Abstract CT002: Circulating tumor DNA status to direct adjuvant immunotherapy for mismatch repair deficient tumors

Background: Patients with early-stage solid tumors who harbor minimal residual disease (MRD) following surgical resection as detected by circulating tumor DNA (ctDNA), have a high risk of recurrence. It remains uncertain whether therapeutic intervention of MRD in this context reduces cancer recurrence. We evaluated the efficacy of PD-1 blockade in resected early-stage mismatch repair deficient (MMRd) tumors with ctDNA-detected MRD, given high sensitivity of MMRd tumors to immune checkpoint blockade. Methods: We conducted a prospective clinical study assessing PD-1 blockade with pembrolizumab in patients with resected MMRd solid tumors treated with surgery and standard of care adjuvant therapy. Treatment with PD-1 blockade was guided by ctDNA status, measured 6-10 weeks after curative intent surgery and standard of care adjuvant therapy. Study arms included, Arm A (Interventional) comprised of ctDNA-positive patients treated with pembrolizumab for 6 months, and Arm B (Observational) comprised of ctDNA-negative patients. The primary endpoint was ctDNA clearance at 6 months in 40% of study patients. Recurrence-free survival (RFS) and overall survival (OS) were included as exploratory endpoints. Results: Three-hundred and three patients with resected MMRd solid tumors were screened and ctDNA status was measured in 174 of these patients in 16 different tumor types. Twenty-two patients (12.6%) were ctDNA positive and enrolled in Arm A (Interventional). Of these 22, 13 ctDNA-positive patients received six months of PD-1 blockade and 9 did not because of radiographically detected disease recurrence prior to initiation of therapy. Fifty-two ctDNA-negative patients were enrolled in Arm B (Observational) and observed. The median follow-up time for all patients was 32.1 months. The study met the primary endpoint; 85% (11/13) of patients in Arm A (Interventional) achieved ctDNA clearance at 6 months, the median RFS was not reached, and the recurrence rate was 38% (5/13). In those that were ctDNA positive that did not receive PD-1 blockade the median RFS was 0.8 months (95% CI 0.3-1.3) and the recurrence rate was 100% (9/9). In Arm B (Observational) the median RFS was not reached, and the recurrence rate was 5.9% (9/152). Overall survival at 2 years was 92% (95%CI: 79-100%) in ctDNA positive patients who received PD-1 blockade and 78% (95%CI: 55%-100%) in patients that did not receive PD-1 blockade. In ctDNA negative patients, the OS at 2 years was 98% (95%CI: 96%-100% ). Conclusion: Adjuvant PD-1 blockade directed by ctDNA status post-resection early-stage MMRd malignancies may provide clinical benefit in a agnostic of tumor type. Citation Format: Yelena Yuriy Janjigian, Michael B. Foote, Melissa Lumish, Marinela Capanu, Joanne Chou, Julio Garcia-Aguilar, Martin Weiser, Jason Konner, Vivian Strong, Elizabeth Jewell, Jennifer Mueller, Steven Maron, Ping Gu, Rona Yaeger, Sree Chalasani, Andrea Cercek, Jia Li, Maliha Nusrat, Ryan Sugarman, David Jones, Daniela Molena, David Solit, Brian Loomis, Marc Ladanyi, Michael Berger, Luis A. Diaz. Circulating tumor DNA status to direct adjuvant immunotherapy for mismatch repair deficient tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited s); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2): nr CT002.