Real-Life Analysis Confirms Benefit of Sorafenib/Regorafenib Sequence in HCC

In an interview with <em>Targeted Oncology</em>, Mar&iacute;a Varela, MD, PhD, discussed the rationale of the findings from the real-life analysis and their importance for patients with HCC being treated outside of a clinical trial.

The phase III RESORCE trial demonstrated the efficacy of regorafenib (Stivarga) for patients with hepatocellular carcinoma (HCC) who have progressed on prior sorafenib (Nexavar).1This study led to the approval for regorafenib as a second-line therapy for patients with HCC. A real-life analysis presented in a poster session at the 2019 ILCA Annual Conference, confirmed the benefit of the sorafenib/regorafenib sequence for patients with HCC from the RESORCE trial in a real-world setting.2

The investigators in the multidisciplinary HCC team at the Hospital Universitario Central de Asturias in Oviedo, Spain conducted a unicentric study of 109 consecutive patients with HCC. The patients were treated with sorafenib and then switch to receive regorafenib at the time of radiological progression if the patient tolerated sorafenib, had compensated liver disease, and an ECOG performance status of 0 or 1. Patient and disease characteristics were assessed at baseline before sorafenib and at the moment of progression as well as adverse events that occurred with each treatment.

The median age of patients was 66 (range, 59-71), 88% of patients were male, 71% had Barcelona Clinic Liver Cancer stage C disease, and 72% were asymptomatic. Sixty-five of the patients had received prior treatment for HCC, including transcatheter arterial chemoembolization in 42% and surgical resection in 17%, whereas sorafenib was the first treatment for 40% of patients.

The median survival with sorafenib was 15 months (95% CI, 8.502-21.498) and the median duration of treatment was 6 months (range, 3-10).

Twenty-nine of 72 patients with radiological progression on sorafenib received second-line regorafenib, with clinical progression (33%) and cirrhosis decompensation (21%) serving as the main reasons for not receiving regorafenib. The median overall survival was 5 months from the time of radiological progression and was 3 months (95% CI, 2.636-3.364) in those with continued on sorafenib past progression versus 13 months (95% CI, .718-22.282) in those who received regorafenib (P= .012).

The median survival from starting regorafenib was 12 months (95% CI, 9.605-14.395) and the median duration of regorafenib treatment was 8 months (range, 6-13). The median overall survival from initiation of sorafenib in the patients who went on to receive regorafenib was 28 months (95% CI, 13.255-42.745). Additionally, only 7.2% of patients stopped treatment with regorafenib due to adverse events.

In an interview withTargeted Oncology, María Varela, MD, PhD, a pathologist in the Liver Unit at the Hospital Universitario Central de Asturias, discussed the rationale of the findings from the real-life analysis and their importance for patients with HCC being treated outside of a clinical trial.

TARGETED ONCOLOGY: What was the rationale for conducting this analysis?

Varela: This is a real-life experience with sorafenib, and in this situation, if the patients are candidates to receive regorafenib, we have [shown] the real-world experience, the dosing modifications, and the adverse events for the patients that have been treated with sorafenib plus regorafenib in a real-life setting.

TARGETED ONCOLOGY: Which patients were candidates for receiving regorafenib in the real-life sequencing analysis?

Varela: We strictly followed the conditions of the eligibility criteria of the RESORCE trial. These patients would, under perfect circumstances, be Child-Pugh A or B, but would definitely be well compensated, [have an] ECOG [performance status] of 0 or 1, and they should be tolerant of sorafenib. Some patients with radiological progression continued on sorafenib, but most of them moved on to second-line therapy with regorafenib.

TARGETED ONCOLOGY: What was the design of the analysis?

Varela: It's a cohorted study, we had to assign a clinical protocol with radiological studies at fixed time points. We analyzed the baseline characteristics and the characteristics at the time of radiological progression to assess the follow-up and the overall survival from these different points.

TARGETED ONCOLOGY: What were the main findings of the real-life analysis?

Varela: The findings are that if the patients move to regorafenib at the moment of radiological progression, they obtained better survival, 28 months, versus 8 months if they continued on sorafenib.

This is just a real-life cohort observational study, so there is some bias if you consider that it's not the same thing as making a randomized study of sorafenib plus sorafenib on progression versus sorafenib plus regorafenib on progression, it's not the case. All of the patients had the opportunity to move to regorafenib, but if they presented with clinical progression or decompensated cirrhosis, they had to stop therapy or they would have to continue with sorafenib. So only the better patients moved on to regorafenib, and perhaps some baseline conditions influenced the overall survival being as high as 28 months.

TARGETED ONCOLOGY: What safety findings were noted in the analysis compared with the RESORCE trial?

Varela: The patients had more than 8 months under regorafenib, that is longer than in the RESORCE trial. When the patients presented with serious adverse events related to regorafenib, this happened very late in treatment, about 11 months from the start of regorafenib. So really, it's not toxic, it's very well tolerated in this cohort of patients that are sensitive to sorafenib and are tolerant of sorafenib.

In general, the patients that are tolerant of sorafenib have very good tolerance of regorafenib, so this is the main message, that you have to choose these patients specifically. We have not tested regorafenib in patients that are intolerant of sorafenib. We strictly followed the RESORCE criteria.

TARGETED ONCOLOGY: How do you see these findings impacting the treatment landscape? What should oncologists take away from this analysis?

Varela: This is a confirmation of the trial. But, the most important issue is that in real life with very simple and dedicated medical assistants, you can obtain the best results in these patients, so you don't need to enroll the patients in a trial to obtain these results, you can do it in your clinical practice. So, I think it's valuable because of that, in a real-life system.

If you take care of the patients and you [choose] the moment to treat with a second line you can obtain a higher overall survival and better quality of life. But you have to pay attention to the moment in which you have to switch to the second line. It is the main important issue when you have approval for second-line therapies, you have to choose the best moment to move to second-line therapy.


  1. 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.
  2. Casta&ntilde;o-Garc&iacute;a A, Florez P, Mesa A, et al. Analysis of efficacy and safety in a real-life cohort of hepatocellular carcinoma treated with sorafenib-regorafenib. Presented at: 2019 ILCA Annual Conference; September 20-22, 2019; Chicago, IL. Abstract P-067.