Topline results from the phase III RESORCE trial1
demonstrated that second-line treatment with regorafenib (Stivarga) represented a 38% reduction in the risk of death compared with best supportive care in patients with unresectable hepatocellular carcinoma (HCC). Additionally, findings show that the median overall survival (OS) with regorafenib was 10.6 months and 7.8 months for placebo versus best supportive care (HR, 0.62; 95% CI, 0.50-0.78; P
The patient population is of those who progressed after receiving sorafenib (Nexavar). 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.
Structurally related to sorafenib, which is the frontline standard of care, regorafenib is a potent inhibitor of kinases involved in angiogenic, oncogenic, and stromal/tumor environment-related signaling cascades, including VEGFR1-3 and TIE2, c-kit, Ret, BRAF, and PDGFR, among others.
The multistep oncogenic transformation underlying HCC involves alterations in several signaling cascades, resulting in molecularly heterogeneous tumors. Presumptive key carcinogenic signaling pathways include the Wnt/β-catenin pathway, chromatin remodeling, oxidative stress, and signaling involving EGF, PDGF, FGF, VEGF, and IGF, and intracellular mediators such as RAS/RAF/MAPK and PI3K/AKT.
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 ≥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
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).
The availability of a second-line therapy represents the potential to greatly improve outcomes for patients. Prior to this achievement, outcomes in the setting of sorafenib resistance or intolerance were poor, with a median expected OS for the placebo arms of second-line trials in the range of 7 to 8 months.
A recent study evaluating survival among 260 patients with HCC permanently discontinuing sorafenib reported median OS durations of 4.1 months overall, 4.6 months in patients with progression, and 1.8 months in patients with decompensated disease.2
Second-Line Setbacks Highlight Importance of RESORCE
Prior to the success of regorafenib in the second-line setting, there had been very little progress. Within the past few years, 3 candidate agents failed to meet primary endpoints in large phase III trials, including brivanib (BRISK-PS study), everolimus (EVOLVE-1 study), and ramucirumab (REACH study).
Brivanib, a dual inhibitor of VEGFR and FGFR, was the first agent evaluated in second-line therapy for HCC. For this agent, the phase III BRISK-PS study involving 395 patients with HCC who progressed during or after sorafenib treatment or were intolerant to the drug failed to demonstrate a survival benefit versus placebo.3