Multicenter phase 2 trial of perioperative pembrolizumab in dMMR/MSI localized colorectal cancer

Mismatch repair deficiency (dMMR) or microsatellite instability (MSI) represents a distinct phenotype among solid tumors resulting in the generation of highly immunogenic neoantigens. Pembrolizumab has been approved in first-line unresectable or metastatic dMMR/MSI colorectal cancer (CRC). The multicenter phase 2 IMHOTEP trial evaluated perioperative pembrolizumab in localized dMMR/MSI CRC. The study enrolled 81 patients who received one or two cycles of intravenous pembrolizumab 400 mg once every 6 weeks before surgery and one-year total duration thereafter. Median age was 66 years (range 21-89), 52% were women, and 71% had clinical stage III at baseline. Out of 72 patients included in the efficacy population, 38 had pathologic complete response (52.7%; 95% CI 41.4-63.9). Exploratory post hoc analysis showed that the pCR rate increased from 46% after one cycle to 68.2% after two cycles of neoadjuvant pembrolizumab. With a median follow-up of 24.5 months, three disease recurrences were observed. Grade ≥ 3 immune-related toxicities were reported in 14 patients (15.7%) including one grade 5 (myasthenia)> The authors conclude that IMHOTEP showed promising results, with pCR achieved after one or two cycles of neoadjuvant pembrolizumab in 53% of patients with dMMR/MSI CRC