Botensilimab Plus Balstilimab Elicits Durable Responses in Treatment-Refractory HCC

Botensilimab Plus Balstilimab in Treatment-Refractory

HCC | Image Credit: © Sebastian Kaulitzki – stock.adobe.com

Botensilimab paired with balstilimab induced responses with a manageable toxicity profile in patients with treatment-refractory hepatocellular carcinoma (HCC), according to findings from the first-in-human, phase 1 C-800-01 study (NCT03860272) presented during the 2025 AACR Annual Meeting.1

In evaluable patients (n = 18), the doublet elicited an objective response rate (ORR) of 17% (95% CI, 4%-41%) with best overall responses of partial response in 17% of patients, stable disease in 56% of patients, and progressive disease in 28% of patients. The disease control rate (DCR) achieved with the combination was 72% (95% CI, 47%-90%), and the clinical benefit rate was 50% (95% CI, 26%-74%). The median duration of response (DOR) was not yet reached (NR; 95% CI, 9.8-NR). Moreover, the median progression-free survival (PFS) was 4.4 months (95% CI, 1.4-6.9) and the median overall survival (OS) was 12.3 months (95% CI, 8.4-21.4).

“Botensilimab/balstilimab demonstrated durable responses and prolonged stable disease in patients with treatment-refractory HCC, with a median of two prior lines of therapy and progressed on or after I-O, including patients who received prior atezolizumab [Tecentriq]/bevacizumab [Avastin],” Anthony B. El-Khoueiry, MD, of USC Norris Comprehensive Cancer Center in Los Angeles, CA, and colleagues wrote in a poster of the data. “The DCR and survival data provide early evidence of antitumor activity in the setting of prior I-O–based therapy.”

Diving Into Study Design: Population, Treatment, Objectives

The study enrolled patients with histologically or cytologically confirmed metastatic or locally advanced solid tumor for which no standard therapy is available or for which standard treatment has failed.2 Patients had measurable disease by RECIST 1.1 criteria with the exception of prostate cancer, a life expectancy of at least 3 months, and an ECOG performance status of 0 or 1. They were also required to have acceptable organ and bone marrow function.

The specific cohort reported on at the meeting included patients with HCC who experienced disease progression on or following previous I-O who did not have encephalopathy or recent paracentesis.1 Those with controlled hepatitis B or C were permitted.

Participants received botensilimab at 1 or 2 mg/kg every 6 weeks plus balstilimab at 3 mg/kg every 2 weeks for up to 2 years. The key efficacy end points are ORR, DCR, DOR, PFS, and OS, and investigators also evaluated adverse effects (AEs).

A total of 19 patients comprised the safety analysis population; these patients had received 1 or 2 mg/kg of botensilimab every 6 weeks paired with 3 mg/kg of balstilimab every 2 weeks. The efficacy evaluable population was comprised of 18 patients who had received at least 1 post-baseline 6-week imaging scan.

In the 19 total patients, the median age was 67 years (range, 39-82). Most patients were male (79%) and had an ECOG performance status of 0 (53%). Patients had received a median of 2 prior lines of therapy (range, 1-7), with 26% of patients having received at least 3 months. All patients had prior exposure to a PD-(L)1 agent, 63% received prior TKIs, and 58% previously received atezolizumab/bevacizumab. With regard to botensilimab dose, 47% of patients received 1 mg/kg of the agent and 53% received 2 mg/kg.

Moreover, patients had a median baseline alpha fetoprotein of 293.1 ng/mL (range, 0.7-91,989). Slightly more than half of patients (53%) had an ALBI score of 1, and the remainder had a score of 2. Forty-two percent of patients had hepatitis B virus and 21% had hepatitis C. Notably, 68% of patients had extrahepatic metastases.

The median follow-up for the data shared during the meeting was 11.4 months (range, 1.5-34.3) and the data cutoff date was December 5, 2024.

Safety Spotlight

“The safety profile was manageable and consistent with other disease cohorts treated with botensilimab/balstilimab,” the study authors wrote. No new safety signals were observed, and no treatment-related deaths occurred.

Immune-mediated treatment-related AEs occurred in 68% of patients at any grade; 37% of these cases were grade 3 in severity. The most common effects included diarrhea/colitis (any grade, 37%; grade 3, 16%), hepatitis (21%; 16%), skin adverse reactions (21%; 5%), constitutional (16%; 0%), adrenal insufficiency (11%; 5%), hypothyroidism (11%; 0%), myocarditis/pericarditis (5%; 5%), myositis/rhabdomyolysis (5%; 5%), pituitary dysfunction (5%; 5%), and thyroiditis (5%; 5%).

Limitations and Looking Ahead

“This cohort is limited by the small sample size and the high percentage of patients with ALBI 2 liver disease who have a poorer prognosis,” the study authors concluded. “These results support further investigation of botensilimab/balstilimab in HCC in future randomized studies.”

Disclosures: Dr El-Khouiery disclosed receiving honoraria or serving in a consulting or advisory role for Agenus Inc., AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Gilead Sciences, Merck, QED Therapeutics, Qurient, Roche/Genentech, Senti Biosciences, Servier Laboratories, and Tallac Therapeutics. Research funding was received from Astex Pharmaceuticals, AstraZeneca, and Fulgent Genetics.

References

1. El-Khoueiry AB, Abou-Alfa GK, Wilky BA, et al. Results from a phase 1 study of botensilimab and balstilimab in treatment refractory hepatocellular carcinoma. Presented at: 2025 AACR Annual Meeting; April 25-30, 2024; Chicago, IL. Abstract LB365.
2. Fc-engineered anti-CTLA4 monoclonal antibody in advanced cancer. ClinicalTrials.gov. Updated February 6, 2025. Accessed May 5, 2025. https://clinicaltrials.gov/study/NCT03860272