Neoadjuvant Botensilimab/Balstilimab Shows Activity in Colon Cancer

Neoadjuvant botensilimab (investigational) plus balstilimab (investigational) produced major pathological responses in patients with resectable, locally advanced proficient mismatch repair (pMMR) and deficient mismatch repair (dMMR) colon cancer, according to findings from the phase 2 UNICORN trial (NCT05845450) published in Nature Medicine.^1,2

Among 14 patients with pMMR disease receiving the combination, 36% achieved a major pathological response (pMR), defined as 10% or less residual viable tumor, including 29% who achieved a pathological complete response (pCR). In the dMMR cohort, the pMR rate was 100%, with 93% achieving a pCR. No recurrences were reported among patients receiving the combination at the data cutoff of February 9, 2026.

“For many years, [microsatellite stable] colon cancer has largely been considered resistant to immunotherapy. The UNICORN study challenges that assumption in the curative-intent setting,” Filippo Pietrantonio, MD, head of the Gastrointestinal Oncology Unit at Fondazione IRCCS Istituto Nazionale dei Tumori, in Milan, Italy, and UNICORN principal investigator, stated in a news release. “The purpose of moving treatment earlier is not simply to shrink the tumor before surgery. It is to prevent the disease from returning and ultimately increase the number of patients who may be cured. Seeing deep responses after only a short course of treatment, with patients able to proceed to planned surgery and no recurrences observed to date in the combination cohorts, provides a strong rationale to test that objective in a larger randomized trial.”

UNICORN Background and Study Design

UNICORN is an open-label, nonrandomized, multicenter phase 2 platform trial evaluating short-course preoperative therapies in patients with resectable, locally advanced colorectal cancer.³ The analysis included 56 patients with radiologically staged T3/T4, N0/N-positive, M0 colon adenocarcinoma enrolled across 4 cohorts. Patients were sequentially assigned to botensilimab monotherapy or botensilimab plus balstilimab according to MMR status, with 14 patients in each cohort.

Botensilimab, a multifunctional, Fc-enhanced anti-CTLA-4 antibody, was administered at 1 mg/kg on day 1. Patients receiving the combination also received balstilimab, an anti-PD-1 antibody, at 3 mg/kg on days 1 and 15. Surgery was planned for day 35, within a 5-day window. The primary end point was centrally assessed pMR.

Safety and Surgical Feasibility

All 56 patients underwent surgery, and 54 (96%) completed the planned preoperative treatment. Surgery occurred within the prespecified timeframe in 98% of patients. One patient had a 10-day delay because of grade 3 hyperthyroidism, suggesting that the short treatment course was generally feasible before resection.

Adverse events were reported in 54% of patients, while 41% experienced immune-related adverse events. Immune-related events occurred in 29% of patients receiving botensilimab alone and 54% receiving the combination. Grade 3 or 4 immune-related adverse events occurred in 2% of the overall population. No adverse event resulted in death or unresolved sequelae.

ctDNA Findings

Circulating tumor DNA (ctDNA) was assessed as a potential marker of treatment response. Across the study population, ctDNA positivity decreased from 94% at baseline to 16% after neoadjuvant treatment. Among patients with pMMR tumors who achieved pMR with the combination, all 5 with evaluable samples had cleared ctDNA before surgery. No recurrence was reported among patients who achieved ctDNA clearance at the data cutoff.

These findings support further evaluation of ctDNA as a potential biomarker of response in the neoadjuvant setting. However, the small number of evaluable patients and limited follow-up mean that these results should be considered exploratory.

Next Steps in Clinical Development

At a median follow-up of 19.2 months in the pMMR combination cohort and 16.7 months in the dMMR combination cohort, 12-month event-free survival was 100% in both groups. The findings provide a rationale for further evaluation of the combination in resectable colon cancer.

Looking ahead, the sponsor plans to evaluate botensilimab plus balstilimab in the global, randomized phase 3 ROBBIN trial in patients with high-risk stage II or stage III pMMR colon cancer, where event-free survival is planned to serve as the trial’s primary end point.

REFERENCES

1. Ghelardi F, Ambrosini M, Raimondi A, et al. Neoadjuvant botensilimab with or without balstilimab in pMMR and dMMR colon cancer: the phase 2 UNICORN trial. Nature Medicine. Published online November 2, 2026. doi:10.1038/s41591-026-04710-1

2. Agenus Announces Nature Medicine Publication of Multicenter UNICORN Phase 2 Trial Demonstrating Deep Responses with Neoadjuvant BOT+BAL in Resectable Colon Cancer. News release. Agenus. November 2, 2026. Accessed November 2, 2026. https://tinyurl.com/52f6677s

3. Pre-operative Targeted Treatments in Molecularly Selected Resectable Colorectal Cancer (UNICORN). ClinicalTrials.gov. Updated September 11, 2026. Accessed November 2, 2026. https://clinicaltrials.gov/study/NCT05845450