Neoadjuvant BOT + BAL Yields Pathologic Responses in pMMR/dMMR Colon Cancer

Short-course neoadjuvant botensilimab (BOT) plus balstilimab (BAL) produced pathologic major responses (pMRs) in patients with resectable, locally advanced mismatch repair–proficient (pMMR) and mismatch repair–deficient (dMMR) colon cancer, according to results from cohorts 4 and 7 of the phase 2 UNICORN trial (NCT05845450) published in Nature Medicine and announced in a press release from the developer, Agenus Inc.^1,2 The pMR rate was 36% (95% CI, 12.8%-64.9%) in the pMMR BOT plus BAL cohort and 100% (95% CI, 76.8%-100%) in the dMMR BOT plus BAL cohort.

What did UNICORN find?

The primary end point of centrally assessed pMR, defined as 10% or less residual viable tumor at surgery, was met in all cohorts except pMMR BOT alone. In that cohort, the pMR rate was 0% (95% CI, 0%-23.2%), and 6 of 14 patients (43%) had a pathologic partial response (pPR; more than 10% and 50% or less residual tumor). In the pMMR BOT plus BAL cohort, 4 patients (29%) had a pathologic complete response (pCR), 5 (36%) a pPR, and 4 (29%) no response.

In the dMMR BOT cohort, the pMR rate was 36% (95% CI, 12.8%-64.9%), with pCR in 4 patients (29%) and pPR in 29%. In the dMMR BOT plus BAL cohort, all 14 patients had a pMR, including 13 (93%) with pCR.

At the February 9, 2026, data cutoff, median follow-up ranged from 16.7 to 25.6 months across cohorts. The 12-month event-free survival (EFS) rate was 100% in both BOT plus BAL cohorts, 93% (95% CI, 59%-99%) in pMMR BOT, and 79% (95% CI, 47%-93%) in dMMR BOT. All 6 EFS events occurred in BOT-alone cohorts (3 each in pMMR and dMMR), and 1 patient with dMMR disease died of progressive disease.

“UNICORN gave us a rare opportunity to look beyond whether a tumor responded and examine what was changing biologically during a very short period before surgery,” stated Filippo Ghelardi, MD, first author and medical oncology fellow of the Department of Medical Oncology at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, in the press release.² “The alignment we observed between deep pathologic responses, clearance of circulating tumor DNA and changes within the tumor immune environment provides multiple signals of treatment activity.”

How was UNICORN designed?

UNICORN is an open-label, nonrandomized, window-of-opportunity umbrella trial for patients with molecularly selected, resectable colorectal cancer. From June 2023 to July 2024, 56 patients with radiographically staged cT3-4 N0/N+ M0 colon adenocarcinoma were enrolled, with 14 patients in each cohort: pMMR BOT (cohort 4), pMMR BOT plus BAL (cohort 5), dMMR BOT (cohort 6), and dMMR BOT plus BAL (cohort 7). No patients with rectal cancer were enrolled in these cohorts.

Eligible patients were at least 18 years of age with an ECOG performance status of 0 or 1, absence of distant metastases at baseline, no prior systemic treatment for colorectal cancer, and adequate bone marrow, renal, and hepatic function.

In cohorts 4 and 6, BOT, a multifunctional Fc-enhanced anti-CTLA-4 antibody, was given at 1 mg/kg intravenously on day 1. In cohorts 5 and 7, patients also received BAL, an anti-PD-1 antibody, at 3 mg/kg intravenously on days 1 and 15. Surgery was performed 30 to 40 days after treatment start. Secondary end points included safety, quality of life, and translational analyses.

What safety findings were reported?

All 56 patients started treatment, and 54 (96%) completed it; 2 did not receive the second BAL dose because of immune-related adverse events (irAEs; grade 3 hyperthyroidism and grade 2 flu-like syndrome). All patients underwent surgery, which was timely in 98%, defined as having a delay of 14 days or fewer from day 35. Any-grade AEs occurred in 54% (n = 30) of patients, and irAEs in 41% (n = 23). In those who received BOT alone, 29% (n = 8) experienced irAEs vs 54% (n = 15) who received BOT plus BAL, most commonly flu-like syndrome and diarrhea. No adverse event led to death or unresolved sequelae.

Among patients with pMMR disease who received BOT plus BAL, European Organisation for Research and Treatment of Cancer QLQ-C30 scores declined from 77.8 points at baseline to 61.1 points at the end of treatment (P = .01).

What did the translational analyses show?

Circulating tumor DNA (ctDNA) clearance before surgery was observed in 22% of evaluable patients with pMMR disease, including all 5 patients with a pMR, and in 74% of those with dMMR disease. No disease-free survival events occurred in patients who cleared ctDNA. Spatial transcriptomic analyses of matched samples showed higher baseline stromal CD274 (PD-L1) expression and lower post-treatment regulatory T-cell signatures in pMMR responders, whereas dMMR responders had higher baseline FCGR2A and FCGR3A expression in intratumoral macrophages. The investigators described these findings as hypothesis generating.

What are the limitations and next steps?

The authors noted that the cohorts were small and nonrandomized with differing follow-up, enrolled almost exclusively White patients, and that results in cohorts near the decision boundary for the primary end point should be interpreted cautiously.

“For many years, [microsatellite stable (MSS)] colon cancer has largely been considered resistant to immunotherapy,” said Filippo Pietrantonio, MD, senior author, study principal investigator, and head of the Gastrointestinal Oncology Unit at Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, in the press release. “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.”

Steven O’Day, MD, chief medical officer of Agenus, added, “UNICORN delivers compelling, independent evidence that BOT [plus] BAL can produce deep responses in MSS colon cancer, a disease historically resistant to conventional immunotherapy. With no recurrences observed to date, these findings reinforce the promise of treating earlier. Together with NEST [(NCT05571293)], they provide a strong foundation for our planned phase 3 ROBBIN trial and our ambition to change how MSS colon cancer is treated in the curative-intent setting.”

UNICORN was amended to evaluate 8-week BOT plus BAL in a cohort of 29 patients with locally advanced pMMR colon cancer, which the authors said will inform a global, randomized phase 3 trial. Agenus said the planned ROBBIN trial will compare neoadjuvant BOT plus BAL followed by standard of care with standard of care alone in previously untreated, high-risk stage II or III pMMR colon cancer.²

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. Nat Med. 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 Inc. November 2, 2026. Accessed November 2, 2026. https://tinyurl.com/3sx4pcxh