Neoadjuvant Pembrolizumab Enhances Response in dMMR Colon Cancer

A pCR rate of 44% was observed when neoadjuvant pembrolizumab was given to patients with dMMR colon cancer.

For patients with deficient DNA mismatch repair (dMMR) colon cancer, neoadjuvant pembrolizumab (Keytruda) given in a single cycle was deemed efficacious and safe, according to results from the phase 2 RESET-C trial (NCT05662527) presented at the 2025 ASCO Gastrointestinal Cancer Symposium.

A pathological complete response (pCR) was noted in 44% (95% CI, 33%-55%) of patients and a major pathological response (mPR) in 57% (95% CI, 46%-68%). For stage I or II, the pCR rate was 61% and for stage III it was 33%.

At the survival follow-up date of December 2024, 70 patients had a minimum of 1 year of follow-up, 57 had a 1-year CT scan done, 2 had died within 30 days of surgery, and there were 0 instances of recurrence.

Grade 3 adverse effects (AEs) were observed in 8% of patients, with 4% experiencing immune-related grade 3 AEs. Of those included were 2 patients with hepatitis and 1 patient with colitis. There were no grade 4 or 5 immune-related AEs noted.

In 31 patients (37%), there were 41 surgical complications observed (95% CI, 27%-48%). These included grade 3a or above Clavien-Dindo (n = 8), and post-operative deaths (n = 2) at age 80 or above. These deaths were related to either gastric stress ulcer-related perforation (n = 1) or ischemic bowel (n = 1).

“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,” Camilla Qvortrup, MD, PhD, clinical associate professor at Rigshospitalet - Center for Cancer and Organ Disease in Denmark, stated during the presentation.

Of the 85 patients enrolled, all were given pembrolizumab and included in the safety analysis. One patient did not undergo surgery because of their own wishes, so 84 patients underwent surgery and were included in the efficacy analysis.

The median patient age was 74 years old, and 65% of patients were older than 70. A majority of patients were female (72%) and had an ECOG performance status of 0 (61%). The most common clinical tumor stages were T3 (48%), T2 (25%), and T4 or T4a (15%). Clinical node stage was observed as N0 (40%), N1 (33%), and N2 (27%). Tumor locations included right colon (65%), transverse colon (22%), and left colon (13%).

To be included, patients must have dMMR stage I to III colon cancer and have no contraindication for immunotherapy. The primary end point was pCR rate and secondary end points included safety, surgical complications, mPR, and overall survival.

Patients were screened at diagnosis and then included if eligible. They were then given pembrolizumab at 4 mg/kg with a max of 400 mg/kg followed by tumor restaging with a CT scan and colonoscopy. Patients then moved to surgery 3 to 5 weeks after completing pembrolizumab treatment with a CT scan as follow-up at 1 and 3 years.

“By integrating the results of the re-endoscopy, the biopsies after treatment, and ctDNA, we are aiming to develop a reliable response assessment tool to pave the path for a future organ preservation strategy,” Qvortrup stated.

The study posed to answer a few key questions for this disease state. Previously, neoadjuvant immune checkpoint inhibitors had shown positive results in dMMR colorectal cancer. However, the optimal duration of treatment and response evaluation had not yet been determined. Investigators believed that the use of a PD-1 inhibitor for single-cycle therapy would reduce toxicity and costs.

Reference

Qvortrup C, Freyberg T, Justesen F, et al. Single-cycle neoadjuvant pembrolizumab in patients with stage I-III MMR-deficient colon cancer: final analysis of the RESET-C study. J Clin Oncol. 2025;43(4):19. doi:10.1200/JCO.2025.43.4_suppl.19