Real-Life Experiences Demonstrate Benefit of Sorafenib-Regorafenib Sequential Therapy in Advanced HCC

Sequential therapy with sorafenib (Nexavar) followed by regorafenib (Stivarga) for patients with advanced hepatocellular carcinoma demonstrated real-life benefit in a study of patients treated in a Japanese hospital.

Sequential therapy with sorafenib (Nexavar) followed by regorafenib (Stivarga) for patients with advanced hepatocellular carcinoma (HCC) demonstrated real-life benefit in a study of patients treated in a Japanese hospital.1Although the number of patients who received second-line treatment with regorafenib was limited due to eligibility criteria, the overall survival (OS) benefit with the sequence of targeted therapies was significant when calculated from the initiation of first-line treatment.

“Our results demonstrated the benefit of sorafenib-regorafenib sequential therapy in patients with advanced HCC using clinical data at the time of starting sorafenib,” Sae Yumita, MD, said when presenting the findings at the EASL 2019 International Liver Congress. “Although a limited population of patients have switched sorafenib to regorafenib in the field, it is necessary to increase the rate of conversion from sorafenib to regorafenib in patients with advanced HCC.”

Findings from the phase III RESORCE trial led to the approval in April 2017 of regorafenib as a second-line therapy for patients with unresectable HCC who had previously received treatment with sorafenib.2The trial randomized patients 2:1 to either regorafenib or placebo. The patients were carefully selected, explained Yumita, of the Department of Gastroenterology, Graduate School of Medicine, Chiba University in Japan, based on patients who had tolerated sorafenib well. Eligibility criteria for the trial included documented radiological progression during sorafenib treatment, a Child-Pugh score of A, an ECOG performance status of 0 or 1 at the time of sorafenib discontinuation, and tolerability of prior sorafenib at ≥400 mg/day for ≥20 of the last 28 days of treatment.

In the RESORCE trial, patients with HCC who received regorafenib (n = 379) after progression on sorafenib treatment demonstrated a median OS of 10.6 months (95% CI, 9.1-12.1) compared with 7.8 months (95% CI, 6.3-8.8) in those who received placebo (n = 194; HR, 0.63; 95% CI, 0.50-0.79; one-sidedP<.0001). The median progression-free survival (PFS) was 3.1 versus 1.5 months with regorafenib and placebo, respectively (HR, 0.46; 95% CI, 0.37-0.56;P<.001). The median time to progression (TTP) in the regorafenib group was 3.2 versus 1.5 months with placebo (HR, 0.44; 95% CI, 0.036-0.55;P<.001).

“However, in clinical practice, the patients who are available candidates for regorafenib are very limited,” Yumita said. She said that recent studies have shown that only 30% to 40% of patients treated with sorafenib are then candidates for regorafenib. Clinical benefit, however, could also be seen in newer analyses of the RESORCE trial regardless of the starting dose of sorafenib or the time until progression, which could extend the number of eligible patients.3

Additionally, she noted that in the RESORCE trial, baseline clinical data were not collected at the time of starting sorafenib to show the true benefit of sequential therapy. Their study aimed to analyze the impact of sorafenib-regorafenib sequential therapy from the first day of administering sorafenib to patients with advanced HCC.

The investigators retrospectively identified patients with advanced HCC who received sorafenib as a first-line treatment (n = 385). Patients were treated at the Chiba University Hospital between June 2009 through December 2017. Clinical parameters were identified at the start of therapy and also once progression was identified during treatment.

Based on the RESORCE trial inclusion criteria, the investigators excluded patients who started sorafenib at below 400 mg/day, those who had an ECOG performance status higher than 1, and patients that were Child-Pugh B at baseline from receiving regorafenib second line. Based on these criteria, only 66 were excluded, yet only 23 patients ended up receiving regorafenib. In baseline characteristics comparisons, Yumita noted that the characteristics were similar between those who did and did not receive second-line therapy with regorafenib.

Overall, the median OS from the time of sorafenib administration was 13.9 months (95% CI, 12.0-15.8) and the median TTP from initiation of sorafenib was 3.8 months (95% CI, 3.0-4.7). The median duration of sorafenib treatment was 4.7 months (95% CI, 3.9-5.5).

Median OS from the time of sorafenib administration through regorafenib treatment was 27.1 months (95% CI, 22.5-31.7), whereas those who were not eligible for regorafenib therapy had a median OS of 12.6 months (95% CI, 10.8-14.4;P<.001).

By multivariate analysis, having a TTP after sorafenib of more than 3.8 months and receiving regorafenib after sorafenib were both statistically significant positive prognostic factors for improved survival.

The investigators then identified 83 patients of the 296 not treated with regorafenib who had confirmed radiological progression who they thought would be good candidates for regorafenib and compared the OS from the date of sorafenib administration in these patients. When comparing those who did receive regorafenib (n = 23) to those who potentially could have received it (n = 83), more of the candidates had multiple interhepatic lesions (>7) as compared with the patients who received regorafenib as well as higher AFP scores and higher initial doses of sorafenib. However, these patients also tended to have a shorter time to progression, which was found to be statistically significant.

The OS in the potential-candidate patients was 15.1 months (95% CI, 12.5-17.6;P= .006). “As a possible result, receiving regorafenib provides a survival benefit,” Yumita commented.

The median OS from radiological progression date of sorafenib was 22.5 months (95% CI, 16.3-28.9) in patients who did receive regorafenib second line, and was 11.1 months (95% CI, 8.4-13.8) in patients who were candidates for regorafenib but did not receive it (P= .016).

Multivariate analysis in the candidates showed that a TTP of more than 3.8 months was a better prognostic factor for improved survival.


  1. Yumita S, Ogasawara S, Ooka Y, et al. Analysis of sorafenib-regorafenib sequential therapy in patients with advanced hepatocellular carcinoma using baseline data of sorafenib. Presented at: EASL International Liver Congress 2019; April 10-14, 2019; Vienna, Austria. Abstract PS-142.
  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.2016;389(10064):56-66. doi: 10.1016/S0140-6736(16)32453-9.
  3. Finn RS, Merle P, Granito A, et al. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial.J Hepatol.2018;69(2):353-358. doi: 10.1016/j.jhep.2018.04.010.