Two phase 2 trials (NEONAPIGA, INFINITY) show that preoperative combination immunotherapy achieves pathologic complete response rates of nearly 60% in MSI-high gastric cancers. This success establishes a new paradigm, potentially allowing non-operative management and avoidance of surgery for patients who respond well.
In the Matterhorn trial, while completing the full perioperative FLOT plus durvalumab regimen yields the best outcomes, the immunotherapy's benefit persists even with partial adherence. Patients receiving some or even no adjuvant durvalumab still showed superior event-free survival compared to chemotherapy alone, a key finding for real-world practice.
While the Keynote 585 trial (doublet chemo + pembrolizumab) failed overall, its small FLOT chemotherapy subgroup mirrored the positive results of the Matterhorn trial (FLOT + durvalumab). This suggests the choice of a less aggressive chemotherapy backbone, not the immunotherapy concept, was the critical factor in the trial's negative outcome.
The ATTRACTION-6 trial surprisingly found that adding combination immunotherapy (ipilimumab + nivolumab) to first-line chemotherapy did not improve overall survival over chemotherapy alone in metastatic gastric cancer. This negative result reinforces that adding a single-agent checkpoint inhibitor to chemotherapy remains the global standard of care.
Long-term follow-up from multiple major trials (Checkmate 649, Keynote 590) consistently demonstrates that adding a checkpoint inhibitor to first-line chemotherapy produces durable benefits. This combination more than doubles or triples the 5-year overall survival rate from ~3-5% with chemotherapy alone to over 11-13% with immunotherapy.