Investigational Drug
Botensilimab
TrialFetch AI Analysis
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Overview
Botensilimab (AGEN1181; BOT) is an investigational, fully human, Fc-engineered IgG1 monoclonal antibody targeting CTLA-4. It is being studied both alone and—more commonly—in combination with the investigational anti-PD-1 antibody balstilimab. Clinical development includes colorectal, ovarian, liver and other difficult-to-treat solid tumors. Evidence remains preliminary because most results come from small, non-randomized phase 1–2 studies; a randomized phase 2 colorectal-cancer trial is ongoing and has not posted results. (cancer.gov)
Mechanism of action
Botensilimab blocks CTLA-4-mediated suppression of T-cell activation. Its engineered Fc region has increased affinity for activating Fcγ receptors on antigen-presenting and natural-killer cells. Preclinical and translational studies indicate that this design may strengthen T-cell priming and memory, activate innate immunity, and promote depletion of intratumoral regulatory T cells. Whether these properties produce better clinical outcomes than established CTLA-4 antibodies has not yet been demonstrated in randomized trials. (pmc.ncbi.nlm.nih.gov)
Efficacy
The most extensive published evidence is for botensilimab plus balstilimab:
- Previously treated microsatellite-stable metastatic colorectal cancer: In a phase 1 trial, 101 response-evaluable patients had a confirmed objective response rate (ORR) of 17%, including one complete response, and a disease-control rate of 61%. Median progression-free survival was 3.5 months; median duration of response was not reached. All responses occurred in patients without active liver metastases. The study was single-arm, and efficacy data for 47 additional treated patients were immature at publication. (pmc.ncbi.nlm.nih.gov)
- Localized colorectal cancer: In the 24-patient phase 2 NEST study, neoadjuvant treatment produced major pathological responses in 41% of mismatch-repair-proficient tumors and 100% of mismatch-repair-deficient tumors. Treatment did not delay planned surgery. These results are promising but derive from a small, non-randomized study using pathological rather than long-term survival outcomes. (aacrjournals.org)
- Treatment-refractory ovarian cancer: A phase 1b cohort reported an ORR of 23% among 35 efficacy-evaluable patients, including one complete and seven partial responses; the 24-week clinical-benefit rate was 31%. (pubmed.ncbi.nlm.nih.gov)
- Treatment-refractory hepatocellular carcinoma: Among 18 efficacy-evaluable patients, the ORR was 17%, the 18-week clinical-benefit rate was 50%, median progression-free survival was 4.4 months, and median overall survival was 12.3 months. (pmc.ncbi.nlm.nih.gov)
- Responses have also been reported in phase 1 sarcoma cohorts, particularly angiosarcoma, but sample sizes were small and histologies heterogeneous. (pmc.ncbi.nlm.nih.gov)
Safety
Toxicity resembles that expected from CTLA-4/PD-1 checkpoint inhibition, particularly immune-mediated gastrointestinal and hepatic events. In the 148-patient metastatic colorectal-cancer safety population, 89% experienced a treatment-related adverse event; 31% had grade 3 and 1% had grade 4 events. Common events included fatigue (35%), diarrhea (32%) and fever (24%). Immune-mediated diarrhea/colitis occurred in 33%, including grade 3–4 events in approximately 11%. Twelve percent discontinued both drugs because of toxicity, and no treatment-related deaths were reported. (pmc.ncbi.nlm.nih.gov)
Further reading
- Phase 1 metastatic colorectal-cancer trial in Nature Medicine
- Mechanistic and translational study in Cancer Discovery
- NEST phase 2 neoadjuvant colorectal-cancer study
- Phase 1b ovarian-cancer study
- ClinicalTrials.gov randomized colorectal-cancer study
Last updated: Sep 2026
Active trials using Botensilimab
Found 7 active trials using this drug:
TrialFetch AI summary: Adults with previously treated pMMR/MSS metastatic colorectal cancer and measurable liver metastases receive balstilimab (anti-PD-1), botensilimab (Fc-enhanced anti-CTLA-4), and agenT-797, an allogeneic invariant natural killer T-cell therapy that recognizes CD1d-presented glycolipid antigens. Patients must have received fluorouracil, oxaliplatin, and irinotecan, plus an EGFR inhibitor or bevacizumab when appropriate, and must not have had prior immunotherapy.
ClinicalTrials.gov ID: NCT07550088
TrialFetch AI summary: Adults with chemorefractory MSS/pMMR metastatic colorectal cancer, 1–5 liver lesions suitable for SBRT, and at least one measurable unirradiated extrahepatic lesion receive liver-directed SBRT plus botensilimab (an Fc-engineered anti-CTLA-4 antibody) and balstilimab (an anti-PD-1 antibody).
ClinicalTrials.gov ID: NCT07128355
TrialFetch AI summary: Adults with microsatellite-stable metastatic pancreatic ductal adenocarcinoma that has progressed after at least one systemic therapy receive SBRT followed by botensilimab, an investigational Fc-engineered anti-CTLA-4 antibody, plus balstilimab, an investigational anti-PD-1 antibody. Eligible patients must have ECOG 0–1 and a previously unirradiated, biopsy-accessible lesion.
ClinicalTrials.gov ID: NCT06843551
TrialFetch AI summary: Adults with measurable, microsatellite-stable, KRAS-mutant metastatic colorectal cancer who have progressed on, cannot tolerate, or cannot receive fluoropyrimidine, oxaliplatin, and irinotecan receive botensilimab (an Fc-engineered anti-CTLA-4 antibody) plus balstilimab (an anti-PD-1 antibody), high-dose IV vitamin C, and a fasting-mimicking diet. Prior anti-PD-1 or anti-CTLA-4 therapy and current diabetes are exclusions.
ClinicalTrials.gov ID: NCT06336902
TrialFetch AI summary: Adults with unresectable or metastatic mismatch repair–proficient colorectal cancer or pancreatic ductal adenocarcinoma (PDAC) and a vaccine-covered KRAS mutation receive a mutant KRAS long-peptide vaccine with poly-ICLC, plus balstilimab (anti-PD-1) and botensilimab (Fc-engineered anti-CTLA-4). Cohorts include patients after 4–6 months of first-line chemotherapy and a PDAC cohort allowing up to three prior regimens, including a KRAS inhibitor.
ClinicalTrials.gov ID: NCT06411691
TrialFetch AI summary: Adults with unresectable or metastatic esophageal, gastric, or gastroesophageal junction adenocarcinoma after one prior metastatic treatment line, or recurrence during or within six months of perioperative therapy, receive ramucirumab plus paclitaxel with investigational agenT-797 (CD1d-directed invariant natural killer T cells), botensilimab (Fc-enhanced anti-CTLA-4), and balstilimab (anti-PD-1).
ClinicalTrials.gov ID: NCT06251973
TrialFetch AI summary: Adults with newly diagnosed IDH-wild-type, MGMT-promoter-unmethylated glioblastoma who have completed radiotherapy, with or without temozolomide, receive implanted SonoCloud-9 ultrasound-mediated blood–brain barrier opening with liposomal doxorubicin and two investigational checkpoint antibodies: balstilimab (anti-PD-1) and botensilimab (Fc-engineered anti-CTLA-4).
ClinicalTrials.gov ID: NCT05864534
