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Evidence From NEST And UNICORN Supports the Potential of BOT+BAL in the Neoadjuvant Treatment Setting For MSS Colon Cancer

Agenus

DOI: 10.26303/ccb1-fp44

Key takeaways

  • NEST demonstrated deep responses with encouraging longer-term disease control following short-course BOT+BAL, supported by presurgical ctDNA clearance and no reported colorectal cancer recurrences at the analysis.
  • UNICORN independently supported the importance of the combination, reproducing deep responses across multiple centers and providing evidence of BAL’s contribution.
  • The clinical and biological findings support Phase 3 evaluation, with ROBBIN designed to determine whether the early activity translates into improved event-free survival.

What is it about?

NEST (NCT05571293) and UNICORN (NCT05845450) are independent, investigator-sponsored Phase 2 studies evaluating short-course botensilimab plus balstilimab (BOT+BAL) before surgery in resectable colorectal cancer. Both included MSS/pMMR tumors, which have historically shown limited sensitivity to conventional immunotherapy, and provide complementary evidence of deep pathological responses, molecular responses and encouraging recurrence-free outcomes.

NEST:

  • This single-center, nonrandomized Phase 2 study evaluated two BOT+BAL schedules in patients with pMMR/MSS or dMMR/MSI-H colorectal tumors, with surgery approximately four (NEST-1) or eight (NEST-2) weeks after treatment began.
  • Among 22 evaluable pMMR/MSS tumors, 41% achieved a major pathological response (MPR), including 32% with a pathological complete response (pCR). Seven of eight evaluable patients with detectable circulating tumor DNA (ctDNA) at baseline cleared ctDNA before surgery.
  • No colorectal cancer recurrences were reported after median follow-up of 32.2 months in NEST-1 and 23.5 months in NEST-2, corresponding to 100% disease-free survival at the data cutoff. All patients underwent resection, with no treatment-related delays to surgery.

UNICORN:

  • Conducted across 11 centers in Italy, this nonrandomized Phase 2 study enrolled 56 patients with resectable, locally advanced colon cancer into four sequential cohorts evaluating BOT alone or BOT+BAL in pMMR or dMMR disease.
  • In the pMMR BOT+BAL cohort, 36% achieved major pathologic response (MPR), including 29% with complete pathologic response (pCR). No major or complete pathological responses were observed with BOT alone, supporting the contribution of BAL’s PD-1 blockade to the combination’s activity. All five evaluable pMMR major pathological responders cleared ctDNA by the end of treatment.
  • No recurrences were reported in either BOT+BAL cohort after median follow-up of 19.2 months in pMMR disease and 16.7 months in dMMR disease. All patients underwent surgery, with 98% proceeding within the protocol-defined timeframe.

Why is it important?

NEST and UNICORN provide consistent evidence of deep responses following brief BOT+BAL treatment in MSS/pMMR tumors. NEST adds longer-term recurrence follow-up, while UNICORN independently reproduces activity in a multicenter setting and provides additional translational insight and support into BAL’s contribution.

The findings extend beyond pathological response. ctDNA clearance and exploratory evidence of treatment-associated immune remodeling support the combination’s biological activity.

Although small and nonrandomized, these studies provide a clinical and biological rationale for the registrational Phase 3 ROBBIN trial, which will evaluate whether neoadjuvant BOT+BAL improves event-free survival in resectable, high-risk Stage II/III MSS/pMMR colon cancer. Click on the next story below – The Phase 3 ROBBIN Trial Will Evaluate Neoadjuvant BOT+BAL in High-Risk Stage II/III MSS Colon Cancer – to learn more about the global, registrational Phase 3 study designed to further investigate BOT+BAL in the neoadjuvant setting.

Page published: 12-Nov-2026

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Who is involved?

Important information

In October 2026, BOT+BAL reached an important milestone with its first marketing authorizations in Armenia, where Botvymo® (botensilimab) and Evamplix® (balstilimab) were approved for use in combination in eligible adults with microsatellite-stable (MSS) metastatic colorectal cancer without active liver metastases who have previously received available standard therapies.

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