In addition, researchers noted during the trial that there is a strong correlation between regorafenib activity and the occurrence of hand-foot skin reaction (HFSR), which suggests that HFSR is can aid in gauging patient response.
Jordi Bruix MD, head of the Barcelona Clinic Liver Cancer (BCLC) at the University of Barcelona, presented an updated analysis of OS at approximately 1 year after the primary analysis.
“The phase III RESORCE trial met the primary endpoint: regorafenib improved OS versus placebo in patients with unresectable HCC who progressed during sorafenib (Nexavar) treatment,” said Bruix. “The results of this updated analysis of data from the RESORCE trial confirm the primary OS results.”
The RESORCE trial is an ongoing randomized, double-blind, placebo-controlled, multicenter phase III study of regorafenib in patients with HCC. The trial enrolled 573 patients with HCC and documented radiological progression after treatment with sorafenib. Patients were randomized to receive regorafenib at 160 mg once daily (n = 379), for 3 weeks on/1 week off, or placebo (n = 194). The primary endpoint of the study was OS, and secondary efficacy endpoints were time to progression, progression-free survival, objective response rate, and disease control rate.
Patient characteristics were balanced between the treatment arms: 88% of patients were male in both arms and the median age in the regorafenib arm was 64 (range, 54-71) years compared with 62 (range, 55-68) years in the placebo arm. Hepatitis B infection was reported in 38% and hepatitis C infection in 21% of patients in both groups. Microvascular invasion occurred in 29% versus 28% of patients in the respective groups and extrahepatic disease in 70% versus 76%. Cirrhosis was present in 74.5% of patients.
The updated analysis revealed OS was slightly improved over the primary analysis. Updated OS was a median 10.7 months (95% CI, 9.1-12.2) with regorafenib versus 7.9 months (95% CI, 6.4-9.0) with placebo (HR, 0.61; 95% CI, 0.50-0.75; P <.0001). In the primary analysis, median OS was 10.6 versus 7.8 months with regorafenib versus placebo (HR, 0.63; 95% CI, 0.50-0.79; P < .0001).
Part of the significance of the updated results is that they more clearly show the effects of prolonged treatment with regorafenib, Bruix said. Using a Swimmer plot to illustrate, she explained “What you see here is that all of the events have shifted farther to the regorafenib side, demonstrating that any subgroup events of OS that were borderline in the primary analysis now firmly favor regorafenib.”
The updated safety profile was similar to that reported in the primary analysis, with an interesting update regarding HFSR, which causes redness, numbness, sensitivity, and sometimes blistering on the palms of the hands and soles of the feet and is a commonly reported adverse event with regorafenib. The incidence of any grade HFSR with regorafenib was 53% versus 8% with placebo; grade 3 HFSR incidence was 13% versus 1%, respectively. The median time to first occurrence was 14 days. A review of baseline characteristics revealed the HFSR was more like to occur following regorafenib in Asian patients and in patients infected with the hepatitis B virus.
A subgroup analysis of OS by occurrence of HFSR at any time during regorafenib treatment suggested that HFSR may be a marker for regorafenib activity. OS was significantly prolonged in patients developing HFSR. They demonstrated median OS of 14.1 months (95% CI, 11.7-16.5) over those who did not, who had median OS of 6.6 months (95% CI, 5.0-8.5).
“Although a retrospective analysis suggests that HFSR is associated with better OS with regorafenib, this analysis may be confounded by baseline or other unknown factors, and further evaluation is needed,“ said Bruix.
An analysis of OS in patients developing HFSR early on, during the first regorafenib treatment cycle revealed patients with HFSR had median OS of 13.2 months (95% CI, 10.6-15.5) versus patients with no HFSR, whose median OS was 8.2 months (95% CI, 7.0-10.0).
“Regorafenib is an effective treatment option for patients with unresectable hepatocellular carcinoma who progress on prior sorafenib,” Bruix concluded, adding that "effective treatment options are urgently needed for patients with unresectable liver cancer."
The RESORCE trial was supported by Bayer.
Bruix J, Merle P, Granito A, et al. Updated overall survival (OS) analysis from the international, phase 3, randomized, placebo-controlled RESORCE trial of regorafenib for patients with hepatocellular carcinoma (HCC) who progressed on sorafenib treatment. Ann Oncol. 2017;28(suppl 3): mdx262.008. doi.org/10.1093/annonc/mdx262.008. Accessed June 30, 2017.