- First-line nivolumab+chemotherapy yields improved OS and PFS compared with chemotherapy alone in previously untreated patients with advanced gastric cancer (GC)/gastroesophageal junction cancer (GEJC)/esophageal adenocarcinoma (EAC).
- The safety profile in this trial was manageable.
- This combination is a potential new standard first-line treatment in this population.
Why this matters
- Survival is poor after standard first-line chemotherapy in patients with advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative GC/GEJC.
- Randomized, open-label phase 3 study (CheckMate 649).
- Previously untreated patients with unresectable or metastatic GC/GEJC/EAC without known HER2-positive status enrolled regardless of programmed cell death ligand 1 (PD-L1) expression.
- Randomization (1:1:1):
- Nivolumab+chemotherapy (data not reported here);
- Nivolumab (360 mg 3×/week or 240 mg 2×/week) + chemotherapy (XELOX: oxaliplatin and capecitabine 3×/week or FOLFOX: fluorouracil, leucovorin, and oxaliplatin 2×/week); or
- Chemotherapy alone.
- 1581 patients concurrently randomly assigned to nivolumab+chemotherapy or chemotherapy alone.
- Dual primary endpoint: OS and PFS in patients with PD-L1 combined positive score (CPS) ≥5.
- Secondary endpoints: OS (PD-L1 CPS ≥1 or all randomized), OS (PD-L1 CPS ≥10), PFS (PD-L1 CPS ≥10, 1 or all randomized), objective response rate.
- Funding: Bristol-Myers Squibb.
- Minimum follow-up: 12 months.
- Median OS (interim analysis) in PD-L1 CPS ≥5 tumors:
- 14.4 months with the combination vs 11.1 months with chemotherapy only.
- HR, 0.71 (P<.0001>
- Median PFS (final analysis):
- 7.7 months with the combination vs 6.1 months with chemotherapy only.
- HR, 0.68 (P<.0001>
- Superior OS and PFS benefit also in PD-L1 CPS ≥1 and all randomly allocated patients with the combination vs chemotherapy alone.
- No new safety concerns emerged with the combination (no grade 5 treatment-related adverse events).
“These results are likely to lead a paradigm shift in the treatment of first-line advance gastroesophageal cancers. For patients with PD-L1 CPS ≥1, breaking through the 1-year barrier in OS is a milestone,” commented Elizabeth Smyth, medical oncologist, Cambridge University Hospitals NHS Foundation Trust, who was not involved in the study.
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