Multicenter study of neoadjuvant single-cycle pembrolizumab for stage I-III MMR-deficient colon cancer

Neoadjuvant immune checkpoint inhibition has shown promise in localized deficient mismatch repair (dMMR) colorectal cancer, yet the optimal treatment duration and regimen remain undefined. The multicenter RESET-C trial in Denmark evaluated a single neoadjuvant cycle of pembrolizumab (4 mg/kg, max 400 mg, every-6-weeks dosing regimen) followed by a preoperative endoscopy with biopsies and surgery 3-5 weeks later for patients with stage I-III dMMR colon cancer. The primary endpoint was pathologic complete response (pCR). A total of 85 patients (median age 74 years) were enrolled. All patients received pembrolizumab; one patients declined surgery. Among 84 patients, pCR was achieved in 44% (95% CI 33-55) and major pathologic response in 57% (46-68). Two patients died of complications within 30 days of surgery. At a median follow-up of 18.4 months (IQR 16.3-21.1), one patient had a recurrence, resulting in overall and disease-free survival rates of 98% and 96%, respectively. Grade 3 treatment-related adverse events occurred in three patients. In 81 patients, the sensitivity, specificity, and accuracy of the biopsies for predicting pCR were 68%, 75%, and 72%, respectively, whereas in 76 patients, the sensitivity, specificity, and accuracy of the endoscopic images for predicting pCR were 77%, 93%, and 86%, respectively. The authors conclude that a single cycle of neoadjuvant pembrolizumab led to pCR in nearly half of patients undergoing surgery for localized dMMR colon cancer.