Phase III Study of Stivarga (Regorafenib) For Progressed Hepatocellular Carcinoma Interview with:

Dr. Jordi Bruix, MD Professor of Medicine University of Barcelona Director of the Barcelona Clinic Liver Cancer (BCLC) Group Liver Unit Hospital Clinic of Barcelona

Dr. Bruix

Dr. Jordi Bruix, MD
Professor of Medicine
University of Barcelona
Director of the Barcelona Clinic Liver Cancer (BCLC) Group Liver Unit
Hospital Clinic of Barcelona What is the background for this study? What are the main findings?

Response: The RESORCE Phase III pivotal trial is an international, multicenter, placebo-controlled trial which investigated the efficacy of Stivarga (regorafenib) in adults with Child-Pugh A and Barcelona Clinic Liver Cancer Stage Category B or C hepatocellular carcinoma (HCC) who had documented disease progression following first-line treatment with Nexavar (sorafenib).

Trial participants were administered a daily oral 160mg dose (three weeks on/ one week off) of regorafenib plus best supportive care (BSC), or placebo plus BSC.

Results from the trial demonstrated that participants treated with regorafenib experienced a statistically significant and clinically meaningful improvement in the study’s primary endpoint—overall survival (OS). Participants treated with regorafenib demonstrated a median overall survival of 10.6 months vs. 7.8 months with placebo.

At ASCO 2017, an exploratory analysis evaluated the impact of baseline alpha-fetoprotein (AFP) and c-Met as predictors of poor prognosis in patients enrolled in the RESORCE trial (Abstract #4078). What should clinicians and patients take away from your report?

Response: Based on the pivotal RESORCE study, Stivarga was approved in second-line hepatocellular carcinoma in April 2017 as the first systemic treatment to demonstrate a survival benefit in HCC patients since the approval of Nexavar for unresectable HCC 10 years ago.  Hepatocellular carcinoma is difficult to treat, and Stivarga fills an unmet therapeutic need in the second-line setting for HCC patients whose disease has progressed after first-line treatment with Nexavar. The improvement in OS [HR 0.63, 95% CI 0.50-0.79; p<0.0001] translates to a 37 percent reduction in the risk of death over the study period.

The exploratory analysis presented at ASCO found that regorafenib treatment benefit for both OS and time to progression was independent of AFP and c-Met protein concentration in plasma in the RESORCE study. While increased levels of both AFP (HR 1.09, 95% CI 1.07, 1.12; P<0.001) and c-Met (HR 1.32, 95% CI 1.06, 1.63; P=0.011) were associated with a worse prognosis for OS, increased AFP levels were also associated with poor prognosis for time to progression (HR 1.05, 95% CI 1.03, 1.07; P<0.001). The baseline characteristics of patients were balanced across protein subgroups, with the treatment benefit of regorafenib in patients with HCC independent of AFP and c-MET baseline plasma concentration. The protein–treatment interaction effect was not statistically significant. So far, no single protein has been associated with regorafenib clinical benefit What recommendations do you have for future research as a result of this study?

Response: Regorafenib has already proven efficacy and safety in this patient population but we continue to explore the data to reach even more patients in need. Thus, we will continue to evaluate the efficacy and potential therapeutic application of the compound in liver cancer. Now that we have shown that patients with hepatocellular carcinoma have an effective second line option, the research has to focus in potential combinations to multiply the benefit. At the same time, it is needed to develop effective options for those patients who may not be fit for the current available options that are sorafenib and regorafenib in a sequential approach. Is there anything else you would like to add?

Response: Hepatocellular carcinoma is the most common form of liver cancer and is the third cause of death globally. It represents approximately 80% of liver cancers in Western countries. However, liver cancer remains one of the few cancers that is still on the rise, and for the last 10 years, no Phase III trials have yielded positive data for patients in HCC in the first-line or second-line setting following sorafenib—until RESORCE. This Phase III pivotal trial marks an important milestone in the advancement of treatment options for HCC patients in the U.S. and around the world and should prime further research efforts. As shown with sorafenib and regorafenib, continued research and efforts ultimately translate in a clinical benefit for the patients and this should be the driving force in clinical investigation.

I advise and provide counsel to a number of pharmaceutical companies including: Abbvie; ArQule; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; BTG; Gilead Sciences; Kowa; Novartis; Onxeo; OSI Pharmaceuticals; Roche; Sirtex; TERUMO.

Bayer funded the RESORCE Phase III pivotal trial. Thank you for your contribution to the community.

Citation: Abstract presented at 2017 ASCO meeting June 2017

Efficacy of regorafenib (REG) in patients with hepatocellular carcinoma (HCC) in the phase III RESORCE trial according to alpha-fetoprotein (AFP) and c-Met levels as predictors of poor prognosis.

J Clin Oncol 35, 2017 (suppl; abstr 4078)

Author(s): Michael Teufel, Karl Köchert, Gerold Meinhardt, Jordi Bruix; Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ; Bayer AG, Berlin, Germany; BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.