Is Neoadjuvant Checkpoint Blockade Sufficient to Treat Mismatch Repair-Deficient Rectal Cancer?

Cercek A, Foote MB, Rousseau B, et al. Nonoperative Repair of Mismatch Repair-Deficient Tumors. NEJM. 2025;392(23):2297-2308. 

Previous research has shown that patients with mismatch repair-deficient (dMMR) locally advanced rectal cancer can avoid surgery via treatment with a neoadjuvant checkpoint blockade. To explore whether the same approach can aid all patients with early stage dMMR cancers, regardless of tumor site, Cercek et al. recruited 117 patients with stage I, II, or III disease. 

In their study, published this month in The New England Journal of Medicine, the recruited patients underwent treatment with dostarlimab, a programmed cell death-1 blocking agent, for 6 months.

A total of 103 patients completed the care regimen: 49 patients with rectal tumors, all of whom experienced a clinical complete response, and 54 with non-rectal tumors, of whom 35 (65%) experienced a clinical complete response. All but two patients with such responses chose not to undergo surgery. 

Tumor location affected treatment response. All patients with rectal, urothelial, and hepatopancreatobiliary tumors experienced clinical complete responses, but variable levels of clinical complete response occurred in patients with bowel, gastroesophageal junction, and gastric cancer. Those with esophageal, small bowel, endometrial, and prostate cancer had a mix of incomplete clinical response and residual disease, with 0% of a clinical complete response.

Among the full cohort of 117 patients, recurrence-free survival at 2 years was 92%. The median time to recurrence was 20.0 months.

The authors, who are largely associated with Memorial Sloan Kettering Cancer Center in New York, New York, advocated for larger studies of the treatment approach, including randomized trials.