# Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial

Source: https://onco.cc/key-papers/paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024/  
OnCo record `paper-bullock-botensilimab-balstilimab-mss-colorectal-nat-med-2024` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The first immunotherapy signal in the 95 percent of bowel cancers that have always ignored it: an engineered CTLA-4 antibody plus a PD-1 antibody shrank tumours in 17 percent of 101 heavily treated patients.

## Summary

Bullock, Schlechter, Fakih and colleagues report outcomes in 148 heavily pre-treated patients with microsatellite stable metastatic colorectal cancer (six from dose escalation, 142 from dose expansion) treated with botensilimab, an Fc-enhanced multifunctional anti-CTLA-4 antibody designed to extend therapy to poorly immunogenic tumours, plus balstilimab, an anti-PD-1 antibody. The primary endpoint was safety and tolerability; secondary endpoints included investigator-assessed objective response, disease control, duration of response and progression-free survival. One hundred and one patients were response evaluable with at least six months of follow-up.

Treatment-related adverse events occurred in 131 of 148 patients (89 percent), most commonly fatigue (35 percent), diarrhoea (32 percent) and pyrexia (24 percent), with no grade 5 treatment-related events and a 12 percent discontinuation rate.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Tags: colorectal-evidence
- Journal: Nature Medicine
- Year: 2024
- DOI: 10.1038/s41591-024-03083-7
- Authors: Bullock AJ, Schlechter BL, Fakih MG, et al.
- Findings: Objective response 17 percent (17 of 101; 95 percent CI 10 to 26) and disease control 61 percent (62 of 101; 51 to 71) in the response-evaluable population.; Median duration of response not reached (95 percent CI 5.7 months to not reached); median progression-free survival 3.5 months (2.7 to 4.1) at a median 10.3 months of follow-up.; Treatment-related adverse events in 89 percent (131 of 148); no grade 5 events; 12 percent discontinued for toxicity.
- What it means: The first credible response signal in microsatellite stable colorectal cancer, and the reason the field's attention has moved to Fc engineering and to excluding patients with active liver metastases, in whom responses are rare.
- Caveats: Phase 1 expansion, single-arm, investigator-assessed: the response rate is not a randomised estimate.; Responses concentrate in patients without active liver metastases, so the population is narrower than the headline figure implies.; Immune-mediated toxicity is substantial and a randomised phase 3 has not yet reported.

## Sources

- Nat Med 2024: https://doi.org/10.1038/s41591-024-03083-7
- PubMed: https://pubmed.ncbi.nlm.nih.gov/38871975/
- Europe PMC full text (PMC11405281): https://europepmc.org/article/MED/38871975

## Connected records

- ideas: [Making microsatellite-stable colorectal cancer immunotherapy-responsive](https://onco.cc/ideas/idea-immunotherapy-mss-crc/), [Select microsatellite stable patients for immunotherapy by a measured immune biomarker, not by how many treatments they have already failed](https://onco.cc/ideas/idea-crc-mss-immunotherapy-by-biomarker-not-by-line/)
- key papers: [PD-1 blockade in tumors with mismatch-repair deficiency](https://onco.cc/key-papers/paper-le-pd1-blockade-mismatch-repair-deficiency-nejm-2015/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- fronts: [Immunotherapy](https://onco.cc/fronts/immunotherapy/)
- technologies: [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- targets: [CTLA-4](https://onco.cc/targets/ctla4/), [PD-1](https://onco.cc/targets/pd1/)
- drugs: [Balstilimab](https://onco.cc/drugs/balstilimab/), [Botensilimab](https://onco.cc/drugs/botensilimab/)
- companies: [Agenus](https://onco.cc/companies/agenus/)
- pathways: [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/), [The cancer-immunity cycle](https://onco.cc/pathways/cancer-immunity-cycle/)
- terms: [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR)](https://onco.cc/terms/mss-pmmr/)
- people: [Heinz-Josef Lenz](https://onco.cc/people/heinz-josef-lenz/)
- bottlenecks: [Cold tumours and the immunosuppressive microenvironment](https://onco.cc/bottlenecks/b-tme-immunosuppression/), [No one can predict who responds to immunotherapy](https://onco.cc/bottlenecks/b-immunotherapy-response/)
- journals: [Nature Medicine](https://onco.cc/journals/nature-medicine/)
- roadmaps: [Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation](https://onco.cc/roadmaps/colorectal-roadmap/)

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