Lancet Data Highlight OS Benefit for Regorafenib in HCC

Jordi Bruix, MD

Regorafenib (Stivarga) has demonstrated the first survival benefit for a systemic therapy in the second-line setting for patients with advanced hepatocellular carcinoma (HCC) who have progressed on sorafenib (Nexavar), according to results from the phase III RESORCE trial published in The Lancet.¹

"What we have shown is that regorafenib very much clinically impacted survival. It delayed tumor progression and progression-free survival was also significantly improved," lead author Jordi Bruix, MD, head of the Barcelona Clinic Liver Cancer (BCLC) at University of Barcelona, told OncLive in an interview. We have again, success as we had with sorafenib, and this will become now a sequential therapy, starting patients on sorafenib and then when they progress moving them to regorafenib."

In the RESORCE trial, the oral multikinase inhibitor demonstrated a survival benefit of 2.8 months over placebo, with a median overall survival (OS) of 10.6 months (95% CI, 9.1-12.1) with regorafenib versus 7.8 months (95% CI, 6.3-8.8) on placebo, this represented a 37% reduction in the risk of death (HR, 0.63; 95% CI, 0.50-0.79; one-sided P <.0001).

Complete responses were achieved by 2 patients on regorafenib while partial responses were noted in 38 patients (10%) for an objective response rate of 11%. Stable disease was achieved in 206 patients (54%).

“The clinical improvement is very relevant. It is clinically meaningful to have an improvement in survival that is more than 30%,” said Bruix. “It makes a big jump in terms of life expectations.”

Patients in the trial had Barcelona Clinic Liver Cancer (BCLC) stage B or C, at least 1 lesion by RECIST v1.1 criteria, unresectable disease, and progression on prior sorafenib treatment. Overall, 573 patients were enrolled in the trial from 152 centers across 21 countries. The participants were randomized 2:1 to regorafenib at 160 mg or placebo.

A majority of the participants were male (88% in each arm), had an ECOG performance status of 0 (65% and 67% in regorafenib and placebo groups, respectively), extrahepatic disease (70% and 76%, respectively), and BCLC stage C (86% and 89%, respectively).

Median progression-free survival in the regorafenib arm (n = 379) was 3.1 months (95% CI, 2.8-4.2) versus 1.5 months (95% CI, 1.4-1.6) on placebo (n = 194). The authors noted that both the progression-free and overall survival benefits were maintained in all subgroup analyses.

Eighty-three percent of the patients receiving regorafenib and 95% of the patients on placebo discontinued treatment, most often due to disease progression. The median duration of treatment on regorafenib was 3.6 months (range, 1.6-7.6) and 1.9 months (range, 1.4-3.9) on placebo.

“Regorafenib had a bad reputation in colorectal patients because there it was said to be poorly tolerated because the patients had undergone several other treatments before receiving regorafenib,” said Bruix. “In GIST, which is another indication of regorafenib, the tolerability is quite good, and in HCC we only had 10% of the patients that had to interrupt treatment because of adverse events. This means that 90% of the patients tolerated the drug properly, with some dose adjustments.”

All patients in the regorafenib arm experienced a treatment-emergent adverse event (AE). The most common grade 3/4 AEs included hypertension (15% vs 5% in regorafenib and placebo groups, respectively), hand-foot skin reaction (13% vs 1%, respectively), fatigue (9% vs 5%, respectively), and diarrhea (3% vs 0, respectively). AEs experienced by patients on regorafenib were similar to those experienced on sorafenib.

Serious AEs occurred in 166 patients (44%) in the regorafenib group, with 10% attributed to the study drug, and in 90 patients (47%) on placebo. Seven treatment-related deaths occurred in the regorafenib arm and 2 in the placebo arm.

In the report, the authors noted that this is the first systemic therapy to show a survival benefit in patients with HCC after treatment with sorafenib, which was echoed in an editorial by Jean-Charles Nault, MD, of the Génomique fonctionnelle des Tumeurs solides in Paris, France.²

“It is clear that regorafenib will become the standard of care as a second-line treatment following sorafenib failure in patients with advanced HCC,” Nault stated in his editorial.

A supplemental new drug application for regorafenib as a second-line treatment for patients with unresectable HCC was submitted to the FDA in November based on the findings from the RESORCE trial.

References:

1. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. [Published online December 5, 2016] Lancet. doi: 10.1016/S0140-6736(16)32453-9.
2. Nault J-N. The end of almost 10 years of negative RCTs in advanced hepatocellular carcinoma. [Published online December 5, 2016] Lancet. doi: 10.1016/S0140-6736(16)32480-1.