Neoadjuvant pembrolizumab with a watch‑and‑wait strategy for localized MSI/dMMR colon cancer: Study protocol for a randomized GERCOR 109 - PRODIGE 84 phase II trial (PREMICES).

BACKGROUND: Microsatellite instability (MSI) or mismatch‑repair deficiency (dMMR) defines a biologically distinct subgroup of colorectal cancers that are highly responsive to immune checkpoint inhibition. Major and complete pathological responses have been observed with neoadjuvant immunotherapy, raising the possibility of avoiding upfront surgery in selected patients.

METHODS: PREMICES is a multicenter, open‑label, randomized (1:1), non‑comparative phase II trial evaluating neoadjuvant pembrolizumab followed by a structured watch‑and‑wait strategy versus standard-of-care surgery ± adjuvant chemotherapy in adults with resectable, localized MSI/dMMR colon or upper rectal adenocarcinoma. Sixty patients will be randomized across nine French centers. The primary endpoint is 6-month strategy success after randomization (or after two successive colonoscopies), defined as the absence of death, disease progression, a decision to operate due to residual tumor on biopsies, or any primary‑tumor surgery. Secondary endpoints include the 24-month success, event‑free and overall survival, postoperative morbidity, health‑related quality of life (EORTC QLQ‑C30/CR29), tumor regression, and endoscopic complete response. Embedded translational studies include circulating tumor DNA and gut microbiota analyses. Randomization started in September 2025.

DISCUSSION: PREMICES will determine whether a neoadjuvant PD‑1 blockade‑based non‑operative approach can be pursued safely and effectively in localized MSI/dMMR colon cancer and will generate prospective patient‑centered outcomes and biomarker data to inform future phase III trials.

TRIAL REGISTRATION: EU‑CT (CTIS) number: 2023‑509322‑22‑00. Registered prior to first patient enrolment.