PD-1 blockade with the PD-1 inhibitor dostarlimab-gxly induced complete tumor clearance and resolved the need for surgery in patients with locally advanced, mismatch repair–deficient (dMMR) cancers, according to preliminary results from a phase II trial presented at the 2025 American Association for Cancer Research (AACR) Annual Meeting (Abstract CT003). The results of this study were simultaneously published in The New England Journal of Medicine.
Immune checkpoint inhibitors (ICIs) are approved as part of standard-of-care neoadjuvant therapy in combination with chemotherapy for several cancer types and as single agents or in combination with other ICIs for the treatment of metastatic and unresectable dMMR solid cancers. Initial evidence from this trial previously demonstrated the benefits of neoadjuvant use of dostarlimab in early-stage dMMR rectal cancer. Though this biomarker occurs most frequently in cancers of the colon and rectum, dMMR tumors are found across many solid tumors, explained lead author Andrea Cercek, MD, attending and Section Head of Colorectal Cancer at Memorial Sloan Kettering (MSK) Cancer Center, New York.
“In collaboration with my MSK colleague Michael Foote, MD, we sought to determine how effectively immunotherapy could induce tumor elimination in a broad range of early-stage dMMR cancers, and if these patients with complete clinical responses could then forgo surgical resection,” said Dr. Cercek.
Study Details and Updates
This trial update included 103 patients with stage II to III resectable dMMR cancers who were treated with dostarlimab for 6 months. The first cohort included 49 patients with rectal cancer, and the second cohort included 54 patients with nonrectal cancers, including gastroesophageal, hepatobiliary, genitourinary, and gynecologic cancers. Patients who experienced clinical complete response could choose not to undergo resection or any other treatment.
Both cohorts shared the primary endpoint of clinical complete response after dostarlimab and exploratory endpoints involving circulating tumor DNA (ctDNA). Baseline tumor mutational burden and microsatellite instability scores were similar between the two cohorts, and 95% of patients had detectable ctDNA prior to immunotherapy.
The researchers previously reported that the first 41 patients with rectal cancer experienced complete clinical responses, and new data shared here extended that 100% complete response rate to 49 patients with rectal cancer. In addition, the team revealed the first data in patients with nonrectal cancers, showing that 65% of these patients (35 of 54) experienced complete clinical responses. Of the 84 patients in both cohorts who experienced complete clinical responses, 82 chose to skip surgery.
Regarding ctDNA, lower levels during therapy were linked to a higher likelihood of complete tumor clearance after treatment completion. Although Dr. Cercek noted that some patients had excellent tumor downstaging, after 6 months, they did not experience a complete response.
The investigators also provided an update on the duration of complete response in the rectal cancer cohort, finding that overall, 92% of patients were still disease-free at 2 years. At the time of this reporting, the complete responses of four patients had lasted 5 years.
Clinical Implications
“These findings are very important for patients with early-stage dMMR tumors, because it’s likely they do not need surgery or radiation if they are treated first with immunotherapy for a sufficient amount of time,” Dr. Cercek said. “Surgical resection can be complicated and risky, especially in organs such as the stomach, pancreas, or rectum, so this approach can lead to organ preservation, which offers a better quality of life as well as a potential survival benefit.”
In addition to enrolling more patients, Dr. Cercek and colleagues are studying the tumor microenvironment’s potential role in patients whose tumors exhibited less robust responses to therapy, such as prostate and gastroesophageal tumors. Ultimately, they hope to uncover insights that enable them to expand this approach beyond dMMR cancers to benefit many more patients.
“We believe this study provides a basis for treatment approaches and clinical trials in the neoadjuvant setting, where effective therapy can lead to responses, preserve organs, and drastically improve survivorship,” concluded Luis A. Diaz, Jr, MD, FAACR, senior author and Head of Solid Tumor Oncology at MSK.
Disclosure: The study was funded by Swim Across America, Stand Up To Cancer, the National Institutes of Health and National Cancer Institute, and GSK. Dr. Cercek has served as an advisor to Amgen, Agenus, AbbVie, Daiichi Sankyo, Janssen, Merck, GSK, Pfizer, 3T Biosciences, Summit, UroGen, and Regeneron; has received research funding from GSK and Pfizer; and has a patent pending related to this study. Dr. Diaz has provided consulting services to Absci, Blackstone, GSK, Innovatus Capital Partners, and Neophore; has stock ownership in Amgen, Delfi Diagnostics, and Neophore; has a role as fiduciary officer at Epitope and Quest Diagnostics; and has intellectual property related to this work.
