On May 15, 2026 Agenus Inc. (Nasdaq: AGEN), a leader in immuno-oncology innovation, reported the publication of Phase 1b data evaluating botensilimab (BOT), an Fc-enhanced anti-CTLA-4 antibody, in combination with balstilimab (BAL), an anti-PD-1 antibody, in patients with treatment-refractory hepatocellular carcinoma (HCC) who had progressed following prior immunotherapy. The manuscript, titled "A phase 1b study of botensilimab and balstilimab in treatment-refractory hepatocellular carcinoma," was published in Liver Cancer and is available at DOI: 10.1159/000551630.
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The publication reports results from an expansion cohort of the Phase 1b C-800-01 study in 19 patients with HCC who had progressed on or after prior immunotherapy. The cohort represents a difficult-to-treat population for which prospective data remain limited, including 47% of patients with albumin-bilirubin (ALBI) grade 2 liver function, a marker of poorer liver reserve and prognosis in HCC. In published HCC studies, ALBI grade 2 liver function has been linked to a 4- to 10-month decrement in median overall survival compared with ALBI grade 1, underscoring the poor prognosis and reduced responsiveness typically observed in this population.i
Among 18 efficacy-evaluable patients, BOT+BAL demonstrated an objective response rate (ORR) of 17%, including one complete response and two partial responses. The 18-week clinical benefit rate (CBR) was 50%. Median duration of response (mDOR) was not reached, median progression-free survival (mPFS) was 4.4 months, and median overall survival (mOS) was 12.3 months. All patients had received prior anti-PD-(L)1 therapy, 68% had received prior tyrosine kinase inhibitors, and 58% had received prior atezolizumab/bevacizumab. One patient experienced stable disease for 66 weeks, supporting the conclusion that benefit with BOT+BAL was not confined to RECIST response alone.
Treatment options after immune checkpoint inhibitor (ICI) therapy in advanced HCC remain limited, and available systemic therapies have generally shown modest activity. Published studies evaluating lenvatinib, cabozantinib and regorafenib after ICI-based therapy have reported objective response rates of 6–14%, median progression-free survival of approximately 4–5 months and median overall survival of ≤10.5 months.ii The BOT+BAL results therefore, provide early prospective evidence of activity in a post-ICI HCC population that included patients with adverse prognostic features often underrepresented in later-line studies.
"This publication adds to a consistent body of clinical evidence showing BOT plus BAL activity across difficult-to-treat, late-line solid tumors," said Steven O’Day, MD, Chief Medical Officer of Agenus. "In HCC, where tumor biology and underlying liver function both shape treatment outcomes, these data further support the rationale for botensilimab’s Fc-enhanced CTLA-4 design and its potential to drive immune activity in settings where conventional checkpoint approaches have had limited impact."
"Patients with advanced HCC who progress after immunotherapy have limited treatment options, and outcomes can be especially poor when liver function is compromised," said Anthony B. El-Khoueiry, MD, Chief of Section of Developmental Therapeutics and Associate Director for Clinical Research at USC Norris Comprehensive Cancer Center, part of Keck Medicine of USC, and principal investigator of the study. "In this exploratory cohort, seeing objective responses, prolonged disease control and a median overall survival of 12.3 months is encouraging and supports continued study of BOT plus BAL in this post-immunotherapy setting."
The safety profile of BOT+BAL in the HCC cohort was consistent with prior reports across the broader Phase 1b program. There were no treatment-related deaths and no new class safety signals. Immune-mediated treatment-related adverse events occurred in 68% of patients, with grade 3 events in 37%. The most common immune-mediated treatment-related adverse events were diarrhea/colitis, hepatitis and dermatologic events. No grade 4 or higher immune-mediated treatment-related adverse events were reported. All immune-mediated hepatitis events resolved to grade 1 or lower.
HCC is the most common form of liver cancer and is often diagnosed at an advanced stage. Immune checkpoint inhibitor combinations have improved outcomes in the frontline setting, but patients who progress after immunotherapy have limited prospective evidence to guide subsequent treatment. In the published manuscript, the authors concluded that BOT+BAL demonstrated promising efficacy and manageable safety in previously treated HCC, including patients who progressed after frontline immunotherapy, and that these findings warrant further investigation.
About the C-800-01 Study
C-800-01 (NCT03860272) is an open-label, multicenter Phase 1b clinical trial evaluating botensilimab in combination with or without balstilimab in patients with advanced solid tumors. The trial enrolled over 400 patients with refractory disease and included tumor types with limited or no responsiveness to prior checkpoint inhibitors.
The HCC expansion cohort enrolled 19 patients between March 2021 and September 2023 across six U.S. sites. Patients received botensilimab at 1 mg/kg or 2 mg/kg once every six weeks plus balstilimab 3 mg/kg once every two weeks. The safety analysis included all 19 patients who received at least one dose of study drug, and the efficacy-evaluable analysis included 18 patients with at least one post-baseline imaging scan.
(Press release, Agenus, MAY 15, 2026, View Source [SID1234665787])