Regorafenib Sustains OS Benefit in RESORCE Trial Update

Jordi Bruix, MD

Regorafenib (Stivarga) maintained a prolonged overall survival (OS) benefit as second-line therapy for patients with advanced hepatocellular carcinoma (HCC) in a 2-year updated analysis of key findings from the pivotal RESORCE trial, according to results presented at the 2018 International Liver Cancer Association (ILCA) Annual Conference.

In the follow-up data, the multikinase inhibitor improved median OS to 10.7 months (95% CI, 9.1-12.2) compared with 7.9 months (95% CI, 6.4-9.0) with placebo, which translated into a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.51-0.75; P <.0001).¹

Those results were highly similar to findings from the primary analysis that prompted the FDA to approve regorafenib in April 2017 for patients with HCC who have been previously treated with sorafenib (Nexavar).

The updated findings are worth revisiting considering regorafenib’s place in the timeline of HCC advancements, according to lead study investigator Jordi Bruix, MD, PhD, who presented the data at ILCA. “This was the trial that suddenly opened an era of more success after 10 years of failures,” said Bruix, director of the Barcelona Clinic Liver Cancer (BCLC) Group at the Hospital Clinic of Barcelona in Spain.

The RESORCE trial (NCT01774344) randomized patients 2:1 to receive regorafenib at 160 mg daily (3 weeks on/1 week off) versus placebo until progression, death, or unacceptable toxicity. In all, 573 patients participated in the study; 379 received regorafenib and 194 were given placebo.

The study recruited patients with radiologic progression during sorafenib treatment who had Child-Pugh A status and BCLC stage B or C disease not amenable to resection or locoregional therapy. The median age was 64 years (range, 54-71) in the regorafenib arm and 62 years (range, 55-68) in the placebo group.

The efficacy population was balanced at baseline between regorafenib and placebo, respectively, for macrovascular invasion (29% vs 28%), extrahepatic disease (70% vs 76%), alpha-fetoprotein ≥400 ng/mL (43% vs 45%), and the presence of cirrhosis (75% vs 74%).

Tolerance to prior sorafenib also was required; this was defined as having taken ≥400 mg daily for at least 20 days of the last 28 days of treatment. Additionally, patients had to be randomized within 10 weeks after their last sorafenib dose.

“We had a very tight definition of tolerance to sorafenib,” Bruix said. “We had a maximum time period between the last period of sorafenib before entrance into the trial. This was intended to secure patients who were upon progression and not indolent cases.”

Bruix noted that regorafenib improved outcomes for the primary OS endpoint as well as the secondary endpoints of progression-free survival, time to progression, disease control rate, and overall response rate. The most common clinically relevant grade 3/4 treatment-related adverse events were hypertension, hand—foot skin reaction, fatigue, and diarrhea.

In the primary analysis, which had a data cutoff of February 29, 2016, the median OS with regorafenib was 10.6 months (95% CI, 9.1-12.1) versus 7.8 months (95% CI, 6.3-8.8) with placebo (HR, 0.62; 95% CI, 0,50-0.78; P <.0001).

As of January 14, 2018, the data cutoff for the updated analysis, the estimated OS rates for regorafenib compared with placebo at 12, 18, and 30 months were 47% versus 28%, 32% versus 15%, and 16% versus 8%, respectively, Bruix and colleagues reported in their conference abstract. Results for OS favored regorafenib in all preplanned subgroup analyses. “We have seen a consistent benefit,” he said.

The new data show that patients who developed new extrahepatic lesions during sorafenib therapy had a longer probability of postprogression survival (PPS) with second-line regorafenib than with placebo. The median PPS for patients with new extrahepatic lesions on sorafenib was 10.6 months (95% CI, 8.4-12.3) with regorafenib versus 8.2 months (95% CI, 5.9-10.0) with placebo (HR, 0.66; 95%CI, 0.50-0.89). For those without new extrahepatic lesions during prior sorafenib, the median PPS was 14.1 months (12.3-15.7) on regorafenib versus 10.6 months (95% CI, 9.5-12.8) with placebo (HR, 0.67; 95% CI, 0.52-0.85).

In response to a question from an audience member, Bruix said investigators had tested many potential targets for biomarkers but these efforts have not yet yielded actionable data. “There are suggestions of all sorts but there is nothing that is robust,” he said.

Biopsies were not required for entry when RESORCE was launched in 2013, so investigators are confined to testing with blood samples, Bruix said.

References

1. Bruix J, Merle P, Granito A, et al. Overall survival (OS) update: 2-year follow-up from the phase 3 RESORCE trial of regorafenib for patients with hepatocellular carcinoma (HCC) progressing on sorafenib. Presented at: 2018 International Liver Cancer Association Annual Meeting; September 14-16; London, England. O-023. ilca2018.org/wp-content/uploads/2018/08/ILCA-2018-Final-Programme-and-Book-of-Abstracts_LR_compressed-2.pdf.
2. Bruix J, Qin S, Merle P, et al; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial [erratum in 2017;389(10064):36. doi: 10.1016/S0140-6736(16)32615-0]. Lancet. 2017;389;10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.

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Bruix said the updated findings support the validity of analyzing outcomes by patterns of progression. In prior research, the development of new vascular invasion or extrahepatic spread has emerged as a significant predictor of a worse survival.²