FDA Approval Sought for Regorafenib in Advanced Liver Cancer

Jordi Bruix, MD

A supplemental new drug application (sNDA) has been submitted to the FDA for the use of regorafenib (Stivarga) as a second-line treatment for patients with unresectable hepatocellular carcinoma (HCC), according to Bayer, the manufacturer of the multikinase inhibitor.

The sNDA is based on the phase III RESORCE trial, in which the median overall survival (OS) was 10.6 months with regorafenib plus best supportive care compared with 7.8 months for placebo plus best supportive care, representing a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.50-0.78; P <.001).

“Regorafenib is the first treatment to demonstrate overall survival benefit in the second-line setting for unresectable HCC in clinical trials and, if approved, has the potential to change the treatment landscape for patients who progress on sorafenib,” Jordi Bruix, MD, BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Spain, the principal investigator on the RESORCE trial, said in a statement.

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 (Nexavar) was administered for ≥20 days at ≥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 ≥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.

The most common grade ≥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).

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.

“For nearly a decade and counting, Bayer has been committed to meeting the needs of those with liver cancer with our proven first-line systemic therapy in unresectable HCC patient’s therapy, Nexavar,” Dario Mirski, MD, senior vice president and head of Medical Affairs for the Americas at Bayer, said in a statement. “Clearly, more options are needed for these patients, especially in the second-line setting. The filing of Stivarga in HCC demonstrates our commitment to ongoing research in this difficult-to-treat cancer.”

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.