Promising Results for Triplet Blockade Therapy in Unresectable Hepatocellular Carcinoma

A novel phase II study investigating the triplet blockade of IL-27, PD-(L)1, and VEGF pathways in unresectable, locally advanced, or metastatic hepatocellular carcinoma (uHCC) demonstrated encouraging antitumor activity and a manageable safety profile. Presented at the 2025 ASCO Gastrointestinal Cancers Symposium by Daneng Li, MD, of the City of Hope National Comprehensive Cancer Center, the study highlights the potential of the first-in-class IL-27–targeting antibody, casdozokitug (casdozo), combined with atezolizumab (atezo) and bevacizumab (bev), as a promising treatment strategy.

Study Design and Methods

This open-label phase II trial enrolled 30 patients with previously untreated uHCC who received intravenous casdozo (10 mg/kg), atezo (1200 mg), and bev (15 mg/kg) every three weeks. The primary endpoints were safety and tolerability, with secondary endpoints including objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and duration of response (DOR). The study population was predominantly male (77%), Asian (67%), and included patients with viral etiology (53% with hepatitis B virus, 17% with hepatitis C virus), metastatic spread (67%), and macrovascular invasion (13%).

Key Results

With a median follow-up of 15 months, triplet therapy demonstrated notable efficacy in patients with unresectable hepatocellular carcinoma. The ORR was 38% based on Response Evaluation Criteria In Solid Tumors (RECIST1.1) and 43% based on modified RECIST (mRECIST), with 17% of patients achieving a complete response. The median PFS was 8.1 months according to RECIST1.1 and 8.4 months according to mRECIST. In addition, median OS reached 19.9 months, and the 12-month survival rate was an impressive 85%. The DOR was not reached according to both RECIST1.1 and mRECIST evaluations, indicating that responses were both meaningful and durable. These results underscore the potential of the therapy to provide significant clinical benefit in this patient population.

Safety Profile

The combination therapy was associated with adverse events consistent with known profiles of the individual agents. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 67% of patients, with hypertension (20%) being the only TRAE reported in more than 10% of participants. Treatment-emergent adverse events led to study drug discontinuation in 30% of patients, but no treatment-related deaths were reported.

Biomarker Insights

Archival tissue from responders revealed IL-27+ tumor-associated macrophages (TAMs) in both viral and nonviral HCC cases, suggesting a potential biomarker for therapeutic response. Further biomarker analyses are underway to correlate immune responses and IL-27 pathway activity with clinical outcomes.

Implications and Future Directions

The study reinforces the potential of triplet blockade with casdozo, atezo, and bev as an innovative approach for managing uHCC, especially given its manageable safety profile and promising efficacy in a challenging patient population. The findings support continued investigation into IL-27–targeting therapies, with plans for additional clinical studies combining casdozo with toripalimab.