First-line regorafenib with nivolumab and FOLFOX or CapeOX in patients with advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: A single-arm, phase Ib/II trial (REGONIVOCTx, EPOC2104).

4052 Background: We previously reported anti-tumor activity of regorafenib plus nivolumab for advanced gastric cancer (AGC) patients at a third or later line (1). Recently, first-line regorafenib with nivolumab and FOLFOX in AGC showed promising results in a phase 2 in the United States. CapeOX requires less frequent outpatient visits than FOLFOX and is preferred in Asian countries. We investigated the safety and efficacy of regorafenib with nivolumab and chemotherapy including CapeOX for AGC in the first-line treatment. Methods: Enrolled patients received regorafenib with nivolumab and CapeOX (Cohort A) or FOLFOX (Cohort B) in the phase Ib part (safety lead-in) to determine the recommended dose. Additional patients were enrolled in the phase II part. Regorafenib of 90 mg was administered once daily for 21 days on/7 days off with nivolumab 360 mg every 3 weeks (Cohort A) or 240 mg every 2 weeks (Cohort B) and chemotherapy. The primary end point was dose-limiting toxicity (DLT) during the first 4 weeks in the phase Ib part and objective response rate (threshold 60%, expected 80%, α = 0.1, β = 0.2) in patients with the recommended dose in the phase Ib/II part. The primary endpoint would be met if at least 22 of 30 patients showed objective tumor response. We also conducted biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: A total of 30 patients (14 in Cohort A and 16 in Cohort B) were enrolled from June 2022 to April 2023. All patients had MSS/pMMR tumors. No DLTs were observed in both cohorts. Objective tumor response was observed in 22 of 30 (73%; 80%CI 60.3-83.8) patients, thus the primary endpoint was achieved. Disease control rate was 97%. Six-month progression-free survival was 66.7% (95%CI 46.9-80.5). The most common grade 3 or worse treatment-related adverse events included neutropenia (33%), AST/ALT increased (13%), hypertension (13%), and leucopenia (7%) without unexpected safety signals. Conclusions: First-line regorafenib with nivolumab and chemotherapy including CapeOX showed anti-tumor activity with acceptable safety profiles in AGC patients. The results of biomarker analysis will be presented. A randomized, phase III trial is planned. 1. Fukuoka S, J Clin Oncol 2020. Clinical trial information: NCT05394740 .