Nonoperative Management of Mismatch Repair-Deficient Tumors

Area of Science:

• Oncology
• Immunotherapy
• Clinical Trials

Background:

• Neoadjuvant checkpoint blockade has shown promise in treating mismatch repair-deficient (dMMR) locally advanced rectal cancer, eliminating the need for surgery in many patients.
• The efficacy of this approach across all early-stage dMMR solid tumors, irrespective of primary site, remains to be determined.

Purpose of the Study:

• To evaluate the effectiveness of neoadjuvant dostarlimab, a programmed cell death 1 (PD-1) blocking agent, in patients with early-stage dMMR solid tumors.
• To assess the rate of clinical complete response and the feasibility of nonoperative management in patients with dMMR rectal and nonrectal solid tumors.

Main Methods:

• A phase 2 clinical trial was conducted involving patients with stage I, II, or III dMMR solid tumors.
• Patients received neoadjuvant dostarlimab for 6 months. Response was assessed in two cohorts: dMMR locally advanced rectal cancer (cohort 1) and dMMR nonrectal solid tumors (cohort 2).
• Patients achieving a clinical complete response could opt for nonoperative management; those with residual disease proceeded to resection. The primary endpoint was sustained clinical complete response at 12 months in cohort 1.

Main Results:

• In cohort 1 (rectal cancer), all 49 patients completing treatment achieved a clinical complete response and opted for nonoperative management, with 37 demonstrating a sustained response at 12 months.
• In cohort 2 (nonrectal tumors), 35 of 54 patients completing treatment achieved a clinical complete response, with 33 proceeding to nonoperative management.
• Across both cohorts, 103 patients completed treatment, 84 achieved a clinical complete response, and 82 avoided surgery. Two-year recurrence-free survival was 92%. Adverse events were predominantly reversible and low-grade.

Conclusions:

• Neoadjuvant PD-1 blockade is effective in achieving organ preservation for a significant proportion of patients with early-stage dMMR solid tumors.
• The study supports nonoperative management as a viable option for patients with dMMR solid tumors who achieve a clinical complete response after neoadjuvant PD-1 blockade.
• The safety profile was favorable, with most adverse events being low-grade and reversible.