Second-line treatment with regorafenib displayed safety in patients with advanced hepatocellular carcinoma who were not eligible for treatment on the phase 3 RESORCE trial, according to data from the phase 2 REGAIN trial.
Second-line treatment with regorafenib (Stivarga) displayed safety in patients with advanced hepatocellular carcinoma (HCC) who were not eligible for treatment on the phase 3 RESORCE trial (NCT01774344), according to data from the phase 2 REGAIN trial (CRB3180015; jRCTs031190103) presented at the 2023 International Liver Cancer Association Conference.1
Findings from REGAIN showed that among all patients who received the standard dose of 160 mg of regorafenib per day in the second line (n = 18), 17.6% discontinued treatment at any point due to adverse effects (AEs). One of 6 patients (16.7%) in arm C who received frontline treatment with atezolizumab (Tecentriq) plus bevacizumab (Avastin) prior to standard second-line regorafenib discontinued to treatment within 4 weeks due to AEs. In all patients treated with a reduced dose of 80 mg of regorafenib in the second line (n = 18), 25.0% discontinued treatment due to AEs. Notably, no patients treated with the reduced dose of regorafenib discontinued treatment within 4 weeks.
Findings also showed that the median time to progression (TTP) in the standard-dose group was 4.6 months (95% CI, 2.6-10.3) and 3.0 months (95% CI, 2.8-6.5) for the reduced-dose group.
“The safety of regorafenib as second-line therapy for patients who were not included in the RESORCE trial was verified,” Keisuke Koroki, MD, of the Department of Gastroenterology in the Graduate School of Medicine at Chiba University in Japan, and colleagues, wrote in a poster presentation of the data.
Previously, the phase 3 RESORCE trial evaluated regorafenib vs placebo in patients HCC who received prior sorafenib. To be eligible for the study, patients were required to have disease progression after receiving at least 400 mg of sorafenib per day for at least 20 days of the final 28 days of treatment.
However, in clinical practice, doses of sorafenib are often reduced due to AEs, and the efficacy and safety of second-line regorafenib in patients who required dose reductions of sorafenib is unclear. Additionally, further data are needed to evaluate the efficacy and safety of regorafenib in patients who received first-line treatment with the combination of atezolizumab plus bevacizumab or single-agent lenvatinib (Lenvima), which are 2 standard frontline treatment options.
The phase 2 REGAIN trial was designed to assess the safety and efficacy of regorafenib in patients with advanced HCC who were not included in the RESORCE trial to provide evidence for an optimized regorafenib regimen for use in current clinical practice.
The randomized, open-label trial enrolled patients at least 20 years of age with unresectable HCC, Barcelona Clinic Liver Cancer stage B/C disease, a Child-Pugh score of A, and an ECOG performance status of 0 or 1.
Patients were classified into 1 of 3 arms based on prior treatment: sorafenib at a reduced dose of 200 mg per day (arm A; n = 12), lenvatinib (arm B; n = 12), or the combination of atezolizumab and bevacizumab (arm C; n = 12). Patients were then randomly assigned 1:1 to receive the standard dose of regorafenib at 160 mg per day or the dose-reduction group of regorafenib at 80 mg per day.
The primary end point of the study was TTP. Secondary end points consisted of safety—including the incidence of AEs and discontinuation rates due to AEs—progression-free survival and overall survival (OS).
In the overall populations for the standard-dose and reduced-dose groups, 94.4% of patients in both groups were male. The median age was 69.5 years (range, 53-81) for the standard-dose group and 74.5 years (range, 52-84) for the reduced-dose group. In the standard-dose group, 11.1% of patients had hepatitis B, 33.3% had hepatitis C, and 61.1% of patients had an intrahepatic tumor number of at least 8. In the reduced-dose group, those rates were 16.7%, 27.8%, and 44.4%, respectively. The median maximum tumor diameter was 44.0 mm (range, 12.5-121.7) in the standard-dose group and 30.9 mm (range, 0-114.5) in the reduced-dose group. Extra hepatic spread was observed in 50% and 55.5% of patients in the standard- and reduced-dose groups, respectively.
Additional data showed that patients in arm A treated with the standard dose of regorafenib achieved a median TTP of 8.3 months (95% CI, 4.1-15.7), and the median TTP was 13.5 months (95% CI, 2.8-21.4) for those treated with a reduced dose of regorafenib. In arm B, the median TTP was 10.2 months (95% CI, 1.0-15.9) for those given the standard dose of regorafenib and 2.8 months (95% CI, 0.9–not applicable [NA]) for those given a reduced dose of regorafenib. In arm C, the median TTP was 2.6 months (95% CI, 1.6-2.8) and 4.1 months (95% CI, 2.5-NA) for those treated with standard- and reduced-dose regorafenib, respectively.
For all patients treated with the standard dose of regorafenib, the median OS was 18.1 months (95% CI, 5.6-NA). The median OS for patients in arms A, B, and C treated with standard regorafenib was 18.1 months (95% CI, 5.6-NA), 20.6 months (95% CI, 3.5-20.6), and 10.5 months (95% CI, 0.3-NA), respectively.
For the overall population treated with reduced-dose regorafenib, the median OS was 17.7 months (95% CI, 7.43-NA). The median OS for patients in arm A treated with a reduced dose of regorafenib was 17.7 months (95% CI, 7.9-NA), and the median OS was not reached for both arms B and C.
All patients across both dosing groups experienced at least 1 any-grade AE. The most common any-grade AEs included hand-foot skin reaction, hypertension, increased lipase, fatigue, hoarseness, anorexia, and decreased lymphocytes.
Koroki K, Ogasawara S, Fujiwara K, et al. Randomized phase II trial to assess safety and efficacy of regorafenib in patients with advanced hepatocellular carcinoma who were not included in the RESORCE trial: REGAIN trial. Presented at: 2023 International Liver Cancer Association Conference; September 7-9, 2023; Amsterdam, Netherlands. Abstract P-97.