Is One Cycle of Neoadjuvant Pembro OK in dMMR Colon Cancer?

For most patients with clinical stage I-II deficient mismatch repair (dMMR) colon cancer, a single cycle of neoadjuvant pembrolizumab may be sufficient to achieve a pathologic complete response, according to the final analysis of the RESET-C study.

After one cycle of neoadjuvant pembrolizumab, 61% and 33% of patients with clinical stage I-II and stage III diseases, respectively, achieved a pathologic complete response, according to lead author Camilla Qvortrup, MD, PhD, who presented the findings at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (GICS) 2025 in San Francisco.

Neoadjuvant immune checkpoint inhibitor therapy has led to “impressive” responses in patients with localized dMMR colorectal cancer, said Qvortrup, an oncologist at Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark. However, the optimal type and duration of treatment are yet to be established. In most studies, a longer duration of immunotherapy or combination therapy has been used, and surgery is the standard of care therapy in this population, Qvortrup added.

In the phase 2, single-arm RESET-C study, 85 patients with resectable stage I-III dMMR colon cancer received a single cycle of pembrolizumab 4 mg/kg (maximum 400 mg). Of these, 84 proceeded to surgery within 3-5 weeks, and one patient with stage I disease decided not to have surgery.

Qvortrup noted that the cohort was a “typical dMMR” population, made up of mostly women (72%) with right-sided tumors (65%), and patients had a median age of 74 years.

Of the 84 patients included in the efficacy analysis, 37 (44%) achieved a pathologic complete response (the primary outcome), and 48 (57%) achieved a major pathologic response.

The pathologic complete response rate was stage dependent, with a significantly higher rate seen in patients with stage I-II (61%, or 20 of 33 patients) than in those with stage III (33%, or 17 of 51 patients) disease.

At 1-year follow-up, no patient had a recurrence.

There were no new safety signals with pembrolizumab in this population, Qvortrup noted. Seven of 85 (8%) patients experienced grade 3 adverse events, three of which were immune-related (two cases of hepatitis and one case of colitis). No grade 4 or 5 immune-related adverse events occurred.

There were two deaths within 30 days of surgery; none was related to immunotherapy treatment, and both were in patients older than 80 years.

“This is an important study, as it demonstrates that a single dose of immunotherapy with pembrolizumab can achieve marked alterations in tumors over a short period of time,” said Paul Oberstein, MD, medical oncologist at NYU Langone’s Perlmutter Cancer Center in New York City, who wasn’t involved in the study. “This is further proof of concept that immunotherapy can profoundly alter tumors in certain patients with MSI-H [microsatellite instability–high] tumors.”

But does the study indicate that a single cycle of pembrolizumab is effective enough for patients to be able to delay surgery?

The evidence for delaying surgery in the population is not yet there, according to Oberstein.

Surgery will continue to be “the standard of care therapy for patients with colon cancer,” Oberstein said, adding that the current study recommended surgery regardless of the treatment.

Oberstein noted that a single cycle of pembrolizumab seemed to work much better in early stage I and II disease and had less impact in stage III disease, which should “cause some caution” in future studies that are looking at bypassing surgery in these patients.

The study had no commercial funding. Qvortrup disclosed consulting or advisory roles with Merck and Pierre Fabre and research funding to her institution from Miratis, MSD Oncology, Pfizer, Pierre Fabre, Roche, and SERVIER. Oberstein had no relevant disclosures.