A single cycle of neoadjuvant pembrolizumab (Keytruda) has shown promising efficacy and safety in treating patients with deficient DNA mismatch repair (dMMR) colon cancer. The findings come from the phase 2 RESET-C trial, presented at the 2025 ASCO Gastrointestinal Cancer Symposium, and suggest a potential for reduced toxicity and costs compared to longer treatment durations.
Pathological Response Rates
The study revealed a pathological complete response (pCR) in 44% of patients (95% CI, 33%-55%) and a major pathological response (mPR) in 57% (95% CI, 46%-68%). Notably, the pCR rate was 61% for stage I or II tumors and 33% for stage III tumors. These results indicate a substantial impact of pembrolizumab on tumor regression prior to surgery.
Safety Profile and Surgical Outcomes
While the treatment was generally well-tolerated, grade 3 adverse events (AEs) were observed in 8% of patients, with 4% experiencing immune-related grade 3 AEs, including hepatitis and colitis. No grade 4 or 5 immune-related AEs were reported. Surgical complications occurred in 31% of patients, including grade 3a or above Clavien-Dindo complications in 8 patients and post-operative deaths in 2 patients aged 80 or above, due to gastric stress ulcer-related perforation or ischemic bowel.
Study Design and Patient Characteristics
The RESET-C trial enrolled 85 patients with dMMR stage I to III colon cancer who had no contraindication for immunotherapy. All patients received pembrolizumab at 4 mg/kg (max 400 mg/kg), followed by tumor restaging with CT scan and colonoscopy. Surgery was performed 3 to 5 weeks after pembrolizumab treatment. The primary endpoint was pCR rate, with secondary endpoints including safety, surgical complications, mPR, and overall survival. The median patient age was 74 years, with 65% of patients older than 70. The majority were female (72%) and had an ECOG performance status of 0 (61%).
Future Directions
Dr. Camilla Qvortrup, clinical associate professor at Rigshospitalet - Center for Cancer and Organ Disease in Denmark, emphasized the next steps: “Our next step is to integrate the results of the endoscopic evaluation, re-biopsies, and ctDNA aiming to develop a reliable response assessment tool to pave the path for a future organ preservation strategy.” This approach aims to refine response assessment and potentially facilitate organ preservation in select patients.
Implications for dMMR Colon Cancer Treatment
The study addresses critical questions regarding the optimal duration of neoadjuvant immune checkpoint inhibitor therapy and response evaluation in dMMR colorectal cancer. The use of a single-cycle PD-1 inhibitor aims to reduce toxicity and costs while maintaining efficacy. These findings may lead to a more tailored and effective treatment approach for patients with dMMR colon cancer.
