There are few therapeutic options for patients with metastatic chemotherapy refractory esophagogastric cancer, and prognosis for these patients is poor. Immunotherapy with PD-1 targeting immune checkpoint inhibitors has been shown to be a highly effective treatment option across a variety of solid tumors. Preclinical and early clinical data support the role for immune checkpoint blockade in esophagogastric cancer. Based on promising clinical activity observed in the KEYNOTE-059 trial, pembrolizumab gained FDA accelerated approval for the third-line therapy in patients with chemotherapy-refractory PD-L1–positive gastric/gastroesophageal cancer. Furthermore, in phase III ATTRACTION-2 trial, the PD-1 inhibitor nivolumab demonstrated significant improvement in overall survival (OS) compared to placebo, regardless of PD-L1 expression in Asian patients with advanced gastric or gastroesophageal junction cancer. This agent was also recently approved in Japan.
In the phase I/II CheckMate-032 trial (N = 160), the safety and efficacy of nivolumab alone and nivolumab plus ipilimumab was evaluated in Western patients with advanced, chemotherapy-refractory gastric, esophageal, or gastroesophageal junction cancer. Patients received either nivolumab 3 mg/kg (NIVO3), nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1 + IPI3), or nivolumab 3 mg/kg plus ipilimumumab 1 mg/kg (NIVO3 + IPI1).
The objective response rates (ORR) in the three treatment groups were 12% (NIVO3), 24% (NIVO1 + IPI3), and 8% (NIVO3 + IPI1). The median duration of response (DoR) was 7.1 months, 7.9 months, and not yet reached in the three respective treatment groups. PD-L1 expression status did not impact response, and responses were observed in patients regardless of MSI status. The median progression-free survival (PFS) was 1.4 months in the NIVO3 and NIVO1 + IPI3 groups and 1.6 months in the NIVO3 + IPI1 group. The 12-month rates of PFS were 8%, 17%, and 10%, respectively. The median OS was 6.2 months (NIVO3), 6.9 months (NIVO1 + IPI3), and 4.8 months (NIVO3 + IPI1), with 12-month OS rates of 39%, 35%, and 24%, respectively.
The adverse event (AE) profiles were consistent with the known profiles of nivolumab and ipilimumab in other tumor types. Grade 3/4 treatment-related AEs occurred in 17% of patients receiving NIVO3, 47% receiving NIVO1 + IPI3, and 27% receiving NIVO3 + IPI1. Serious treatment-related AEs occurred in 10%, 43%, and 25% of patients, respectively, including one death due to tumor lysis syndrome in the NIVO3 + IPI1 group that was considered treatment related.
The investigators concluded that, combined with data from previous studies, these results indicate that nivolumab-based therapy is a safe and effective treatment option for patients with advanced esophagogastric cancer who have progressed on second-line chemotherapy, regardless of MSI or PD-L1 expression status or ethnicity. Because the study was not powered for cross-group comparisons, no conclusions can be made regarding the relative safety and efficacy of nivolumab alone versus combination nivolumab and ipilimumab. Based on numerically higher overall response and OS rates with the NIVO1+IPI3 combination, this regimen is being compared with chemotherapy and chemotherapy plus nivolumab in phase III trials in patients with advanced esophagogastric cancer in the first-line setting, while nivolumab monotherapy is being compared to placebo in the adjuvant setting.