Organ Preservation Noted With Neoadjuvant Dostarlimab in dMMR Tumors

A phase 2 study found a complete clinical response of 82% with neoadjuvant dostarlimab in dMMR solid tumors.

Results from a phase 2 trial (NCT04165772) found that the use of neoadjuvant dostarlimab-gxly (Jemperli) achieved a complete clinical response (cCR) of 82% (95% CI, 72%-88%) for patients with early-stage mismatch repair–deficient (dMMR) solid tumors, according to a presentation from the 2025 American Association of Clinical Research and subsequently published in the New England Journal of Medicine.1,2

Of 49 patients with rectal cancer, all (100%) achieved a cCR at a median follow-up of 30.2 months. Patients with non-rectal solid tumors (n = 54) achieved a cCR rate of 65% at a median follow-up of 14.9 months. Responses proved durable, with a 2-year recurrence-free survival rate of 96% in the rectal cancer cohort and 85% in the non-rectal solid tumor cohort. Of the 84 patients in both cohorts who achieved cCR, 82 elected to forgo surgery.3

“In collaboration with my Memorial Sloan Kettering [Cancer Center] 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 cCRs could then forgo surgical resection,” Andrea Cercek, MD, lead study author and section head of colorectal cancer and codirector of the Center for Young Onset Colorectal and Gastrointestinal Cancers at Memorial Sloan Kettering Cancer Center in New York, New York, said in a news release.

Patients with stage I to III solid tumors in the stomach, rectum, and kidney are treated with chemotherapy, radiation, and surgery, which can be life-changing.1 However, immunotherapy has shown that it can obviate the need for surgery in patients with early-stage dMMR rectal tumors. Approximately 2% to 3% of all solid tumors are dMMR, and since 2021, dostarlimab has been FDA-approved for use in patients with dMMR recurrent or advanced solid tumors who have progressed on or following prior therapy and who have no satisfactory treatment options.4

On December 18, 2024, the FDA granted breakthrough therapy designation to dostarlimab for the treatment of patients with locally advanced, dMMR/microsatellite instability–high rectal cancer based on preliminary and updated findings from the phase 2 trial presented at the 2022 and 2024 ASCO Annual Meetings, respecitvely.5-7

Initial findings presented with median follow-up of 6.8 months (range, 0.7-23.8) showed that dostarlimab led to a cCR rate of 100% with no evidence of residual tumor among 14 patients with stage II/III, dMMR, locally advanced rectal cancer.6 Subsequent findings, which were presented with median follow-up of 17.9 months (range, 0.3-50.5), demonstrated that all 42 patients with locally advanced dMMR rectal cancer achieved cCR with the PD-1 inhibitor.7

With such encouraging findings, investigators sought to evaluate whether nonoperative management of dMMR tumors with dostarlimab could extend beyond rectal cancer, leading to the launch of a second cohort that enrolled 54 patients with non-rectal solid tumors, including esophagogastric, hepatobiliary, genitourinary, colon, and gynecologic.1 Within the first cohort of patients with rectal cancer, an additional 7 patients were treated (n = 49).

In this updated analysis, a total of 117 patients were treated, 103 of whom completed 6 months of dostarlimab.

The trial enrolled patients with clinical stage II and III dMMR solid tumors. Patients received 500 mg of intravenous dostarlimab every 3 weeks for 9 doses and underwent assessments at baseline, 6 weeks, and 3 months. At 6 months, patients underwent radiologic or endoscopic restaging. If they had achieved cCR, they proceeded to nonoperative follow-up every 4 months. If they had evidence of residual disease, they either underwent surgery or standard-of-care therapy with neoadjuvant chemotherapy or chemoradiation followed by surgery before again being assessed for residual disease or cCR.

“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,” Cercek said.3 “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.”

“We believe that 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 Diaz Jr., MD, senior author and head of the Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center.3

References

1. Cercek A, Foote MB, Shia J, et al. Non-operative management of mismatch repair deficient tumors. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT003.
2. Cercek A, Foote MB, Rousseau B, et al. Nonoperative management of mismatch repair–deficient tumors. N Engl J Med. Published online April 27, 2025. doi:10.1056/NEJMoa2404512
3. Neoadjuvant PD-1 blockade in early-stage mismatch repair-deficient cancers can eliminate the need for surgery regardless of tumor type. News release. American Association for Cancer Research. April 27, 2025. Accessed April 28, 2025. https://www.aacr.org/about-the-aacr/newsroom/news-releases/neoadjuvant-pd-1-blockade-in-early-stage-mismatch-repair-deficient-cancers-can-eliminate-the-need-for-surgery-regardless-of-tumor-type/
4. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. FDA. Updated July 18, 2023. Accessed April 28, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-advanced-solid-tumors
5. Jemperli (dostarlimab) receives US FDA breakthrough therapy designation for locally advanced dMMR/MSI-H rectal cancer. News release. GSK. December 16, 2024. Accessed April 28, 2025. https://www.gsk.com/en-gb/media/press-releases/jemperli-dostarlimab-receives-us-fda-breakthrough-therapy-designation-for-locally-advanced-dmmrmsi-h-rectal-cancer/
6. Cercek A, Lumish MA, Sinopoli JC, et al. Single agent PD-1 blockade as curative-intent treatment in mismatch repair deficient locally advanced rectal cancer. J Clin Oncol. 2022;40(suppl 17):LBA5. doi:10.1200/JCO.2022.40.17_suppl.LBA5
7. Cercek A, Sinopoli JC, Shia J, et al. Durable complete responses to PD-1 blockade alone in mismatch repair deficient locally advanced rectal cancer. J Clin Oncol. 2024;42(suppl 17):LBA3512. doi:10.1200/JCO.2024.42.17_suppl.LBA3512