Background
Phase III RCT included 1581 patients with HER2-negative, untreated, unresectable advanced or metastatic gastric (70%), gastroesophageal junction (18%) or esophageal adenocarcinoma (12%). First-line setting.
Interventions and follow up
Arm A: Nivolumab 360 mg q3wk + XELOX (capecitabine 1000 mg/m² oral BID D1-14, oxaliplatin 130 mg/m² D1) or Nivolumab 240 mg q2wk + FOLFOX (leucovorin 400 mg/m² D1, fluorouracil 400 mg/m² bolus D1 and 1200 mg/m² D1-2, oxaliplatin 85 mg/m² D1)
Arm B: Chemotherapy (XELOX or FOLFOX) alone
Primary endpoint: OS and PFS in PD-L1 CPS≥5
mFollow up: 13.1 mo (minimum)
Arm B: Chemotherapy (XELOX or FOLFOX) alone
Primary endpoint: OS and PFS in PD-L1 CPS≥5
mFollow up: 13.1 mo (minimum)
Results
mOS, CPS≥5: 14.4 vs 11.1 mo, arm A vs B (HR 0.71; 98.4% CI 0.59-0.86; P<.0001)
mPFS, CPS≥5: 7.7 vs 6.0 mo (HR 0.68; 98% CI 0.56-0.81; P<.0001)
mOS, all randomized: 13.8 vs 11.6 mo (HR 0.80; 99.3% CI 0.68-0.94; P=.0002)
mPFS, CPS≥5: 7.7 vs 6.0 mo (HR 0.68; 98% CI 0.56-0.81; P<.0001)
mOS, all randomized: 13.8 vs 11.6 mo (HR 0.80; 99.3% CI 0.68-0.94; P=.0002)
Adverse events
Overall: Grade ≥3 treatment-related events 59% vs 44%, arm A vs B
Most common any-grade: nausea, diarrhea, peripheral neuropathy
Deaths: treatment-related deaths uncommon in both arms
Most common any-grade: nausea, diarrhea, peripheral neuropathy
Deaths: treatment-related deaths uncommon in both arms
Conclusions
First-line nivolumab plus chemotherapy improved OS and PFS versus chemotherapy alone in advanced gastric/GEJ/esophageal adenocarcinoma, with greatest benefit in PD-L1 CPS≥5.
Key Limitations
Magnitude of OS benefit attenuated in PD-L1 CPS<5 subgroup, raising questions about benefit in low-CPS patients. Open-label design.
Clinical Context
FDA approved nivolumab plus fluoropyrimidine- and platinum-containing chemotherapy for first-line advanced gastric/GEJ/esophageal adenocarcinoma (April 2021). ESMO endorses chemoimmunotherapy first-line, with biomarker-driven selection by PD-L1 CPS.