Combination therapy achieves high major pathological response in pMMR colon cancer
The UNICORN phase 2 trial shows neoadjuvant botensilimab plus balstilimab produced a 36% major pathological response in pMMR colon cancer and 100% in dMMR disease, with 100% 12-month event-free survival in both combination cohorts.
A novel immunotherapy combination has demonstrated high major pathological response rates in patients with resectable, locally advanced colon cancer. The phase 2 UNICORN trial found that preoperative botensilimab plus balstilimab produced major pathological responses in patients with both proficient mismatch repair (pMMR) and deficient mismatch repair (dMMR) disease.
Neoadjuvant botensilimab combined with balstilimab achieved a 100% pathological major response rate in the dMMR colon cancer cohort. In the pMMR cohort, the rate was 36%. The analysis included 56 patients with radiologically staged T3/T4, N0/N-positive, M0 colon adenocarcinoma enrolled across four cohorts from June 2023 to July 2024. 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 one. Patients receiving the combination also received balstilimab, an anti-PD-1 antibody, at 3 mg/kg on days one and 15. Surgery was planned for day 35, within a five-day window. All 56 patients underwent surgery, and 54 completed the planned preoperative treatment. Surgery occurred within the prespecified timeframe in 98% of patients.
The primary endpoint of pathological major response rate, defined as 10% or less residual viable tumor, was met in all cohorts except pMMR botensilimab alone. The detailed response rates and 12-month event-free survival for each cohort are shown below.
| Cohort | Pathological Major Response Rate (pMR) | Pathological Complete Response (pCR) | 12-Month Event-Free Survival (EFS) |
|---|---|---|---|
| pMMR Botensilimab Alone | 0% (95% CI, 0%-23.2%) | Not specified | 93% (95% CI, 59%-99%) |
| pMMR Botensilimab + Balstilimab | 36% (95% CI, 12.8%-64.9%) | 29% (4 patients) | 100% |
| dMMR Botensilimab Alone | Not specified | Not specified | 79% (95% CI, 47%-93%) |
| dMMR Botensilimab + Balstilimab | 100% (95% CI, 76.8%-100%) | 93% (13 patients) | 100% |
Among the 14 patients with pMMR disease receiving the combination, five achieved a major pathological response. Four of those were complete responses. In the dMMR cohort, the pMR rate was 100%, with 93% achieving a pCR. The 12-month event-free survival rate was 100% in both combination cohorts. All six EFS events occurred in the monotherapy cohorts, with three each in the pMMR and dMMR groups. One patient with dMMR disease died of progressive disease.
Circulating tumor DNA positivity decreased from 94% at baseline to 16% after neoadjuvant treatment. Among patients with pMMR tumors who achieved a major pathological response with the combination, all five with evaluable samples had cleared ctDNA before surgery. No recurrence was reported among patients who achieved ctDNA clearance at the data cutoff of February 9, 2026. No recurrences were reported among patients receiving the combination.
Safety profile of the combination regimen
The combination therapy showed manageable safety with no treatment-related deaths and a higher incidence of immune-related adverse events compared to botensilimab monotherapy. No adverse event led to death or unresolved sequelae. 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.
Adverse events were reported in 54% of patients, while 41% experienced immune-related adverse events. Two patients did not receive the second balstilimab dose due to immune-related adverse events. One patient had a 10-day surgery delay because of grade 3 hyperthyroidism, suggesting that the short treatment course was generally feasible before resection.
Biomarker insights from spatial transcriptomics
Pre-treatment PD-L1 stromal expression and macrophage FCGR2A/FCGR3A expression predicted response to the combination therapy. Single-cell spatial transcriptomic analysis showed high baseline PD-L1 stromal expression and low post-treatment regulatory T cell signatures in pMMR responders. dMMR responders displayed high baseline FCGR2A and FCGR3A expression on intratumoral macrophages.
Median follow-up ranged from 16.7 to 25.6 months at the February 9, 2026 data cutoff. Median adjuvant chemotherapy duration was 154 days in the pMMR monotherapy cohort, 129 days in the pMMR combination cohort, and 84 days in the dMMR monotherapy cohort. No adjuvant chemotherapy was given in the dMMR combination cohort. The sponsor plans to evaluate botensilimab plus balstilimab in the global, randomized phase 3 ROBBIN trial for high-risk stage II or III pMMR colon cancer.
