Phase 2 trial of circulating tumor DNA to direct adjuvant immunotherapy across mismatch repair-deficient solid tumors

Detection of circulating tumor DNA (ctDNA) harboring mutations that match those identified in resected tumor tissue signals occult residual disease after curative-intent surgery. Such patients are considered mininal residual disease (MRD)-positive and at high risk for recurrence and death. A phase 2 trial at Memorial Sloan Kettering Cancer Center (New York, NY) evaluated whether PD-1 blockade with pembrolizumab could reduce recurrence in MRD-positive tumors with mismatch repair-deficient (dMMR) tumors after curative-intent resection regardless of tumor site of origin. Among 184 screened patients with early-stage dMMR solid tumors after curative resection, 23 (12.5%) were MRD-positive; after excluding one assigned to placebo and three with synchronous radiographic disease, 19 were eligible. Six developed recurrences before pembrolizumab initiation. The remaining 13 MRD-positive patients received 6 months of pembrolizumab, resulting in ctDNA clearance at 6 months in 11 of 13 patients (85%). Five treated patients (38%) developed recurrence during follow-up. Median follow-up for the MRD-positive patients was 59 months. Among 152 MRD-negative patients managed with observation, 14 (9%) developed recurrence during follow-up; 2-year recurrence-free survival rate was 92%. The authors conclude that these findings provide evidence that ctDNA-guided adjuvant therapy may offer clinical benefit in dMMR tumors regardless of tissue of origin (visual abstract).