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Nonoperative Management of Mismatch Repair-Deficient Tumors
Andrea Cercek1, Michael B Foote1, Benoit Rousseau1
1Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York.
Background:
Among patients with mismatch repair-deficient (dMMR), locally advanced rectal cancer, neoadjuvant checkpoint blockade eliminated the need for surgery in a high proportion of patients. Whether this approach can be extended to all early-stage dMMR solid tumors, regardless of tumor site, is unknown.
Methods:
We conducted a phase 2 study in which patients with stage I, II, or III dMMR solid tumors that were amenable to curative-intent surgery were treated with neoadjuvant dostarlimab, a programmed cell death 1 (PD-1) blocking agent, for 6 months. The response to treatment was assessed in two cohorts: patients in cohort 1 had dMMR, locally advanced rectal cancer, and patients in cohort 2 had dMMR nonrectal solid tumors. Patients with a clinical complete response could elect to proceed with nonoperative management; those with residual disease were to undergo resection. In this analysis, the primary end point, assessed in cohort 1, was a sustained clinical complete response at 12 months. Recurrence-free survival and safety were evaluated.
Results:
A total of 117 patients were included in the analysis. In cohort 1, all 49 patients who completed treatment had a clinical complete response and elected to proceed with nonoperative management. A total of 37 patients had a sustained clinical complete response at 12 months, a finding that met the criterion for efficacy. In cohort 2, a total of 35 of 54 patients who completed treatment had a clinical complete response, and 33 elected to proceed with nonoperative management. Among the 103 patients who completed treatment across both cohorts, 84 had a clinical complete response, and 82 did not undergo surgery. Among the 117 total patients, recurrence-free survival at 2 years was 92% (95% confidence interval, 86 to 99); the median follow-up for recurrence was 20.0 months (range, 0 to 60.8). The majority of patients (95%) had reversible, grade 1 or 2 adverse events (60%) or had no adverse events (35%). The option for curative resection was not compromised during or after treatment in any of the patients.
Conclusions:
Among patients with early-stage dMMR solid tumors that were amenable to curative-intent surgery, neoadjuvant PD-1 blockade led to organ preservation in a high proportion of patients. (Funded by Swim Across America and others; ClinicalTrials.gov number, NCT04165772.).
Insights
Neoadjuvant programmed cell death 1 (PD-1) blockade achieved high rates of organ preservation in patients with early-stage mismatch repair-deficient (dMMR) solid tumors. This approach demonstrated significant clinical complete responses and favorable recurrence-free survival, offering a nonoperative management option.
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.
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