Insights into the success and failure of systemic therapy for hepatocellular carcinoma

Abstract

Systemic treatment for hepatocellular carcinoma (HCC) has been boosted by the incorporation of new agents after many negative phase III trials in the decade since the approval of sorafenib. Sorafenib introduced the concept that targeting specific hallmarks of hepatocarcinogenesis could modify the dismal prognosis of this disease, with the drug remaining a cornerstone in the upfront therapy for advanced HCC. The design of clinical trials in this malignancy is complicated by important obstacles related to patient selection, prognostic assessment and the need for endpoints that correlate with improvement in survival outcomes. In addition, the currently used criteria to determine treatment response or progression might prevent physicians from making appropriate clinical judgements and interpreting evidence arising from trials. In this Review, we discuss the advances in systemic therapy for HCC and critically review trial designs in HCC. Although novel therapies, such as new targeted agents and immunotherapies, are being rapidly incorporated, it is paramount to design future clinical trials based on the lessons learned from past failures and successes. The design of clinical trials for hepatocellular carcinoma is complicated by a number of obstacles. In this Review, the authors discuss the advances in systemic therapy for hepatocellular carcinoma and critically discuss trial designs in the context of past successes and failures. The changing landscape of hepatocellular carcinoma treatment demands a critical interpretation of how therapies have evolved and what future challenges lie ahead. Improving overall survival is the main objective in advanced hepatocellular carcinoma, and the use of surrogate endpoints, such as response rate, time to progression or progression-free survival, lacks scientific evidence. Criteria for response to treatment should evolve so that validated signals of activity prime transition into phase III trials. Trial design and analysis should include novel clinical characteristics such as pattern of progression and pattern of adverse events with prior therapy. Phase III trials in ill-defined target populations with limited clinical characterization might provide unreliable (positive or negative) results. Molecular stratification is hampered by tumour heterogeneity and lacks prognostic power and linkage to treatment. The changing landscape of hepatocellular carcinoma treatment demands a critical interpretation of how therapies have evolved and what future challenges lie ahead. Improving overall survival is the main objective in advanced hepatocellular carcinoma, and the use of surrogate endpoints, such as response rate, time to progression or progression-free survival, lacks scientific evidence. Criteria for response to treatment should evolve so that validated signals of activity prime transition into phase III trials. Trial design and analysis should include novel clinical characteristics such as pattern of progression and pattern of adverse events with prior therapy. Phase III trials in ill-defined target populations with limited clinical characterization might provide unreliable (positive or negative) results. Molecular stratification is hampered by tumour heterogeneity and lacks prognostic power and linkage to treatment.