Immunotherapy plus radiation might provide a chemotherapy-free option for patients with locally advanced, mismatch repair-deficient (MMR-D) and microsatellite instability-high (MSI-H) endometrial cancer.

In a phase 2 study, immune checkpoint blockade (ICB) with dostarlimab administered concurrently with standard pelvic radiation therapy was safe and effective, exceeding outcomes seen with radiotherapy alone in historical controls.

Two-year progression-free survival was nearly 81%, surpassing historical benchmarks and meeting the study’s primary endpoint.

“This is the first study to provide a chemotherapy-free option of ICB with radiotherapy for patients with locally advanced MMR-D endometrial cancer,” said Ying Liu, MD, MPH, a gynecologic oncologist with Memorial Sloan Kettering Cancer Center in New York City.

She reported the findings at the Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer 2026.

Roughly 30% of patients with endometrial cancer have MMR-D/MSI-H tumors, which are known to respond well to ICB. The addition of ICB to chemotherapy has demonstrated benefit in the setting of advanced/recurrent and early-stage MMR-D endometrial cancers.

However, Liu said, in the PORTEC-3 trial, subgroup analyses of the MMR-D cohort suggested that chemotherapy conferred no additional survival benefit when added to radiotherapy — raising the question of whether those patients could do well with a chemotherapy-free approach.

To investigate, Liu and her colleagues enrolled 31 patients with newly diagnosed stage III-IVA MMR-D/MSI-H endometrial cancer in the phase 2 D-RT study. All patients underwent surgery followed by pelvic radiotherapy over 5-6 weeks, given concurrently with five cycles of the PD-1 inhibitor dostarlimab.

The primary endpoints were safety and feasibility and 2-year progression-free survival.

At a median of nearly 34 months, with all patients having at least 2 years of follow-up, there were six total events among 31 patients, including five recurrences and one death without progression/recurrence. Overall, 25 patients remained progression-free at 2 years.

Two-year progression-free survival was 80.6% — surpassing the 65% 2-year benchmark from the stage III cohort of PORTEC-3, Liu said. Overall survival at 2 years was 93.5%.

Outcomes appeared particularly strong in certain subgroups: Patients without residual disease after surgery had a 2-year progression-free survival of roughly 90%, whereas no recurrences were observed in the patients with Lynch syndrome or nonmethylated tumors.

However, MSI sensor score and tumor mutational burden were not associated with progression-free survival. Ongoing studies, Liu said, are looking at circulating tumor DNA and other markers of the tumor immune microenvironment and stool microbiome.

Overall, she said, dostarlimab plus radiotherapy was well tolerated. Rates of immune-related adverse events were low, with two cases of colitis, three cases of grade 3 or worse diarrhea, and two cases of pneumonitis.

Notably, Liu said, the duration of ICB was short, mirroring traditional chemotherapy timelines.

Future research will focus on identifying those patients who benefit most from the chemotherapy-free regimen, and how to optimize immune response.

Based on the current findings, chemotherapy-free treatment with immunotherapy and radiation is “feasible and shows encouraging activity,” said study discussant Floor Backes, MD, of The Ohio State University Comprehensive Cancer Center-The James in Columbus, Ohio.

But Backes noted, even without chemotherapy patients still experienced some grade 3 or higher toxicity, including decreased lymphocyte counts and diarrhea — mostly related to radiotherapy.

That leaves “the really big question” of whether immunotherapy alone is sufficient for patients with MMR-D disease, Backes said. The answer, she added, may come from the “highly anticipated” phase 3 Domenica and Keynote-C93 trials, which are pitting immunotherapy against chemotherapy for patients with advanced or recurrent disease.

GSK provided support for this investigator-initiated study. Liu had no disclosures. Backes disclosed having relationships with GSK, Merck, ImmunoGen/AbbVie, and other pharmaceutical companies.