An Investigator-Initiated Phase 2 Study of Nivolumab Plus Low-Dose Ipilimumab as First-Line Therapy for Microsatellite Instability—High Advanced Gastric or Esophagogastric Junction Cancer (NO LIMIT, WJOG13320G/CA209-7W7)

Simple Summary Microsatellite instability-high (MSI-H) is an established biomarker for response to immune checkpoint inhibitors (ICIs). ICIs are not usually administered in the first-line setting for MSI-H tumors including gastric cancer (GC), although such tumors tend to be less responsive to cytotoxic chemotherapy compared with microsatellite-stable tumors. On the basis of evidence suggesting that nivolumab plus low-dose ipilimumab can improve survival in MSI-H colorectal cancer, we plan to investigate the efficacy and safety of this regimen for MSI-H GC, which accounts for ~5% of all GC cases. The NO LIMIT study (WJOG13320G/CA209-7W7) is an investigator-initiated, single-arm, open-label, 14-center phase 2 trial of nivolumab plus low-dose ipilimumab for MSI-H GC in the first-line setting. Its primary objective is to determine the overall response rate for the study treatment as assessed by blinded independent central review. The planned number of subjects is 28. Abstract Nivolumab (NIVO) plus low-dose ipilimumab (IPI) has shown a promising survival benefit in first-line treatment of microsatellite instability-high (MSI-H) colorectal cancer. We hypothesized that this regimen might also be beneficial for MSI-H gastric cancer (GC), which accounts for ~5% of all GC cases. NO LIMIT (WJOG13320G/CA209-7W7) is an investigator-initiated, single-arm, open-label, 14-center phase 2 trial of NIVO plus low-dose IPI for MSI-H GC in the first-line setting. Eligibility criteria include unresectable advanced, recurrent, or metastatic gastric or esophagogastric junction cancer with a histologically confirmed diagnosis of adenocarcinoma; confirmed MSI-H status with the MSI-IVD Kit (FALCO); no prior systemic anticancer therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a measurable lesion per RECIST 1.1. The primary objective of the study is to determine the overall response rate (ORR) for the NIVO+IPI regimen as assessed by blinded independent central review. Secondary end points include progression-free survival, overall survival, duration of response, safety, tolerability, and biomarkers. The number of patients was set at 28 on the basis of the threshold and expected ORR values of 35 and 65%, respectively, with a one-sided alpha error of 0.025 and power of 0.80. Subjects will receive treatment with nivolumab (240 mg) biweekly in combination with ipilimumab (1 mg/kg) every 6 weeks. The results of this study should clarify the therapeutic potential of NIVO+IPI for MSI-H GC in the first-line setting. Trial registration: JapicCTI-205400.