Neoadjuvant botensilimab with or without balstilimab in pMMR and dMMR colon cancer: the phase 2 UNICORN trial

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 .

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Journal
Nature Medicine
Published
2026-11-02
DOI
https://doi.org/10.1038/s41591-026-04710-1
Primary Topic
Cancer Immunotherapy and Biomarkers
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article
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article

Neoadjuvant botensilimab with or without balstilimab in pMMR and dMMR colon cancer: the phase 2 UNICORN trial

Margherita Ambrosini, Stefano Tamberi, Margherita Galassi, Massimo Di Maïo et al.
6 links
Nature Medicine
Cancer Immunotherapy and Biomarkers
article

Neoadjuvant botensilimab with or without balstilimab in pMMR and dMMR colon cancer: the phase 2 UNICORN trial

Margherita Ambrosini, Stefano Tamberi, Margherita Galassi, Massimo Di Maïo, Riccardo Cerantola, Daniele Spada, Alessandra Raimondi, Marcello Guagliò, Emiliano Tamburini, Adham Adel Jurdi, Filippo Ghelardi, Andrea Sartore‐Bianchi, Darryl Nousome, Özlem Kutlu, Andrea Sottoriva, Chiara Rossi, Paolo Manca, Francesco Cambuli, Isacco Montroni, Serenella Maria Pupa, Francesca Bergamo, Federica Palermo, Chiara Ratti, Fabrizio Vittadello, Sara Lonardi, Lorenzo Castagnoli, Giovanna Sabella, Robert William Lentz, Riccardo Rosati, Gian Luca Baiocchi, Luca Azzolin, Federica Morano, Erik Anthony Spickard, Valerio Iebba, Elisa Sottotetti, Vincenzo Nasca, Andrew A. Almonte, Laurence Zitvogel, Cecilia Villa, Samantha Di Donato, Andrea Barina, Filippo Pietrantonio, Claudia Chiodoni, Chiara Cremolini, Eleonora Cristarella, Gina M. Brown, Alessandro Passardi, Anna Chiaramonte, Andrey Tyshevich, Ilaria Mulas, Antony S. Tin, Martinetti Antonia, Eleonora Perissinotto, Stephanie Ni
article en

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 .

Nature Medicine
University of Pisa (IT), University of Padua (IT), Inserm (FR), University of Milan (IT), Université Paris-Saclay (FR), Institut Gustave Roussy (FR), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Ospedale "Santa Maria delle Croci" di Ravenna (IT), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IT), Ospedale Sant Antonio (IT), Istituto Oncologico Veneto (IT), Human Technopole (IT), IRCCS Ospedale San Raffaele (IT), Azienda Ospedale - Università Padova (IT), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), Azienda Ospedaliera Universitaria Pisana (IT), Istituti Ospitalieri di Cremona (IT), Hospital of Prato (IT), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), Azienda Socio Sanitaria Territoriale di Cremona (IT), İzmir Şehir Hastanesi (TR), Pia Fondazione di Culto e Religione Azienda Ospedaliera "Card. G. Panico" (IT), Imperial College London (GB), University of Turin (IT), University of Brescia (IT), University of Bologna (IT)
Ministero della Salute
Good health and well-being
Openalex Percentile: Top 17%
Cancer Immunotherapy and Biomarkers
DOIOpen Access PDFOpenAlex
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