Gastric cancer is the fourth leading cause of cancer death globally, with adenocarcinoma being the most common type of gastric and gastroesophageal junction (GEJ) cancer.1 These cancers share similar molecular profiles and, with systemic chemotherapy, have comparable clinical outcomes.1 Standard first-line treatment for advanced or metastatic unresectable HER2-negative GEJ or gastric adenocarcinoma is fluoropyrimidine plus platinum-based chemotherapy.1 However, this therapy is associated with <1 year median overall survival.1 The phase 3 ATTRACTION-2 study demonstrated that nivolumab, a programmed death (PD)-1 inhibitor, provided significant overall survival benefit when compared with a placebo in pretreated advanced or recurrent GEJ or gastric cancer.1 First-line PD-1 inhibitors were studied in the phase 3 CheckMate 649 study in participants with previously untreated advanced gastric, GEJ, or esophageal adenocarcinoma.1 The use of nivolumab plus chemotherapy gave a superior survival advantage over use of chemotherapy alone in these patients. Based on these results, FDA approval was granted for nivolumab in combination with chemotherapy for metastatic gastric cancer and esophageal adenocarcinoma.
At the European Society for Medical Oncology Congress 2021, Yelena Janjigian, MD, presented further follow-up information on nivolumab plus chemotherapy versus chemotherapy alone and first results on the combination of nivolumab plus ipilimumab versus chemotherapy alone. Patients were enrolled regardless of PD-ligand 1 (PD-L1) expression prior to being randomized into treatment groups, but those with known HER2-positive status were excluded from the study. The study’s primary end points were overall survival and progression-free survival.
There were 1581 patients randomized to receive nivolumab plus chemotherapy or chemotherapy alone with 60% of these patients having PD-L1 combined positive score (CPS) ≥5. Nivolumab dosing was 360 mg every 3 weeks or 240 mg every 2 weeks. Chemotherapy consisted of XELOX (capecitabine and oxaliplatin) every 3 weeks or FOLFOX (fluorouracil, leucovorin, and oxaliplatin) every 2 weeks. The results indicated that participants showed continued improvement over the 12-month follow-up period in overall survival with nivolumab plus chemotherapy when compared with chemotherapy alone.
There were 813 patients randomized into groups receiving nivolumab plus ipilimumab or chemotherapy alone and 58% of these patients had PD-L1 CPS ≥5. Nivolumab dosing was 1 mg/kg and ipilimumab was dosed at 3 mg/kg every 3 weeks for 4 doses, followed by nivolumab at 240 mg every 2 weeks. When the 2 treatment groups’ overall survival was compared, nivolumab plus ipilimumab did not confer any significant overall survival benefit when compared with chemotherapy. There was an acceptable safety profile for nivolumab plus chemotherapy.
Janjigian YY, Ajani JA, Moehler M, et al. Nivolumab (NIVO) plus chemotherapy (Chemo) or ipilimumab (IPI) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 study. Ann Oncol. 2021;32(suppl_5):S1283-S1346.
- Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398:27-40.