Neoadjuvant botensilimab with or without balstilimab in pMMR and dMMR colon cancer: the phase 2 UNICORN trial

Preoperative immune checkpoint inhibitors (ICIs) are active in patients with deficient mismatch repair (dMMR) colon cancer (CC), whereas proficient mismatch repair (pMMR) CC has been consistently considered resistant to first-generation ICIs. In the phase 2 UNICORN trial, we evaluated short-course preoperative botensilimab (BOT; multifunctional Fc-enhanced anti-CTLA-4 monoclonal antibody) alone or in combination with the anti-PD-1 monoclonal antibody balstilimab (BOT + BAL) in 56 patients with resectable, locally advanced CC. Twenty-eight patients with pMMR CC were sequentially enrolled in BOT (n = 14) and BOT + BAL (n = 14) cohorts. Twenty-eight patients with dMMR CC followed the same sequential allocation strategy. The primary endpoint of centrally assessed pathological major response (pMR) rate (≤10% of residual viable tumor) was met in all cohorts, except pMMR BOT. Specifically, the pMR rate was 0% (95% confidence interval (CI): 0−23.2%) in pMMR BOT, 36% (95% CI: 12.8−64.9%) in pMMR BOT + BAL, 36% (95% CI: 12.8−64.9%) in dMMR BOT and 100% (95% CI: 76.8−100%) in dMMR BOT + BAL. Secondary endpoints included safety, quality of life, describing treatment-induced transcriptional dynamics, peripheral blood mononuclear cell dynamics, radiomics and radiogenomics features, fecal microbiota composition and circulating tumor DNA (ctDNA) dynamics. Eight (29%) and 15 (54%) patients treated with BOT and BOT + BAL, respectively, experienced immune-related adverse events, most commonly flu-like syndrome and diarrhea. Single-cell spatial transcriptomic analysis of matched baseline and post-treatment samples highlighted high baseline PD-L1 stromal expression and low post-treatment regulatory T cell signatures in pMMR responders, whereas dMMR responders displayed high baseline FCGR2A and FCGR3A expression on intratumoral macrophages. Clearance of ctDNA before surgery correlated with pathological response and lack of recurrence at data cutoff. Preoperative BOT + BAL elicits pathological responses in patients with pMMR or dMMR CC, supporting the combination as a promising strategy to expand ICI benefits to the early-stage setting. ClinicalTrials.gov identifier: NCT05845450 . In the phase 2 UNICORN trial, a short course of neoadjuvant botensilimab and balstilimab achieved the primary endpoint of pathological major response rate in patients with pMMR or dMMR colon cancer.