Regorafenib in Second-Line Setting for Hepatocellular Carcinoma: Balancing Benefit With Toxicity

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We now have a new drug in the armamentarium for the management of advanced hepatocellular carcinoma, which was a clear unmet need.
— Josep M. Llovet, MD, PhD

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During the past 40 years, hundreds of randomized trials testing treatments for advanced hepatocellular carcinoma have been published.1 Conventional systemic chemotherapy and radiotherapy lack survival advantages for these patients.1,2

In 2007, a phase III trial demonstrated survival benefits for sorafenib (Nexavar), thus representing a breakthrough in the management of the disease and the first effective systemic therapy for patients at advanced stages.3 Sorafenib became the standard of care as a result of showing a substantial increased survival from 7.9 months to 10.7 months compared with placebo (hazard ratio [HR] = 0.69; 31% reduction in the risk of death).

Several phase III trials have been conducted to challenge sorafenib in the front-line (testing sunitinib [Sutent], brivanib, erlotinib [Tarceva], linifanib, or doxorubicin) or second-line setting vs placebo in patients progressing on sorafenib (brivanib, everolimus [Afinitor], ramucirumab [Cyramza]). All these trials have been negative, with the major reasons related to lack of powerful antitumoral activity or in some instances toxicity. In addition, no study was designed with biomarker-based trial enrichment.

Substantial Clinical Benefit

Almost 10 years later, a second drug, regorafenib (Stivarga), has been shown to benefit patients progressing to sorafenib and is awaiting regulatory approval.4 In the phase III RESORCE trial reviewed in this issue of The ASCO Post, regorafenib (a more potent multikinase inhibitor than sorafenib that targets similar kinases) was compared vs placebo in patients progressing on sorafenib and was associated with a benefit in survival from 7.8 to 10.6 months (HR = 0.62; 38% reduction in the risk of death).4

These results represent a substantial clinical benefit, and the treatment will be adopted by clinical practice guidelines as the standard of care for patients at second-line treatment. Treatment improved survival in all patient subgroups. Around 30% of patients presented with macrovascular invasion; 70%, with extrahepatic spread; and 45%, with alpha-fetoprotein level > 400 ng/mL. The response rate was 10% based upon modified Response Evaluation Criteria in Solid Tumors. Treatment was started at 160 mg/d (3 weeks on/1 week off). Median time on treatment was 3.5 months. Prevalence of toxicity (hand-foot reaction, fatigue, and hypertension) was higher compared with the reported toxicity with sorafenib, but adverse events led to treatment discontinuation in only 10% of cases.

Diverse Study Consequences

The consequences of this study are diverse. First, we now have a new drug in the armamentarium for the management of advanced hepatocellular carcinoma, which was a clear unmet need. Second, the drug is unquestionably effective, and thus it will be approved by regulatory agencies and accepted in clinical practice guidelines of management of hepatocellular carcinoma. Third, toxicity was higher than sorafenib but manageable. Toxicities can be an important drawback in the administration of regorafenib in patients with colorectal cancer. However, in the RESORCE trial, patients were already selected on the basis of sorafenib tolerance, and thus drug-related adverse events leading to treatment discontinuation were marginal. Fourth, survival on the placebo arm was 7.8 months, similar to the outcome of patients on front-line treatment. This reflects an enrichment effect of patients with a good performance status.

Finally, the approval of regorafenib as the standard of care for second-line patients opens the field for third-line therapies. In this sense, there are questions about what would be the role of drugs currently tested in the second-line setting, such as tivantinib, cabozantinib (Cabometyx), ramucirumab (Cyramza), and pembrolizumab (Keytruda). In the event of positive findings, certainly the results will apply to patients intolerant to sorafenib/regorafenib. Otherwise, the magnitude of benefit—compared with the hazard ratio of 0.63—and the landscape of adverse events will dictate their future role in the decision-making scheme for advanced hepatocellular carcinoma.

Dr. Llovet is a coauthor of the RESORCE trial. ■

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. 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.

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

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

4. Bruix J, Qin S, Merle P, et al: Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389:56-66, 2017.

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