Neoadjuvant Immunotherapy With Prolgolimab in Patients With Locally Advanced Microsatellite Instability/Defective Mismatch Repair Colorectal Cancer

PURPOSE Although adjuvant chemotherapy is standard for locally advanced colon cancer, defective mismatch repair (dMMR)/microsatellite instability (MSI) tumors show high sensitivity to immune checkpoint inhibitors. We aimed to investigate the efficacy of the PD-1 inhibitor prolgolimab in this setting. METHODS We conducted phase II nonrandomized open-label clinical trial (ClinicalTrials.gov identifier: NCT06428487 ) in patients with locally advanced colorectal cancer (CRC) and dMMR/MSI. Prolgolimab (1 mg/kg) was administered once every 2 weeks, and surgery was performed after 6 months of immunotherapy. In case of surgical treatment refusal, the systemic treatment proceeded for 1 year. The primary end point was the rate of pathologic complete response (pCR, in operated cases) + clinical complete response (cCR, in nonoperated cases). Secondary end points included pCR, major pathologic response (MPR), objective response (ORR) rates, safety, disease-free survival (DFS), and overall survival. RESULTS Of the 30 enrolled, 26 (86.6%) patients underwent surgery after the end of immunotherapy. The study met its primary end point, with 17 (56.7%) of 30 patients achieving pCR (n = 16) + cCR (n = 1 as nonoperated case). According to histologic examination, an MPR (TRG 1-2) was observed in 21 (80.8%) of 26 patients, including 16 (61.6%) patients with pCR. Radiographic ORR was 89.7%, and cCR was observed in six cases (20.7%, five patients underwent surgery further). Three patients with low rectal primary tumors refused to undergo a surgical treatment. The median follow-up was 19 months (range, 13-32). The 18-month DFS was 90%: two progressions and one unrelated death were detected. Grade 3-4 immune-related adverse effects were recorded in one (3.3%) patient. CONCLUSION The use of prolgolimab in locally advanced dMMR/MSI CRC is associated with high rates of pCR and cCR, allowing for further exploration of organ-sparing approaches in these patients.