 31 pts completed planned neoadjuvant treatment and 1 pt discontinued because of gastric perforation. R0 resection was achieved in all 32 pts. MPR was observed in 15 of 32 (47%; 80%CI 34-60) pts, thus the primary endpoint was achieved. The pCR rate was 22% (95%CI 9-40). The most common grade 3 or worse treatment-related adverse events included AST/ALT increased (28%), and platelet count decreased (19%) without unexpected safety signals.ConclusionsLenvatinib with pembrolizumab and FLOT showed promising activity with acceptable safety profiles for locally advanced gastric or gastric and GEJ adenocarcinoma.Clinical trial identificationNCT04745988.Legal entity responsible for the studyNational Cancer Center Hospital East.FundingMerck.DisclosureA. Kawazoe: Financial Interests, Personal, Advisory Board: Zymeworks, Merck & Co.; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Eli Lilly, Bristol Myers Squibb, Ono Pharmaceutical Co., Ltd. K. Shitara: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Takeda, Ono Pharmaceutical, MSD, Novartis, Daiichi Sankyo, Amgen, Guardant Health Japan Corp, Astellas Pharma Inc., Astellas, Bayer, AstraZeneca, Zymeworks Biopharmaceuticals Inc., ALX Oncology Inc.; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Janssen, AstraZeneca, Eli Lilly, Astellas, Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Eisai, Amgen, PRA Health Sciences. All other authors have declared no conflicts of interest.