Beyond second-line therapy: Strategic sequencing of systemic treatments in advanced hepatocellular carcinoma

Systemic therapy for advanced hepatocellular carcinoma (HCC) has evolved from a linear, stepwise algorithm into a multidimensional and truly polyhedral process shaped by treatment response, liver function, and access to therapy. This review integrates evidence from phase II and III trials and real-world studies, including more than 4,000 patients across different and diverse global regions, to outline how sequencing beyond first-line immunotherapy is redefining clinical practice. After immune-based combinations, tyrosine kinase inhibitors (TKIs) remain active and feasible options, achieving a median overall survival of approximately 10–11 months, while preservation of liver function consistently determines treatment eligibility and post-progression survival. Incorporation of the Barcelona Clinic Liver Cancer (BCLC) concept “upon response” (BCLC-UR) refines classification for patients achieving major responses or conversion and aligns staging with contemporary treatment dynamics. The CUSE framework—encompassing Complexity, Uncertainty, Subjectivity, and Emotion—reframes sequencing as an adaptive, patient-centered, and multifaceted process that integrates toxicity, feasibility, and patient values alongside efficacy. By structuring diverse clinical inputs into a unified interpretive model, CUSE supports multidisciplinary reasoning and enhances conceptual coherence in treatment sequencing. Conversion therapy and “drug-off” strategies following complete or major responses represent emerging frontiers, emphasizing that sequencing in HCC now extends beyond second-line therapy. Additionally, preserving hepatic function and applying polyhedral, data-informed decision frameworks are key to sustaining eligibility and optimizing outcomes across the continuum of care.