Pursuing Combination Strategies With Checkpoint and Tyrosine Kinase Inhibitors in Hepatocellular Carcinoma

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“The results of the phase III trial might represent a new breakthrough in the management of the disease [advanced hepatocellular carcinoma]….”
— Josep M. Llovet, MD, PhD

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PRIMARY LIVER CANCER is the second leading cause of cancer-related death worldwide. Hepatocellular carcinoma accounts for 90% of liver cancer, with around 800,000 new cases diagnosed globally each year.1 In contrast to the stable or declining trends observed for most neoplasms, the incidence and death rates for primary liver cancer have been rising worldwide. 

During the past several years, there has been a clear delineation of the landscape of genetic alterations in hepatocellular carcinoma, with the most common mutations being nonactionable (TERT promoter in 60%, TP53 and CTNNB1 in 25% to 30%, and others at a frequency of less that 10%—eg, AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2). Translation of these discoveries into therapeutic strategies is an unmet medical need in this field.1-3 

According to clinical practice guidelines, seven treatments are accepted for management of hepatocellular carcinoma: resection; liver transplantation; local ablation; chemoembolization; and the molecular targeted therapies sorafenib (Nexavar), regorafenib (Stivarga), and lenvatinib (Lenvima).4 Most patients are still diagnosed at an intermediate or advanced disease stage (> 50% of cases), where curative approaches are often not feasible. 

Introducing Molecular Concepts Into Clinical Decision-Making 

Dr. Llovet is Professor of Medicine and Director of the Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Ichan School of Medicine at Mount Sinai, New York; and Professor of Research-ICREA, Liver Cancer Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Universitat de Barcelona, Institució Catalana de Recerca i Estudis Avançats, Barcelona.

AFTER THE APPROVAL of sorafenib, more than 15 randomized studies have been conducted in the adjuvant setting, in combination with chemoembolization in intermediate-stage cases or as first- or second-line options in advanced cases. Only two studies—one of lenvatinib vs sorafenib (noninferiority design) and one of regorafenib vs placebo in patients progressing on sorafenib—have had positive outcomes, the latter showing an increase in overall survival of around 3 months. All other studies have been negative. 

Potential reasons for these failures include drugs’ not being potent enough or being toxic in cirrhotic individuals and the lack of translating current knowledge on molecular pathogenesis into predictive biomarkers of response. Thus, to overcome this situation, proof-of-concept phase I/II studies (ie, targeting FGF19 overexpression) and trial enrichment studies (ie, ramucirumab [Cyramza] in patients with alpha-fetoprotein > 400 ng/mL) based on biomarkers are ongoing. It is expected that positive results will introduce molecular concepts into the clinical decision-making for hepatocellular carcinoma. 

CheckMate 040: Key Findings 

IN THIS CONTEXT, the exciting phase II trial CheckMate 040 trial of nivolumab (Opdivo) in hepatocellular carcinoma, reviewed in this issue of The ASCO Post, has been published in The Lancet by El-Khoueiry and colleagues.5 In brief, the results in 262 patients with advanced hepatocellular carcinoma treated in either the front-line (30%) or second-line setting (70%) demonstrated clear antitumor efficacy, with an objective response rate of 20%, a median duration of response of 9.9 month, and an overall survival around 16 months. In addition, the study showed that immunostaining for programmed cell death ligand 1 (PD-L1), which is positive in 20% of patients, is not predictive of response to nivolumab. The study establishes a new mark in terms of overall survival outcome, considering that most of the patients were treated in the second-line setting. The U.S. Food and Drug Administration (FDA) Accelerated Approval is being pursued for this latter indication. 

Overall, the results are certainly impressive, compete well in the second-line setting with the FDA-approved drug regorafenib, and pose a positive message for the final outcome of the nivolumab vs sorafenib phase III trial in front-line treatment, which has recently completed recruitment. The results of the phase III trial might represent a new breakthrough in the management of the disease and will pave the path to pursue combination strategies with checkpoint inhibitors and tyrosine kinase inhibitors—for instance, with regorafenib or lenvatinib—in hepatocellular carcinoma. These combinations might increase the survival expectations in a way that might even compete with locoregional therapies in patients with intermediate stages of disease. ■

DISCLOSURE: Dr. Llovet is a consultant for Bayer Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, Blueprint, and Celsion and has received research funding from Bayer Pharmaceuticals, Bristol-Myers Squibb, Blueprint, and Boehringer-Ingelheim. 


1. Llovet JM, Zucman-Rossi J, Pikarsky E, et al: Hepatocellular carcinoma. Nat Rev Dis Primers 2:16018, 2016. 

2. Llovet JM, Villanueva A, Lachenmayer A, et al: Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol 12:436, 2015. 

3. Llovet JM, Ricci S, Mazzaferro V, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378-390, 2008. 

4. European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer: EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 56:908-943, 2012. 

5. El-Khoueiry AB, Sangro B, Yau T, et al: Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389:2492-2502, 2017.

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NIVOLUMAB (OPDIVO) has been found to produce durable responses in patients with advanced hepatocellular...