Nonoperative Management of Mismatch Repair-Deficient Tumors

Abstract

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.).

Figure 1

A. Patient outcome flowchart. 124 patients were enrolled. Seven patients were excluded from the study: two were found to have metastatic disease before treatment; one was diagnosed with a second brain primary tumor and withdrew from the study; four elected to withdraw from the study. At the time of data cut 103 patients completed dostarlimab therapy and 14 remained on treatment. Cohort 1 included 49 patients with rectal cancer and Cohort 2 included 54 patients with non-rectal solid tumors including gastroesophageal, colon, hepatobiliary, genitourinary and gynecologic cancers. B. Clinical responses by tumor type. Tumor responses are defined as clinical complete response (cCR), near complete response (nCR), partial response (PR) and stable disease (SD).

Figure 2

A. Swimmer plot of clinical outcomes in cohort 1 and 2. B. Clinical Vignette. A 55-year-old male with a localized MMRd intrahepatic cholangiocarcinoma. The top panel represents the axial PET images of the tumor at baseline and the bottom panel shows a complete response by PET after completion of 6-months of treatment with dostarlimab.

Figure 3.. Circulating tumor DNA dynamics.

(A) fraction of patients achieving ctDNA clearance over time by type of response, (B) individual patient ctDNA levels normalized to baseline during treatment by type of response. ctDNA fraction is represented as the percent at each timepoint of the original baseline value.