Enhanced Outcomes with ctDNA-Guided Adjuvant PD-1 Therapy in Mismatch Repair-Deficient Cancers

A recent study presented at the AACR Annual Meeting 2025 highlights the promising role of ctDNA-guided immunotherapy in managing mismatch repair-deficient (dMMR) solid tumors. The research focused on the use of pembrolizumab (Keytruda), an anti-PD-1 antibody, to eliminate residual disease and prevent cancer recurrence in early-stage patients. In this phase II trial, 174 patients with resected dMMR tumors were screened for circulating tumor DNA (ctDNA) six to ten weeks post-surgery. Of these, 20 patients exhibited detectable ctDNA, a marker associated with higher recurrence risk. Thirteen of these ctDNA-positive patients received pembrolizumab; six experienced disease progression before treatment, and one was not evaluable. The remaining treated patients showed remarkable results, with 11 out of 13 clearing ctDNA within six months, and most remaining recurrence-free over a median follow-up of just over two and a half years. Importantly, survival rates at two years stood at 92.3% among the treated group, compared to 66.7% in ctDNA-positive patients who did not receive immunotherapy, and 98.5% in ctDNA-negative patients under observation. These findings suggest that personalized, ctDNA-guided immunotherapy could significantly reduce relapse risks, potentially shifting treatment paradigms. This approach emphasizes the benefits of dynamic biomarkers in tailoring early intervention strategies, especially in cancers with high recurrence potential. While the findings are encouraging, they are based on a small sample size, and longer-term studies are necessary to confirm these results and refine assay sensitivity. Ultimately, this research paves the way for more precise treatment frameworks in early-stage cancers, focusing on high-risk patient populations and avoiding unnecessary treatment in low-risk cases.