Nivolumab alone or in combination with ipilimumab met multiple endpoints against metastatic or locally advanced chemotherapy-refractory esophagogastric cancer in the recent phase 1/2 CheckMate-032 trial, thereby opening doors to a future phase 3 trial.
The agents demonstrated “clinically meaningful antitumor activity,” reported Yelena Y. Janjigian, MD, of Memorial Sloan Kettering Cancer Center, New York, and her coauthors.
After the 2017 ATTRACTION-2 trial demonstrated improved survival rates, “nivolumab was approved in Japan for the treatment of patients with chemotherapy-refractory gastric and gastroesophageal junction [GEJ] cancers regardless of programmed death-ligand 1 [PD-L1] status,” the authors wrote in the Journal of Clinical Oncology.
Nivolumab is a checkpoint inhibitor, like pembrolizumab, which “was approved for the treatment of patients with chemotherapy-refractory PD-L1–positive gastric/GEJ cancer on the basis of the promising clinical activity observed in the KEYNOTE-059 trial,” the authors noted. Testing nivolumab in a Western population would therefore build on these previous trials. Combining nivolumab, a PD-l inhibitor, with ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte antigen 4, was based on “synergistic activity” reported in preclinical models, the authors wrote.
Results from the ongoing CheckMate-032 trial included 160 patients with metastatic or locally advanced chemotherapy-refractory esophageal, gastric, or gastroesophageal junction cancer treated at centers in Europe and the United States. Just under 80% of patients had received two or more prior therapies.
In the present trial, patients were given one of three treatment regimens: nivolumab 3 mg/kg every 2 weeks, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles (NIVO1 + IPI3), or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four cycles (NIVO3 + IPI1). The primary endpoint was objective response rate (ORR). Secondary endpoints included 12-month progression-free survival and 12-month overall survival (OS).
Patients in the NIVO1 + IPI3 group achieved the best ORR (24%) and 12-month progression-free survival (17%) and also showed a promising 12-month OS (35%), second only to nivolumab monotherapy (39%). PD-L1 status was not predictive of treatment response.
Although NIVO1 + IPI3 was the most clinically effective, almost half (47%) of these patients also had grade 3 or higher adverse events, compared with more favorable rates of 17% and 27% for nivolumab monotherapy and NIVO3 + IPI1, respectively.
Still, the authors concluded, “on the basis of the numerically higher overall response and landmark OS rates in the NIVO1 + IPI3 arm, this combination was considered more likely to offer clinical benefit relative to currently available treatment regimens for first-line metastatic esophagogastric cancer and was selected for further evaluation in the phase 3 CheckMate-649 study (NCT02872116).” This trial, along with another to investigate nivolumab in the adjuvant setting (NCT02743494), are ongoing.
CheckMate-032 was supported by Bristol-Myers Squibb. The authors also reported funding from Merck, Incyte, Gilead Sciences, and others.
SOURCE: Janjigian YY et al. J Clin Oncol. 2018 Aug 15. doi: 10.1200/JCO.2017.76.6212.