HCC Therapies Rapidly Advance After a Decade of Disappointment

Marijke Vroomen Durning, RN
Published: Sunday, Sep 03, 2017
Dr Bruno Sangro
Bruno Sangro, MD, PhD
After a decade of little movement in the treatment of advanced hepatocellular carcinoma (HCC), there are promising developments on the horizon, according to recent study findings. These advancements include 1 new drug that was approved earlier this year, 2 agents pending FDA decisions, and later-stage clinical trials for multiple therapies.

The potential for new therapies comes at a time of continuing challenges in the treatment of patients with HCC. It is the second most common cause of cancer deaths across the globe, and the incidence of the disease continues to rise in the United States.1 In 2000, there were 4.4 cases of HCC per 100,000 individuals; this number rose to 6.7 cases per 100,000 in 2012.2 Although treatment for early HCC is often successful, advanced cases usually have a poor prognosis.

“The first systemic therapy with a survival benefit for HCC was introduced literally a decade ago,” said Amit G. Singal, MD, MS, associate professor of medicine, medical director of the Liver Tumor Program, and clinical chief of the Hepatology Division of Digestive and Liver Diseases at University of Texas Southwestern Medical Center in Dallas, in an interview with OncologyLive®. In 2007, the FDA approved sorafenib (Nexavar), a multikinase inhibitor that targets angiogenesis, for the treatment of patients with unresectable HCC.3

The drug had previously been approved for patients with renal cell carcinoma and has gained an indication for differentiated thyroid cancer. In HCC, sorafenib provides a median survival and time to radiologic progression that was approximately 3 months longer compared with placebo.4 Unfortunately, this was the last new treatment to be moderately successful for the next 10 years.

“There were many other promising studies, but they all turned out to be negative,” said Tim F. Greten, MD, senior investigator in the Thoracic and Gastrointestinal Oncology Branch and head of the Gastrointestinal Malignancy Section at the National Cancer Institute.

Now, oncologists who treat patients with advanced HCC may have 3 new therapies to administer by the end of this year. In April, the FDA approved regorafenib (Stivarga), a small-molecule multikinase inhibitor, as a second-line treatment for patients with HCC who have previously received sorafenib. The agency is scheduled to decide by September 24 whether to approve a supplemental biologics license application for nivolumab (Opdivo), a PD-1 inhibitor, as second-line therapy for HCC. Additionally, an application is pending for lenvatinib (Lenvima) as a first-line therapy.


Table. Selected Phase III Trials in Hepatocellular Carcinoma

Selected Phase III Trials in Hepatocellular Carcinoma
Given the disappointments from earlier trials, most clinicians remain somewhat guarded when considering current phase II studies that appear to have positive results. But there is room for a positive outlook when it comes to several emerging immunotherapy and targeted therapy agents, experts say, and clinical development has rapidly advanced into phase III trials (Table).

New Hope With Regorafenib

The paradigm in HCC treatment started changing last year when the results of the phase III RESORCE trial demonstrated a survival benefit with regorafenib. The drug, which previously was approved for colorectal cancer and gastrointestinal stromal tumors, targets several kinases that promote tumor angiogenesis, such as vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs), along with other kinases. Similarly, sorafenib also targets VEGFRs and PDGFR-beta.

The international, multicenter, randomized, double-blind, placebo-controlled RESORCE study investigated the use of regorafenib among 573 adult patients with advanced HCC who had progressed following treatment on sorafenib.5,6 The study participants were randomized to receive oral regorafenib at 160 mg once daily during weeks 1 to 3 of each 4-week cycle plus best supportive care (BSC) or placebo plus BSC. The primary endpoint was overall survival (OS), with treatment continuing until disease progression or unacceptable toxicity.

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