Abstract
Simple SummaryMicrosatellite 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.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.
Highlights
Gastric cancer (GC) remains one of the most common and deadly cancers worldwide, especially among older males
In Japan, NIVO+IPI has been approved for treatment of metastatic melanoma and renal cell carcinoma, as well as more recently for that of metastatic microsatellite instability-high (MSI-H) CRC in the second-line setting on the basis of the results of the CheckMate-142 study [13]
Data suggest that a higher dose intensity of ipilimumab is more likely to be associated with a higher incidence of adverse events that can lead to treatment discontinuation
Summary
Gastric cancer (GC) remains one of the most common and deadly cancers worldwide, especially among older males. GC patients often present with unresectable or metastatic disease at diagnosis, with cytotoxic chemotherapy having the potential to prolong survival and improve quality of life (QoL) in such individuals. Such chemotherapy can deliver only a moderately longer duration of disease control and survival, with its efficacy having reached a plateau. Cancer immunotherapy with immune checkpoint inhibitors (ICIs) has recently shown clinical activity and the ability to confer a survival benefit either as monotherapy or in combination with other types of immunotherapy or conventional chemotherapy in multiple types of cancer. The proportion of patients who benefit from ICIs is smaller for GC than for other types of solid tumor, highlighting the importance of biomarker identification for selection of individuals most likely to benefit from such treatment
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