Neoadjuvant botensilimab with or without balstilimab in pMMR and dMMR colon cancer: the phase 2 UNICORN trial
In brief
Botensilimab plus balstilimab produced major pathological responses in 5 of 14 pMMR colon cancers
In this phase 2 trial, the preoperative drug combination produced major pathological responses in 36% of patients with proficient mismatch repair (pMMR) tumors and all 14 patients with deficient mismatch repair (dMMR) tumors; botensilimab alone produced no such responses in pMMR cancer. The cohorts were small and enrolled sequentially, so larger studies are needed to confirm the results and clarify who benefits.
- Journal
- Nature medicine (Q1)
- Published
- 2 November 2026
- Study design
- Non-randomized / quasi-experimental trial
- Evidence level
- Level 2, Moderate (CEBM 2b)
- Authors
- Ghelardi F, Ambrosini M, Raimondi A, Tyshevich A, Palermo F, Bergamo F, et al.
- PMID
- 42972108
- DOI
- 10.1038/s41591-026-04710-1
Why clinicians should know about it
- Picked for Surgical Oncology (paper of the day, 5 November 2026): Neoadjuvant immunotherapy response informs operability and surgical planning
Abstract
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 .
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.