Regorafenib HCC Benefits Consistent in Additional Analyses

Richard S. Finn, MD

Second-line regorafenib (Stivarga) continued to show antitumor activity regardless of prior dose or time to progression (TTP) on frontline sorafenib (Nexavar) for patients with unresectable advanced hepatocellular carcinoma (HCC), according to additional analyses from the phase III RESORCE trial published in the Journal of Hepatology.¹

There was a 33% reduction in the risk of death with regorafenib compared with placebo for patients receiving a frontline dose of 800 mg/day of sorafenib (HR, 0.67). Additionally, a similar benefit in overall survival (OS) was seen for regorafenib in patients receiving a frontline dose of sorafenib less than 800 mg/day (HR, 0.68). In an analysis of TTP on frontline sorafenib, second-line regorafenib continued to show consistent benefit compared with placebo across all quartiles examine, with hazard ratios ranging from 0.26 to 0.66.

The median time from the start of sorafenib to death was 26.0 months for those receiving second-line regorafenib (95% CI, 22.6-28.1) compared with 19.2 months in the placebo group (95% CI, 16.3-22.8), representing a 6.8-month improvement in survival for the therapeutic sequence of sorafenib-regorafenib compared with placebo. Median time from start of sorafenib to progression of disease in the RESORCE trial was 14.7 months for those treated with regorafenib (95% CI, 13.5-16.2) compared with 11.4 months in the placebo group (95% CI, 10.2-12.7).

"The benefit we observed with the sorafenib to regorafenib sequence suggests that integrating new effective systemic treatments may lead to incremental improvements in survival in advanced HCC after initial treatment, and an improved outlook for our patients,” said lead investigator Richard Finn, MD, assistant professor of Medicine at the Geffen School of Medicine at UCLA.

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. Prior sorafenib was administered for ≥20 days at ≥400 mg/day with documented radiologic progression, with most receiving the medication at 800 mg/day (60%). The duration of prior sorafenib was similar in both groups (7.8 months each).

In the RESORCE study alone,² the median OS was 10.6 months with regorafenib versus 7.8 months for placebo (HR, 0.63; 95% CI, 0.50-0.79; P <.0001). The median progression-free survival was 3.1 months in the regorafenib arm compared with 1.5 months in the placebo group (HR, 0.46; 95% CI, 0.37-0.56; P <.0001).

In those with the shortest TTP on prior sorafenib (quartile 1), the median TTP with regorafenib was 3.2 months compared with 1.5 months for placebo (HR, 0.44; 95% CI, 0.36-0.54). Those in quartile 4, with the longest duration of response to sorafenib, had a median TTP of 4.5 months with regorafenib versus 2.4 months for placebo (HR, 0.54; 95% CI, 0.36-0.81).

The estimated survival rate from the start of sorafenib was consistently longer in those receiving second-line regorafenib versus placebo. At 24 months, the estimated survival rate was 53% with regorafenib versus 42% for placebo. At 48 months, the rates were 19% and 12%, respectively, and by week 72, 10% of those in the regorafenib arm remained alive versus 3% in the placebo group.

Adverse events (AEs) were similar regardless of frontline sorafenib dose administered, with more grade 3/4 events for those receiving a lower dose of sorafenib (64% vs 71%). Grade 3 AEs were experienced by 52% of those receiving sorafenib at 800 mg/day compared with 60% in those receiving <800 mg/day. For both dose groups, respectively, grade 4 AEs were experienced by 11% and 10% and grade 5 AEs were seen in 15% and 12%.

Fatigue and anorexia were more common in patients receiving a lower dose of frontline sorafenib. In the <800 mg/day group, 50% of patients experienced fatigue and 40% had anorexia compared with 36% and 25% for the 800 mg/day dose, respectively. In the regorafenib arm, grade 3 hand-foot skin reaction occurred in 10% of those treated with prior sorafenib at 800 mg/day compared with 17% for those receiving <800 mg/day.

"Importantly, we saw that patients benefited from this sequence regardless of their prior treatment period on sorafenib, or whether they were receiving full-dose sorafenib," Finn said. "The incidence of side effects from regorafenib were generally the same regardless of prior dose of sorafenib as well."

Regorafenib was approved by the FDA in April 2017 for the treatment patients with hepatocellular carcinoma (HCC) who have previously received sorafenib, based on findings from the RESORCE trial. The agent is also approved for the treatment of patients with metastatic colorectal cancer and advanced gastrointestinal stromal tumors.

References

1. Finn RS, Merle P, Granito A, et al. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: additional analyses from the phase 3 RESORCE trial [published online April 25, 2018]. J Hepatol. 2018.
2. 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. Lancet. 2017;389:56-66.