AACR 2025: High Response Rates With Dostarlimab Suggest New Standard for dMMR Treatment

Dostarlimab (Jemperli; GSK) yielded complete tumor clearance, resolving the need for surgery, in patients with locally advanced, mismatch repair-deficient (dMMR) cancer. The data from a phase 2 trial (NCT04165772) were presented at the American Association for Cancer Research Annual Meeting 2025.^1,2

3D rendering of an antibody binding to PD-1 receptor | Image Credit: © Alpha Tauri 3D - stock.adobe.com

dMMR describes cells that have mutations in genes that are involved in repairing DNA within cells, which results in high microsatellite instability and a high tumor mutational burden. dMMR is most common in colorectal cancer; however, studies also show it can be found in other types of cancers such as gastrointestinal, endometrial, breast, prostate, bladder, and thyroid. Considering its prevalence across solid tumor types, Andrea Cercek, MD, lead author, attending, and section head of colorectal cancer at Memorial Sloan Kettering (MSK) Cancer Center, alongside colleagues, performed a study evaluating the efficacy of immunotherapy in these types of tumors.^3,4

“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 Cercek in an AACR statement.²

Research shows that dMMR cancers are particularly sensitive to immune checkpoint inhibitors in the metastatic setting, with more pronounced sensitivity in locally advanced disease. In their study, Cercek and Foote evaluated treatment with dostarlimab, a programmed cell death 1 receptor (PD-1)–targeting monoclonal antibody, which has demonstrated favorable efficacy as a monotherapy or in a combination regimen across various clinical trials, leading to its approval as part of standard-of-care neoadjuvant therapy in combination with chemotherapy for metastatic or unresectable dMMR solid tumors.^2,4

"Earlier studies with dostarlimab in locally advanced dMMR rectal cancer showed a surprising 100% complete response rate in a small cohort of 12 patients," said Kevin Chen, PharmD, MS, BCOP, CPP, clinical pharmacy practitioner, Thoracic Oncology & Sarcoma, University of North Carolina (UNC) Medical Center and assistant professor of clinical education, UNC Eshelman School of Pharmacy in Chapel Hill, to Pharmacy Times. "This introduced the idea of potentially curing patients without needing invasive surgery and/or radiation."

In a phase 2 trial, Cercek’s team evaluated 110 patients, of whom 97 completed the full 6-month course of dostarlimab at the time of analysis, who were divided into 2 cohorts: rectal and non-rectal cancers, which included esophagogastric, hepatobiliary, genitourinary, and gynecologic cancers. In cohort one, which included patients with dMMR rectal cancer (n = 49), 100% of those who completed treatment achieved a clinical complete response and did not undergo surgical resection. Of these, 29 patients remained recurrence-free for 12 months or longer, with a median follow-up of 24.8 months (range, 15.6–48.6). At 2 years, 92% were disease-free, and 4 patients have maintained complete responses for 5 years.²

In cohort 2, among the 49 patients who completed therapy, 63% achieved a complete response and also avoided surgery. Across both cohorts, 81% of patients who completed the full 6-month regimen achieved a complete response, and 79% were managed non-operatively. In the larger analysis, 82 of 84 patients with complete response across both cohorts elected to forgo surgery.²

Baseline tumor mutational burden (TMB) and microsatellite instability (MSI) scores were similarly high across both cohorts. In cohort one, the mean TMB was 55.2 mutations per megabase (range, 22.8 to 106) and MSI sensor score was 19 (range, 2.2–37.6); in cohort 2, the mean TMB was 51.1 (range, 4.9 to 145) and MSI sensor score was 18.6 (range, 0.23–39.4). Tumor-informed circulating tumor DNA (ctDNA) was detectable at baseline in 87% of patients. Importantly, lower ctDNA levels during treatment were associated with a greater likelihood of achieving complete tumor elimination by the end of therapy.²

“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,” said Cercek, MD. “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.”²

Additionally, the findings showed that lower levels of ctDNA during therapy were associated with a greater chance of full tumor eradication following the end of treatment. Cercek added that other patients showed great tumor downstaging but did not show a full response after 6 months, which may indicate that more treatment was necessary.²

“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 A. Diaz Jr., MD, FAACR, senior author and head of Solid Tumor Oncology at MSK.²

The authors intend to continue their investigations and further establish the findings by enrolling more patients. Additionally, they plan to study the role of the tumor microenvironment in patients whose tumors have less pronounced therapeutic responses. The initial findings are promising and set the stage for continued research to fully determine the potential role of dostarlimab in the treatment of patients with dMMR cancers.²

"This follow-up study builds upon initial findings in a larger patient cohort confirming the same 100% complete response rate in 49 patients with dMMR rectal cancer, as well as demonstrating high rates of complete response [65%] in non-rectal dMMR solid tumors," Chen said to Pharmacy Times. "Although this early signal is exciting and may usher in a new paradigm of early-stage cancer treatment, it is important to acknowledge the limited long-term follow-up data necessary to ensure this approach is as effective in curing patients as our standard surgical and radiation approaches.""

REFERENCES

1. Study of induction PD-1 blockade in subjects with locally advanced mismatch repair deficient solid tumors. Updated March 4, 2025. Accessed April 23, 2025. https://www.clinicaltrials.gov/study/NCT04165772

2. Cercek A, Foote M, Shia J, et al. Neoadjuvant PD-1 blockade in early-stage mismatch repair-deficient cancers can eliminate the need for surgery regardless of tumor type. American Association for Cancer Research Annual Meeting 2025. April 25, 2025 to April 30, 2025. Chicago, IL. Abstract CT003

3. dMMR. National Cancer Institue. Accessed April 23, 2025. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/dmmr

4. Williams C, Peddle A, Kasi P, et al. Neoadjuvant immunotherapy for dMMR and pMMR colorectal cancers: therapeutic strategies and putative biomarkers of response. Nature Reviews Clinical Oncology. September 24, 2024. doi:10.1038/s41571-024-00943-6