Patients With Multiple Types of Mismatch Repair-Deficient Tumors Avoid Surgery With Dostarlimab

Patients with multiple types of locally advanced, mismatch repair-deficient (dMMR) tumors were able to avoid surgery following treatment with the PD-1 inhibitor dostarlimab (Jemperli, GSK) according to updated data being presented today at the American Association for Cancer Research (AACR) annual meeting in Chicago.1

Andrea Cercek, MD | Image credit: MSK

Results, presented by Andrea Cercek, MD, attending and section head of colorectal cancer at Memorial Sloan Kettering (MSK) Cancer Center, could boost confidence in a nonsurgical option among patients with cancers of the colon and rectum, as well as others with gastrointestinal (GI) cancers, for whom surgery can prove painful and debilitating.

“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,” Cercek said in a statement.2

The phase 2 study (NCT04165772) involved 2 groups of patients, and investigators had already reported that the first 41 patients with rectal cancer experienced complete clinical responses.4 The new data at AACR show that all 49 patients with rectal cancer have complete clinical responses, along with 35 of 54 (65%) of a second group with nonrectal cancers.1,3

Of the 84 patients across both groups who achieved a complete clinical response, 82 opted to not have surgery, according to results reported today in the New England Journal of Medicine (NEJM).3 A complete clinical response was seen in 82% of the 103 patients who completed treatment (95% CI, 72 to 88).

“The primary tumor did not progress or become unresectable during or after treatment in any of the patients,” investigators wrote.

Among the 117 total patients in the study, results showed the following:

• Recurrence-free survival at 2 years was 92% (95% CI, 86-99), with the median follow-up for recurrence reaching 20.0 months, with some patients followed more than 5 years.
• 60% of the patients had reversible, grade 1 or 2 adverse events (AEs) while 35% had no AEs.

Tumor types beyond rectal that had good responses included colon, gastric, hepatobiliary, and urothelial. Ongoing work will examine how the tumor microenvironment affects response to therapy, as patients with prostate and gastroesophageal tumors had less robust results.

Rationale for Nonsurgical Approach

Immune checkpoint inhibitors (ICIs), including treatment with PD-1 blockade, have been used with chemotherapy ahead of surgery for several types of cancer. Some patients receive ICIs as monotherapy or 2 ICIs together to treat metastatic and unresectable dMMR solid tumors.

dMMR refers to a malfunction in the DNA repair mechanism, which causes errors in DNA replication and increases the risk of mutations. However, this also makes these tumors responsive to immunotherapy. About 5% to 15% of colorectal cancers have dMMR with high microsatellite instability (MSI-high).

Based on previous studies, patients received dostarlimab for 6 months, longer than is typical before surgery. “The option for curative resection was not compromised in any of the patients, although the course of treatment was longer than that in other studies of neoadjuvant therapy,” the investigators explained in NEJM. “A major concern with neoadjuvant therapy is that the ‘window of opportunity’ for resection may lapse if the tumor grows and spreads to the point of no longer being amenable to curative-intent surgery.”

The study authors also discussed a “tumor-informed approach,” in which circulating tumor DNA (ctDNA) “provided a unique window onto the dynamic response to PD-1 blockade.” The authors said they used a new assay with very high sensitivity and specificity for detecting ctDNA, due to its capacity to evaluate up to 50 mutations in ctDNA while ignoring artifactual mutations that appear due to the sequencing process.

Nonsurgical Option Addresses Quality of Life Issue

“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 in the statement from AACR. “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.”

Treating colorectal cancer (CRC) or other GI cancers without surgery may be more desirable for the rising number of young adult patients who are being diagnosed with cancer—with CRCs one of the top drivers of this phenomenon. According to the American Cancer Society (ACS), years of decline in CRC mortality have slowed, driven by the uptick in these cancers among those younger than 50. ACS said rates for advanced disease have climbed 3% annually in people younger than 50 years of age since around 2010.

Cercek took part in an AACR educational session Saturday on this issue, as she and Manju George, MD, a cancer survivor and patient advocate, described the level of disruption that CRC causes. Young adult patients fear having to miss work when they are supporting young children and need their health insurance. Besides the loss of productivity, there the cost of surgery itself, which varies but can reach $35,000, according to a 2022 study. Many patients fear the loss of sexual function that can result, experts said Saturday.

During a press conference, Cercek concurred the results presented Sunday are especially important for younger patients.

"They're incredibly important," to this population, she said. "We're seeing more and more young patients, particularly with rectal cancer, whereas ...standard therapy is very morbid in terms of infertility, sexual dysfunction, [and] permanent colostomies."

"And even beyond rectal cancer, early onset cancers are increasing actually, throughout the GI tract. So quality of life is incredibly more important in survivorship, as people are living much, much longer."

In the NEJM article, investigators called for additional work, and possibly a randomized trial, to evaluate overall survival among patients eligible for surgery. Funders for the study included the National Institutes of Health, the National Cancer Institute, Swim Across America, GlaxoSmithKline, Stand Up to Cancer, Haystack Oncology, the Simon and Eve Colin Foundation, and the Dalton Foundation.

References

1. Cercek A, Foote MB, Shia J, et al. Non-operative management of mismatch repair deficient tumors. Presented at: American Association for Cancer Research, April 25-30, 2025; Chicago, IL. Abstract CT003.
2. 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.
3. 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
4. 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): Abstract LBA 3512. https://doi.org/10.1200/JCO.2024.42.17_suppl.LBA3512