Trial Data May Change Standard Second-Line Treatment of Liver Cancer

Stivarga (regorafenib), an oral multikinase inhibitor, has the potential to become the standard of care as second-line treatment in patients with previously treated hepatocellular carcinoma (HCC) who are unsuitable for loco-regional therapy and have progressed on Nexavar (sorafenib).

Safety, efficacy and health-related quality of life findings from the phase 3 RESORCE trial of Stivarga were presented at the European Society for Medical Oncology (ESMO) 2016 Cancer Conference in Copenhagen.

Stivarga improved overall survival (OS), the trial’s primary endpoint, by nearly three months over placebo and demonstrated improved progression-free survival (PFS) and time to progression (TTP), according to Jordi Bruix, M.D., of the Liver Unit Hospital Clinic, University of Barcelona, Spain.

“Regorafenib has the potential to become the new standard or care for patients with hepatocellular carcinoma who progress on [Nexavar],” Bruix remarked.

Median OS was 10.6 months with Stivarga versus 7.8 months with placebo. Stivarga patients had a 37 percent reduction in the risk of death and a 54 percent reduction in the risk of progression compared with placebo.

Significantly prolonged median PFS of 3.1 months was observed in patients treated with Stivarga compared with 1.5 months in patients receiving placebo. Similarly, median TTP was 3.2 and 1.5 months, respectively.

"We had a higher response rate and we doubled the disease control rate in late stage hepatocellular carcinoma, a difficult cancer to treat," Bruix commented.

Patients receiving Stivarga demonstrated a higher disease control rate of 65.2 percent compared with 36.1 percent with placebo, and 10.6 percent of patients receiving Stivarga showed either complete or partial response versus 4.1 percent of placebo patients.

Bruix and colleagues enrolled 573 patients from centers in 21 countries who were stratified by geographic location of Asia or non-Asia, the presence/absence of microvascular invasion or extrahepatic disease, Eastern Cooperative Oncology Group performance of 0 versus 1, and alpha-fetoprotein less than 400 ng/mL versus 400 ng/mL or greater. All patients had Barcelona Clinic Liver Cancer (BCLC) stage B or C designated HCC plus documented radiologic progression after a minimum of 20 days of Nexavar at 400 mg or more per day.

Baseline characteristics were balanced between the Stivarga and placebo arms. The patients’ median age was 63 years, 88 percent were male and 87 percent of patients had BCLC stage C disease.

The patients were randomized in a 2-1 ratio to oral Stivarga at 160 mg or placebo once daily for one to three weeks of a four-week cycle. The median treatment duration was 3.6 months for Stivarga versus 1.9 months for placebo.

Treatment emergent adverse events (TEAEs) leading to treatment interruption occurred in 58 percent of patients in the Stivarga arm versus 29 percent of patients on placebo. Drug related TEAEs leading to treatment interruption occurred in 42 percent versus 8 percent of patients in the respective arms.

The most commonly reported grade 3 or higher adverse events were hypertension (15.2 percent versus 4.7 percent), hand/foot skin reactions (12.8 percent versus 0.5 percent), fatigue (9.1 percent versus 4.7 percent) and diarrhea (3.2 percent versus 0.0 percent) with Stivarga versus placebo, respectively

Bruix also reported on quality of life data that was collected using the EQ-50 index, EQ-50 VAS, Fact-G, FACT-Hep total and Trial Outcome scales. Significant differences among patients receiving Stivarga and placebo were seen only on the last two scales; the difference between the groups was -8.85 on the FACT-Hep total, and -4.05 on the Trial Outcome Index.

Session co-chair Florian Lordick, M.D., Ph.D., of the University Cancer Center in Leipzig, Germany, discussed whether Stivarga would become the new standard of care and summarized: “Maybe, yes, because regorafenib significantly improved overall survival over placebo, but there are no clinically meaningful differences in patient-reported outcomes and there was a high rate of treatment interruption due to adverse events, suggesting that regorafenib was not well-tolerated.”

Bruix responded to this comment by pointing out that Stivarga actually was well tolerated in this cohort: “Nearly 50 percent of patients received the full dose and the tolerance was similar to the tolerance reported in patients with GIST [gastrointestinal stromal tumor].”

Stivarga received FDA approval in 2013 for treatment of patients with advanced GIST who are not candidates for surgery and do not respond to imatinib and Sutent (sunitinib).