Regorafenib 'New Gold Standard' for Second-Line in Liver Cancer

Liam Davenport

July 01, 2016

BARCELONA — The oral multikinase inhibitor regorafinib (Stivarga, Bayer) has shown a significant survival benefit in patients with previously treated hepatocellular carcinoma (HCC), leading experts here to suggest that the drug should become the gold standard second-line therapy after sorafenib (Nexavar, Bayer/Onyx).

Liver cancer could be the next indication for regorafenib, which is already approved for use in colorectal cancer and gastrointestinal stromal tumors.

The new results, from the phase 3 RESORCE trial, were presented here at the 18th World Congress on Gastrointestinal Cancer (WCGC).

Regorafenib improved overall survival by almost 3 months over placebo and offered notable gains in progression-free survival and time to progression (TTP). These were accompanied by a safety and tolerability profile in line with expectations.

Regorafenib, which blocks the activity of protein kinases involved in angiogenesis, oncogenesis, and the tumor microenvironment, is the first drug since the publication of phase 3 data for sorafenib in 2008 to show any significant improvement in overall survival in patients with HCC unsuitable for loco-regional therapy.

The current findings were presented by Jordi Bruix, MD, head of the BCLC Group in the Liver Unit Hospital Clinic, University of Barcelona, and scientific director of the Network for Biomedical Research for Hepatic and Digestive Diseases, Spain.

He told delegates that "it's not difficult to make a conclusion" from the data, namely that regorafenib is "effective and also safe" and offers "a real, relevant and intensive effect on the risk of death."

He continued: "We also had a higher response rate and we doubled the disease control rate…the tolerance was adequate and the adverse events were manageable and consistent with the known regorafenib safety profile."

Discussing the study after the presentation, Jean-Luc Raoul, MD, PhD, from Institut Paoli-Calmettes in Marseille, France, commented that the findings indicate that "regorafenib is now the gold standard in second-line post-sorafenib therapy in patients who tolerate sorafenib."

He added that the drug offers "a real, meaningful benefit in overall survival, in TTP and in the objective response rate" and that "we did not have any major safety issue." This, he pointed out, "means that we certainly have to redesign our planned second-line trials."

However, Dr Raoul also said that a comparison between regorafenib and immunotherapy is now "mandatory" because one drug "fits all," giving a survival gain of several months, while the other (immunotherapy) "fits some, in some cases with major gains." There will also be "a quest for predictive factors" for regorafenib response, he said.

But Dr Raoul also pointed out that randomization for regorafenib occurred up to 10 weeks after completion of sorafenib therapy, which may have affected the findings because of progression in the interim.

He ended by comparing the current findings with regorafenib with those at the same stage for sorafenib. He quoted directly from the abstract of the 2008 New England Journal of Medicine paper on the phase 3 sorafenib results: "In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo."

Study Details

The phase 3 trial was conducted in 573 patients with HCC from 21 countries with documented radiologic progression after at least 20 days of sorafenib at 400 mg or more per day. They were randomly assigned to receive oral regorafenib, 160 mg, or placebo once daily for 1 to 3 weeks of a 4-week cycle in a 2:1 ratio.

The patients, who had HCC Barcelona Clinic Liver Cancer (BCLC) stage B or C, were stratified by geographic region (Asia vs the rest of the world), the presence or absence of microvascular invasion and extrahepatic disease, Eastern Cooperative Oncology Group performance of 0 vs 1, and α-fetoprotein less than 400 ng/mL vs 400 ng/mL or greater.

Baseline characteristics between the treatment and placebo groups were well balanced. The overall median age was 63 years, 88% of patients were male, and 87% had BCLC stage C disease.

The median treatment duration was 3.6 months for regorafenib vs 1.9 months for placebo.

Median overall survival was 10.6 months in the regorafenib group compared with 7.8 months in those receiving placebo, representing a significant reduction in the risk for death, at a hazard ratio of 0.62 (P < .001).

The researchers found that median progression-free survival was significantly longer in regorafenib recipients than in patients given placebo, at 3.1 months and 1.5 months, respectively (hazard ratio, 0.46; P < .001).

Similar results were found for TTP, at a median of 3.2 months in patients given regorafenib vs 1.5 months in the placebo group (hazard ratio, 0.44; P < .001). Crucially, subgroup analysis confirmed that all groups showed improvements in overall and progression-free survival, as well as TTP.

The disease control rate was significantly greater with regorafenib, at 65.2% vs 36.1% for placebo (P < .001), while the complete or partial response rate was 10.6% for regorafenib compared with 4.1% for placebo (P = .01).

Grade 3 or greater adverse events occurred in 79.7% of regorafenib recipients and 58.5% of patients given placebo. The most common grade 3 or greater adverse events were hypertension (15.2% vs 4.7%), hand–foot skin reactions (12.8% vs 0.5%), fatigue (9.1% vs 4.7%), and diarrhea (3.2% vs 0.0%). Dose modifications due to adverse events were made in 68.2% of regorafenib and 31.1% of placebo recipients.

Deaths within 30 days of the last dose of study drug were more common in the placebo group than the regorafenib group: 19.7% vs 13.4%.

Dr Bruix said in a release: "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."

Bayer, which manufactures regorafenib, plans to submit the study data as the basis for marketing authorization for the drug in the treatment of unresectable HCC in the United States and other worldwide markets in 2016.

The study was funded by Bayer. Dr Bruix reports having consulted for AbbVie, ArQule, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, BTG, Gilead, Kowa, Novartis, Onxeo, OSI, Roche, and Terumo. He reports having received research funding from Bayer.

18th World Congress on Gastrointestinal Cancer (WCGC). Abstract LBA-03. Presented 30 June 2016

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