Regorafenib Seeking FDA Approval in HCC Following Findings of OS Boost

Jordi Bruix, MD, BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, Spain

Jordi Bruix, MD

Regorafenib (Stivarga) as a second-line therapy for patients with unresectable hepatocellular carcinoma (HCC) who have progressed on sorafenib (Nexavar), showed an improved overall survival (OS) rate of 2.8 months over placebo, according to findings of the phase III RESORCE trial presented at the 2016 World Congress on Gastrointestinal Cancer

In the study, the median OS was 10.6 months with regorafenib compared with 7.8 months for placebo plus best supportive care, representing a 38% reduction in the risk of death with the multikinase inhibitor (HR, 0.62; 95% CI, 0.50-0.78;P<.001). Findings from the phase III study will be submitted to the FDA and European Medicines Agency (EMA) for potential approval, according to a statement from the developer of regorafenib, Bayer Pharmaceuticals.

"The improvement in overall survival seen with regorafenib in the RESORCE study signals the addition of a potential option in this treatment setting," said lead investigator Jordi Bruix, MD, BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, Spain. "The global incidence of liver cancer continues to increase and has more than tripled in the United States over the last three decades, and currently there are no proven or approved systemic second-line treatment options for patients with advanced HCC."

The phase III RESORCE study randomized 573 patients with HCC in a 2:1 ratio to receive best supportive care plus either regorafenib (n = 379) or placebo (n = 194). Regorafenib was administered at 160 mg once daily for 3 weeks followed by 1 week without treatment.

The median age of patients was 63 years, with the majority being male (88%). Most patients had tumors that were BCLC stage C (87%). Prior sorafenib was administered for &ge;20 days at &ge;400 mg/day with documented radiologic progression. The primary endpoint of the study was OS, with secondary outcome measures focused on progression-free survival (PFS), objective response rate (ORR), and safety.

Median PFS was 3.1 months in the regorafenib arm compared with 1.5 months in the placebo group, representing a 54% reduction in the risk of progression or death (HR, 0.46; 95% CI, 0.37-0.56; P <.001). The median time to progression in the regorafenib group was 3.2 versus 1.5 months with placebo (HR, 0.44; 95% CI, 0.036-0.55;P<.001).

The ORR with regorafenib was 10.6% versus 4.1% with placebo (P= .005). When considering stable disease, the overall disease control rate was 65.2% with the multikinase inhibitor versus 36.1% with placebo.

Median duration of treatment was 3.6 months with regorafenib (range, 0.03-29.4) versus 1.9 months with placebo (range, 0.2-27.4). Grade &ge;3 adverse events (AEs) were experienced by 79.7% of those treated with regorafenib versus 58.5% of patients in the placebo arm. Dose modifications to alleviate AEs were required for 68.2% of patients in the experimental arm compared with 31.1% of patients treated with placebo.

&ldquo;Systemic treatment for hepatocellular carcinoma has long consisted of just one agent, sorafenib, which was shown to provide a significant improvement in life expectancy almost 10 years ago, but no other agent has surpassed its benefits,&rdquo; said Bruix. &ldquo;This is a very difficult to treat cancer but now we have an effective second-line agent, which is good news for the patients and also for the field as interest in further developments will be stimulated.&rdquo;

The most common grade &ge;3 AEs with regorafenib versus placebo, respectively, were hypertension (15.2% vs 4.7%), hand-foot skin reaction (12.6% vs 0.5%), fatigue (9.1% vs 4.7%), and diarrhea (3.2% vs 0%). There were more deaths in the placebo arm versus regorafenib within 30 days following the last dose of treatment (13.4% with regorafenib vs 19.7% for placebo).

&ldquo;The regorafenib data seen in RESORCE may translate into additional hope for patients by providing doctors, nurses, and other healthcare providers with a much needed second proven option for the treatment of liver cancer," Bruix said. "The appropriate and timely start of systemic therapy may be important in improving patients&rsquo; treatment outcomes by potentially providing patients with the opportunity of receiving both proven systemic treatment options.&rdquo;

Regorafenib is an oral kinase inhibitor that blocks VEGFR 1-3, TIE-2, RAF-1, BRAF, BRAFV600, KIT, RET, PDGFR, and FGFR. The agent is currently FDA approved for the treatment of patients with metastatic colorectal cancer and advanced gastrointestinal stromal tumors. Studies continue to assess the agent across various settings.

Reference:

Bruix J, Merle P, Granito A, et al. Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: results of the international, randomized phase 3 RESORCE trial. Presented at: 2016 World Congress on GI Cancer; June 28 - July 2, 2016; Barcelona, Spain. Abstract LBA03.