Strategic drug sequencing in hepatocellular carcinoma in the era of chemo-diversity: maximizing the therapeutic benefit of lenvatinib

The emergence of systemic therapies has ushered in an era of chemo-diversity for hepatocellular carcinoma, in which drug sequencing is pivotal for maximizing outcomes. Among available agents, lenvatinib is notable for its potent anti-angiogenic and immunomodulatory properties. This review proposes a structured building-block strategy for optimizing sequential drug therapy, conceptualizing each treatment line as a block that contributes cumulatively to survival, and grounding the discussion in clinical insights from lenvatinib administration. We comprehensively evaluated clinical trials, preclinical investigations, and real-world data to identify actionable approaches that enhance tolerability and prolong progression-free survival, with a particular focus on mitigating adverse events, optimizing dosing schedules, and integrating with transarterial therapies. Five refinements emerge as central to maximizing therapeutic benefit: early detection and classification of adverse events; use of supportive agents such as L-carnitine, and branched-chain amino acids; structured telephone follow-up; optimization of dosing schedules, including weekend-off regimens; and strategic combination with transarterial therapy. In addition, rationale-based sequencing and clinically relevant switching criteria that extend beyond RECIST are summarized. Collectively, these measures increase the height of each therapeutic block, thereby contributing to cumulative survival within the building-block strategy. In the current era of chemo-diversity, lenvatinib remains a cornerstone agent when accompanied by these clinical refinements. The review provides a practical and conceptual framework for enhancing efficacy through structured sequencing, proactive adverse-event mitigation, and synergistic locoregional strategies, with broad applicability to real-world clinical practice.