Phase 2 study of adjuvant botensilimab in combination with balstilimab in patients with microsatellite-stable colorectal cancer and persistent circulating tumor DNA following surgery and chemotherapy.

Abstract

TPS3689 Background: In patients with localized microsatellite stable (MSS) colorectal cancer (CRC), detection of circulating tumor DNA (ctDNA) after completion of definitive therapy indicates the presence of minimal residual disease (MRD) and predicts metastatic recurrence within months. Novel adjuvant therapies to prevent recurrence are very much needed. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS CRC. BOT plus balstilimab (BAL; PD-1 inhibitor) has previously demonstrated deep, durable responses in treatment-refractory metastatic MSS CRC and no active liver metastases. We hypothesize that treatment of MRD with effective immunotherapy in patents with MSS CRC after definitive therapy will prevent tumor recurrence. Methods: This investigator-initiated, open label, Phase 2 study evaluates the efficacy of BOT/BAL in patients with stage III MSS CRC (cohort 1) or colorectal liver metastases (CRLM) (cohort 2) and MRD following definitive treatment, including surgery and pre-operative chemotherapy. The study is being conducted in 2 parts. Part 1 aims to determine ctDNA clearance, as a surrogate for improved survival. Patients receive BOT/BAL for 6 months followed by BAL alone for 6 months. With a total of 27 patients per cohort, and using an exact single-stage binomial design, we will have 80% power to detect an improvement in ctDNA clearance from 5% to 20% with a type I error rate of 5%. If part 1 is successful, then part 2 of the study may proceed as a randomized, placebo-controlled, double-blind, multicenter study to assess improvement in recurrence-free survival. Translation studies are planned to correlate tumor and immune characteristics with ctDNA clearance and clinical endpoints to further our understanding of immune responsiveness in the setting of MRD in MSS CRC. Enrollment to the study is currently ongoing. Clinical trial information: NCT07227636 .