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A Three-Dimensional Spheroid Model to Investigate the Tumor-Stromal Interaction in Hepatocellular Carcinoma
Published on: September 30, 2021
Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design
Josep M Llovet1, Virginia Hernandez-Gea
1Authors' Affiliations: HCC Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Universitat de Barcelona (UB); Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain; and Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Ichan School of Medicine at Mount Sinai, New York, New York.
Abstract:
Hepatocellular carcinoma (HCC) is a major health problem. Most patients with HCC experience a recurrence after resection/ablation or are diagnosed at advanced stages. Sorafenib remains the only approved systemic drug for these patients. Molecular therapies targeting signaling cascades involved in hepatocarcinogenesis have been explored in phase III clinical trials. However, none of the drugs tested have shown positive results in the first-line (brivanib, sunitinib, erlotinib, and linifanib) or second-line (brivanib, everolimus) setting after sorafenib progression. Reasons for failure are heterogeneous and include lack of understanding of critical drivers of tumor progression/dissemination, liver toxicity, flaws in trial design, or marginal antitumoral potency. These trials are also challenging time to progression as a surrogate endpoint of survival. Trials ongoing testing drugs head-to-head versus sorafenib in "all comers" might have difficulties in achieving superior results in the first line. Novel trials are also designed testing drugs in biomarker-based subpopulations of patients with HCC. Most common mutations, however, are undruggable, such as p53 and CTNNB1. Two types of studies are proposed: (i) phase II pivotal proof-of-concept studies testing drugs blocking potential oncogenic addiction loops, such as the one testing MEK inhibitors in RAS(+) patients or amplification of FGF19 as a target; and (ii) phase II to III studies using biomarker-based trial enrichment for defining HCC subpopulations, such as the case of enriching for MET-positive tumors. These strategies have been deemed successful in breast, melanoma, and lung cancers, and are expected to change the landscape of trial design of HCC.
Insights
Hepatocellular carcinoma (HCC) treatment faces challenges with limited drug options and trial failures. Future strategies focus on targeted therapies and biomarker-driven trials for better patient outcomes.
Area of Science:
- Hepatology and Oncology
- Molecular Targeted Therapy
- Clinical Trial Design
Background:
- Hepatocellular carcinoma (HCC) is a significant global health issue with high recurrence rates and advanced-stage diagnoses.
- Sorafenib is the sole approved systemic therapy, but its efficacy is limited, and subsequent treatments have failed in clinical trials.
- Previous molecular therapies targeting hepatocarcinogenesis signaling pathways have not yielded positive results in first- or second-line settings.
Purpose of the Study:
- To analyze the reasons for the failure of molecular therapies in HCC clinical trials.
- To propose novel strategies for HCC drug development and clinical trial design.
- To highlight the potential of biomarker-based approaches and targeted therapies in overcoming current limitations.
Main Methods:
- Review of phase III clinical trial outcomes for systemic therapies in HCC.
- Analysis of challenges in HCC trial design, including endpoint selection and patient heterogeneity.
- Exploration of emerging strategies, including targeting oncogenic addiction loops and biomarker-driven patient enrichment.
Main Results:
- Numerous molecular therapies have failed in first- and second-line HCC trials due to various factors including toxicity, trial design flaws, and insufficient antitumoral activity.
- Undruggable mutations like p53 and CTNNB1 present significant hurdles in conventional treatment approaches.
- Biomarker-based enrichment strategies, successful in other cancers, are proposed for HCC to define responsive subpopulations.
Conclusions:
- Current systemic treatment paradigms for HCC require significant innovation.
- Targeting specific oncogenic addiction loops and utilizing biomarker-based patient selection are crucial for future therapeutic success.
- The proposed strategies are expected to reshape the landscape of HCC clinical trial design and improve treatment efficacy.
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