Neoadjuvant Keytruda (pembrolizumab) given in a single cycle was deemed efficacious and safe for patients with deficient DNA mismatch repair (dMMR) colon cancer, as shown in results from the phase 2 RESET-C trial 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 1 or 3, the pCR rate was 61% and for stage 3 it was 33%.
At the survival follow-up date of December 2024, 70 patients had a minimum of one year of follow-up, 57 had a one-year CT scan done, two had died within 30 days of surgery and there were no instances of recurrence.
Grade 3 (severe) side effects were observed in 8% of patients, with 4% experiencing immune-related grade 3 side effects. Of those included were two patients with hepatitis and one patient with colitis. There were no grade 4 (life-threatening) or 5 (death) immune-related side effects noted.
Glossary:
Neoadjuvant: treatment given before a main treatment like surgery.
Deficient DNA mismatch repair: when the body’s natural system for correcting errors that occur during DNA replication malfunctions, which can lead to genomic instability.
Pathological complete response: the absence of any remaining invasive cancer cells in tissue samples removed during surgery after neoadjuvant therapy.
Major pathological response: a significant reduction in the number of viable cancer cells.
Grade 3a or above Clavien-Dindo: a surgical complication that requires some form of intervention, but not always under general anesthesia.
Ischemic bowel: when the intestines do not receive enough blood flow.
Overall survival: the time from diagnosis or the start of treatment when a patient with cancer is still alive.
In 31 patients (37%), there were 41 surgical complications observed. These included grade 3a or above Clavien-Dindo (eight patients), and post-operative deaths (two patients) at age 80 or above. These deaths were related to either gastric stress ulcer-related perforation (one patient) or ischemic bowel (one patient).
“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,” Dr. Camilla Qvortrup, 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 Keytruda 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.
To be included, patients must have dMMR stage 1 to 3 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 Keytruda followed by tumor restaging with a CT scan and colonoscopy. Patients then moved to surgery three to five weeks after completing Keytruda treatment with a CT scan as follow-up at one and three 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:
Single-cycle neoadjuvant pembrolizumab in patients with stage I-III MMR-deficient colon cancer: final analysis of the RESET-C study. Dr. Camilla Qvortrup, et al. J Clin Oncol.
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