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.

The success of neoadjuvant immunotherapy trials like Niagara and those with EV-Pembro means most patients will receive immune therapy before surgery. This fundamentally shifts the clinical landscape, making the question of starting adjuvant immunotherapy less relevant as perioperative treatment becomes the standard.

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.

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 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.

The Durvalumab monotherapy arm showed a promising disease-free survival signal (HR 0.74), but due to reduced recruitment from COVID-19, the trial was underpowered for statistical significance. This shows how external factors can compromise a trial's ability to deliver a definitive clinical answer, leaving a potentially effective therapy in limbo.

An overall survival (OS) benefit in an adjuvant trial may not be meaningful for patients in systems (e.g., the U.S.) with guaranteed access to the same effective immunotherapy upon recurrence. The crucial, unanswered question is whether treating micrometastatic disease is inherently superior to treating macroscopic disease later, a distinction current trial data doesn't clarify.

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.

Clinical trial data suggests immunotherapy's timing is crucial in early-stage TNBC. Given with chemotherapy before surgery (neoadjuvant), it improves outcomes. However, when given alone after surgery (adjuvant), the IMPASSION 030 trial showed no benefit and was halted for futility, indicating pre-surgical tumor priming is essential.