Selection of Immunotherapy Doublet Regimens for Patients With Unresectable HCC

Immunotherapy-based doublet regimens have become essential first-line treatment for people with unresectable hepatocellular carcinoma (HCC) who are candidates for such therapy. Yarchoan stresses that providers must offer these regimens rather than continuing to prescribe tyrosine kinase inhibitors alone, which have inferior survival outcomes and more adverse effects. The challenge lies in selecting among 3 approved options—atezolizumab-bevacizumab, durvalumab-tremelimumab, and nivolumab-ipilimumab—without head-to-head trial data to guide decisions.

Each regimen has distinct strengths. Atezolizumab-bevacizumab offers excellent disease control rates by combining 2 therapeutic modalities: anti-VEGF therapy and checkpoint inhibition. The dual checkpoint inhibitor regimens (durvalumab-tremelimumab and nivolumab-ipilimumab) demonstrate a tail on the curve—durable complete responses suggesting potential cures for some patients, likely attributable to anti-CTLA4 therapy. Nivolumab-ipilimumab shows the most encouraging top-line data with the longest median overall survival, highest response rate (36%), and longest median duration of response (over 30 months). However, this efficacy comes with nearly 30% grade 3 to 4 immune-related adverse events.

Clinical decision-making requires individualized assessment. Amit Mahipal, MD,agrees that mechanistically, adding anti-CTLA4 to checkpoint inhibitors should enhance long-term survival compared with combining with VEGF inhibition alone. Trial populations typically included fitter patients than those seen in routine practice, making real-world toxicity management crucial. All 3 regimens have important roles, and clinicians managing HCC should be familiar with each option to match the appropriate therapy to individual patient circumstances, tumor characteristics, and treatment goals.