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Neoadjuvant treatment with a programmed cell death 1 (PD-1) inhibitor induces clinical complete response and leads to organ preservation in a high proportion of patients with early-stage, mismatch repair–deficient (MMRd) solid tumors — regardless of tumor type, new data from a phase 2 study showed.

Six months of treatment with dostarlimab led to nonoperative management in 80% of patients with stages I-III MMRd rectal and non-rectal tumors. And in all patients who had a clinical complete response, organs were preserved without additional therapy.

Early-stage solid tumors are treated in the curative setting with a combination of chemotherapy, radiation, and surgery, which can have “life-changing” negative effects on the quality of life of these patients in survivorship, said lead author Andrea Cercek, MD, with Memorial Sloan Kettering Cancer Center in New York City.

“These findings are very important for patients with early-stage MMRd 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 added.

Cercek presented the data on April 27 at a press briefing at American Association for Cancer Research (AACR) Annual Meeting 2025. The findings were simultaneously published in The New England Journal of Medicine.

‘Exciting’ Early Data Confirmed

Across the board, roughly 2%-3% of all solid tumors are MMRd, although it is more common in certain tumors, such as rectal cancer (10%-15%), Cercek explained.

Metastatic MMRd tumors are sensitive to immune checkpoint blockade with a single-agent anti–PD-1 therapy and combination PD-1/cytotoxic T-lymphocyte–associated protein 4 therapy.

Previous data from the current trial showed that PD-1 blockade with dostarlimab alone led to clinical complete responses in 100% of MMRd early-stage rectal cancers.

“Given that exciting data and the durability of these responses in the rectal group, we really wanted to ask the question — could nonoperative management of MMRd tumors extend beyond rectal cancer?” Cercek said.

The researchers expanded the trial to include 117 patients with MMRd locally advanced solid tumors. At data cutoff, 14 were still receiving treatment with dostarlimab and 103 had completed treatment, including 49 with rectal cancer and 54 with non-rectal solid tumors, which included esophageal, gastric, hepatobiliary, genital, urinary, colon, and gynecologic endometrial cancers.

Patients with a complete response to 6 months of neoadjuvant dostarlimab could elect to proceed with nonoperative management, while those with residual disease would proceed with surgery.

Among all 103 patients who completed treatment, 84 had a clinical complete response and 82 did not have surgery.

All 49 patients with rectal cancer had a complete clinical response and chose nonoperative management; 37 of these patients had a sustained clinical complete response at 12 months, which met the study’s criterion for efficacy.

Among the 54 patients with MMRd non-rectal solid tumors who completed dostarlimab treatment, 35 (65%) had a clinical complete response and 33 chose to skip surgery.

Complete response rates were seen in 100% of urothelial tumors and 82% of colon cancers. The most common tumor types without a complete clinical response were prostate and gastroesophageal tumors.

Cercek noted that complete clinical responses were durable. Recurrences were rare (< 5%) and subsequently responded to rechallenge with PD-1 blockade. Circulating tumor DNA was a “reliable liquid biopsy and marker of response and recurrence,” Cercek said.

For the rectal cohort, the median follow-up was 30.2 months, and the 2-year recurrence-free survival rate was 96%. In the non-rectal solid tumor cohort, the median follow-up was shorter (14.9 months), and the 2-year recurrence-free survival rate was 85%.

Patient-Centered Approach

Cercek noted that the efficacy of immune checkpoint blockade appeared to be relatively tumor-agnostic, driven primarily by the MMRd phenotype rather than the tumor site of origin.

She also said it’s likely that the effects seen are not specific to dostarlimab. “We don’t believe that it’s drug specific, rather just immune checkpoint blockade specific.”

“The opportunity for patients to receive potentially curative immunotherapy without needing to go through surgery or other morbid therapies is just truly remarkable,” said Ryan B. Corcoran, MD, PhD, from Mass General Research Institute, Boston, who moderated the briefing and is co-chair of this year’s annual meeting clinical trials committee.

Invited discussant Michael J. Overman, MD, with The University of Texas MD Anderson Cancer Center in Houston, said both operative and nonoperative approaches “can coexist” for early-stage MMRd solid tumors.

He noted that “salvage surgery for incomplete responders after 6 months of PD-1 therapy does appear to be a successful approach. This is really a key take-home from this presentation.”

Overman also emphasized the need for patient-centered discussions on which approach is best. “This is really up to the patient’s goal and based on a risk-benefit discussion,” he said.

The study was supported by Swim Across America, GSK, Stand Up To Cancer, Haystack Oncology, the Simon and Eve Colin Foundation, and The Dalton Foundation and grants from the National Institutes of Health and the National Cancer Institute. Cercek disclosed having relationships with AbbVie, Amgen, Agenus, Daiichi Sankyo, GSK, Merck, Regeneron, Roche, and Pfizer. Overman disclosed having relationships with Roche, BMS, MedImmune, Merck, Amgen, Takeda, Janssen, Pfizer, Array, Gritstone bio, 3DMed, Nouscom, Atreca, Bayer, Lilly, and Phanes Therapeutics.