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)

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.

Concordance between microsatellite instability testing and immunohistochemistry for mismatch repair proteins and efficient screening of mismatch repair deficient gastric cancer

“…In recent years, the combined positive score derived from IHC utilizing PD-L1 antibody has emerged as a frequent biomarker for guiding the application of ICI in GCs ( 40 ). Moreover, research findings have indicated that the efficacy of ICI monotherapy is comparable to that of ICI plus chemotherapy in MSI-H GCs ( 41 , 42 ), and the combination of nivolumab and ipilimumab may be as highly effective as in MSI-H CRC ( 43 , 44 ). Therefore, the importance of dMMR decision tests for GC is poised to escalate in the future.…”

Exploring the landscape of drug resistance in gastrointestinal cancer immunotherapy: A review

“…Nevertheless, resistance to ICIs can manifest, prompting the investigation of their confluence with other therapeutic modalities, such as chemotherapy, radiation, or targeted therapies, to mitigate this challenge. [ 45 ] A prime example of such investigative efforts is the ongoing single-arm phase II trial (JapicCTI-205400), [ 46 ] which is evaluating the efficacy and safety of nivolumab combined with low-dose ipilimumab in patients with microsatellite instability-high metastatic Gastric/Gastroesophageal Junction Cancers. This trial is a testament to the potential of combination regimens in GI cancers, aiming to bolster the immune response and assail the oncogenic growth and survival mechanisms from varied dimensions.…”

Current Strategy to Treat Immunogenic Gastrointestinal Cancers: Perspectives for a New Era

“…Following the success of nivolumab plus low-dose ipilimumab combination therapy in MSI-H/dMMR mCRC, the NO LIMIT study (WJOG13320G/CA209-7W7), a single-arm phase II trial, to evaluate the efficacy and safety of the nivolumab and low-dose ipilimumab as the first-line setting for MSI-H metastatic GC/GEJC (JapicCTI-205400) is ongoing [ 84 ]. Nivolumab plus ipilimumab (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles, then nivolumab 240 mg every 2 weeks) adopted in CheckMate-649 resulted in an early discontinuation recommendation by the data monitoring committee because of unacceptable toxicities [ 53 ].…”