Nonoperative Management of Mismatch repair deficient Tumors

New England Journal of Medicine, April 2025

Key take aways:

• PD-1–based immunotherapy is especially effective against mismatch repair–deficient tumors due to their high mutational burden, which increases neoantigen expression and immune system recognition.

Background

Mismatch repair–deficient (dMMR) tumors, including certain colorectal, gynecologic, and genitourinary cancers, are highly responsive to PD-1 blockade. Prior studies in rectal cancer showed that neoadjuvant immunotherapy could eliminate the need for surgery. This trial evaluated whether that strategy could extend to all early-stage, resectable dMMR solid tumors.

Study Design

A phase 2 trial enrolled 124 patients with stage I–III dMMR solid tumors. Patients received dostarlimab (500 mg IV every 3 weeks for 6 months). Response was assessed with imaging, endoscopy, and circulating tumor DNA (ctDNA). Patients achieving a clinical complete response (cCR) could opt for nonoperative management.

• Cohort 1: Locally advanced dMMR rectal cancer (n=50)

• Cohort 2: dMMR nonrectal solid tumors (n=67), including colon, gastric, urothelial, and gynecologic malignancies

Results

• Clinical Complete Response (cCR):

  • Cohort 1: 100% (49/49) achieved cCR; 37 maintained it at 12 months

  • Cohort 2: 65% (35/54) achieved cCR; 33 chose nonoperative management

  • Overall: 82/103 (80%) patients avoided surgery without compromise to resectability

• Recurrence-Free Survival at 2 Years:

  • Overall: 92%

  • Rectal cancer cohort: 96%

  • Nonrectal cohort: 85%

  • No patients lost the opportunity for curative resection due to treatment delay

• Adverse Events:

  • Mostly grade 1–2 and reversible (fatigue, rash, pruritus)

  • Grade ≥3 in <5% of patients

Clinical Relevance

This study supports neoadjuvant PD-1 blockade as a viable, organ-preserving strategy for early-stage dMMR tumors. Patients with rectal cancer uniformly avoided surgery, with promising extension to select nonrectal tumors. Importantly, oncologic safety was maintained even with deferred surgery.

Considerations for Practice

• Nonoperative management may now be considered in dMMR tumor patients showing robust response to neoadjuvant PD-1 blockade.