Is pembrolizumab as safe and efficient as neoadjuvant treatment in localized dMMR/MSI esophagogastric cancers?...

Patients with localized mismatch repair deficient (dMMR)/microsatellite instability (MSI)-high esophagogastric adenocarcinomas are rare and derive limited benefit from standard perioperative chemotherapy. Immune checkpoint inhibitors have demonstrated efficacy in metastatic dMMR/MSI tumors, and recent phase II studies have shown promising activity in localized stages.

The multicenter, phase II trial IMHOTEP (NCT04795661) assessed perioperative pembrolizumab in nonmetastatic dMMR/MSI solid tumors. The esophagogastric cohort included patients with localized (cT2-4N0/N+M0) esophagogastric cancer and confirmed dMMR/MSI status. Patients received one or two infusions of neoadjuvant pembrolizumab (400 mg every 6 weeks) and optional post-operative pembrolizumab for up to nine cycles and were candidates for surgery. The primary endpoint was pathological complete response (pCR; ypT0N0).

Between May 2021 and February 2025, among the 41 patients treated with pembrolizumab, 36 received one to two neoadjuvant pembrolizumab infusions and were eligible for surgery and included in the efficacy analysis (surgery: N = 27; no surgery: N = 9). Of note, five patients were excluded from efficacy analysis (inclusion/exclusion criteria not met, N = 3; >2 neoadjuvant pembrolizumab: N = 2). The subgroup of operated patients had R0 resection (N = 27), and four (14.8%) achieved pCR. With a median follow-up of 25.8 months, 25 (93%) patients experienced no progression, recurrence, or death. Grade ≥3 treatment-related adverse events occurred in nine (22%) patients.

Perioperative pembrolizumab is feasible and safe in localized dMMR/MSI esophagogastric cancers. Further investigation is warranted to optimize the duration and nature of neoadjuvant immunotherapy.