RESORCE Trial Analysis Shows Higher AFP Responses Achieved With Regorafenib in HCC

Jordi Bruix, MD

Treatment with regorafenib (Stivarga) resulted in higher rates of alpha-fetoprotein (AFP) level response compared with placebo in patients with unresectable hepatocellular carcinoma (HCC) who had progressed on prior sorafenib (Nexavar), according to an analysis from the phase III RESORCE trial.¹

AFP responses were also associated with longer overall survival (OS) and improved objective response rates (ORRs).

“In the phase III RESORCE trial…the rate of AFP response, defined as a ≥20% decrease in AFP from baseline at the start of cycle 3, was higher in patients treated with regorafenib than in those who received placebo,” the study authors, led by Jordi Bruix, MD, director of the Barcelona Clinical Liver Cancer Group, University of Barcelona, wrote in a poster presented at the 2019 ILCA Annual Conference in Chicago, Illinois, from September 20 to 22.

In the randomized, double-blind, parallel-group phase III RESORCE trial, 573 patients with HCC who had tolerated prior sorafenib but had progressed on treatment were treated with either regorafenib or placebo in a 2:1 randomization.²Regorafenib improved OS compared with placebo with a median OS of 10.6 months versus 7.8 months (HR, 0.63; 95% CI, 0.50-0.79; 1-sidedP<.0001).

The investigators conducted a prior pre-planned analysis of OS in the RESORCE trial and found that regorafenib improved survival in both patients with baseline AFP levels <400 ng/mL and &ge;400 ng/mL.³This finding led the investigators to further explore patient outcomes by AFP response.

In the trial, serum AFP levels had been assessed at baseline, every 4 weeks throughout treatment, and at the end of treatment. This analysis focused on patients who had a baseline AFP level &ge;20 ng/mL and an available measurement of AFP at the start of cycle 3 of treatment.¹A total of 232 patients were evaluable, including 168 who received regorafenib treatment and 64 who received placebo. Of these patients, 153 had a baseline AFP level &ge;200 ng/mL and 130 had &ge;400 ng/mL.

Eighty-four patients achieved an AFP response, including 77 (46%) who were being treated with regorafenib and 7 (11%) receiving placebo. Ninety-one patients being treated with regorafenib and 57 receiving placebo did not have an AFP response.

The median time on treatment for patients who had an AFP response was 6.2 months (range, 1.6-28.8) and 4.1 months (range, 1.2-28.3) in those who did not respond. The median OS was 13.8 months (95% CI, 11.8-16.5) in patients who had an AFP response compared with 8.9 months (95% CI, 8.0-9.7) in those who did not (HR, 0.57; 95% CI, 0.40-0.82).

The investigators also conducted a landmark analysis to account for potential immortal time bias, which found that the median OS from the start of cycle 3 with 12.0 months (95% CI, 9.9-14.6) in patients with an AFP response versus 7.0 months (95% CI, 6.2-7.9) in those who did not achieve an AFP response (HR, 0.57; 95% CI, 0.40-0.82).

The tumor ORR by modified RECIST criteria in evaluable patients was 13% in those with an AFP response, which consisted of all partial responses, versus 9% in those who did not respond, with 2 patients achieving a complete response. The disease control rate was 93% versus 75%, respectively.

&ldquo;A higher proportion of patients without an AFP response versus those with an AFP response received systemic anticancer therapy during follow-up,&rdquo; the study authors wrote. Twenty-four percent of the patients who did not achieve an AFP response required subsequent anticancer therapy compared with 18% in patients who did have an AFP response. The majority of these patients received antineoplastic agents (22% and 13%, respectively).

Grade 3/4 treatment-emergent adverse events (TEAEs) were observed in 67% of patients who had an AFP response versus 58% who did not have a response. The most common grade 3/4 TEAEs were hypertension (13% with a response vs 11% without), hand-foot skin reaction (11% vs 5%, respectively), fatigue (10% vs 7%), increased aspartate aminotransferase (8% vs 16%), and increased blood bilirubin (6% vs 12%).

Notably, the rate of grade 3 hand-foot skin reaction was higher in the patients who achieved an AFP response than in those who did not, whereas the rates of grade 3/4 aspartate aminotransferase increase and blood bilirubin increase were higher in those who did not have an AFP response.

References

1. Bruix J, Reig M, Merle P, et al. Alpha-fetoprotein (AFP) response and outcomes in patients with unresectable hepatocellular carcinoma (HCC) treated with regorafenib or placebo in the phase 3 RESORCE trial. Poster presented at: 2019 ILCA Annual Conference; September 20-22, 2019; Chicago, IL. Abstract P-013.
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.Lancet.2017;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.
3. Merle P, Granito A, Huang Y-H, et al. Updated overall survival (OS) analysis from the international, phase III, randomized, placebo-controlled RESORCE trial of regorafenib for patients with hepatocellular carcinoma (HCC) who progressed on sorafenib treatment. Presented at: 2017 ILCA Annual Conference; September 15-17, 2017; Seoul, South Korea. Abstract O-031.