The Matterhorn clinical trial has simplified the treatment approach for operable gastroesophageal cancer. It established FLOT chemotherapy combined with the checkpoint inhibitor durvalumab as the preferred perioperative regimen, resolving previous debates about the optimal strategy.

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.

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 TOURMALINE study confirmed that pairing the checkpoint inhibitor Durvalumab with various gemcitabine-based chemo combinations (not just cisplatin) is safe and effective in biliary tract cancer. This provides crucial real-world evidence supporting clinical flexibility beyond the rigid protocols of pivotal trials.

While neoadjuvant-only immunotherapy has a strong rationale, a patient-level cross-trial comparison of CheckMate 816 (neoadjuvant) and 770T (perioperative) suggests the addition of adjuvant therapy improves event-free survival, favoring a full perioperative approach.

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.

The Matterhorn study found that adding the immunotherapy drug Durvalumab to FLOT chemotherapy significantly improved survival in localized gastric cancer. Surprisingly, this benefit extended to patients with low or negative PD-L1 expression, challenging the biomarker's predictive value for immunotherapy efficacy in this perioperative setting.

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.

Despite being the backbone for new combination therapies in trials like Matterhorn, the FLOT chemotherapy regimen has significant toxicity. Approximately 30% of patients discontinue treatment due to adverse events, and only half manage to complete the post-surgery adjuvant portion, posing a major clinical challenge in real-world settings.