Real-World Study Confirms Safety of Regorafenib After Sorafenib in Unresectable HCC

Regorafenib (Stivarga) demonstrated a tolerable safety profile as treatment of patients with unresectable hepatocellular carcinoma (HCC) in the real world, according to results from the ongoing prospective observational REFINE study. The agent also showed an overall survival (OS) which appeared consistent with prior data from the RESORCE trial.

Findings from REFINE were presented in a poster during the 2020 International Liver Cancer Association (ILCA) Virtual Conference.

Regorafenib was initiated at a daily dose of 160 mg in 57% of patients, 120 mg in 13%, 80 mg in 28%, and 40 mg in 2%.

The most common TEAEs in the regorafenib-treated patients included hand-foot skin reaction in 30%, diarrhea in 21%, fatigue in 16%, and decreased appetite in 14%. The most common TEAEs in the sorafenib-intolerant patients included diarrhea (25%), hand-foot skin reaction (20%), abdominal pain (15%), and decreased appetite (13%).

Among patients who received sorafenib previously in any line, the median duration of prior sorafenib was 4.8 months (range, 2.5-9.6), and 45% of patients had a last daily dose of sorafenib at 800 mg. Additionally, 8% of patients had an AE that led to discontinuation of sorafenib, which was defined as sorafenib-intolerant. The proportion of patients with Child-Pugh class A liver disease occurred in 67% of patients at study entry, class B in 12%, and class C in 1%.

Most of the study population had received regorafenib in the second line after treatment with sorafenib (Nexavar) or other lines of therapy, and most patients who received regorafenib had tolerated prior sorafenib therapy, whereas only 8% of patients who received sorafenib previously were sorafenib-intolerant.

Compared with that of the RESORCE study (NCT01774344), the median overall survival (OS) was longer in patients who received regorafenib in the second-line setting after sorafenib. However, there was a high proportion of censored patients in the interim analysis, the study investigators noted in their poster. A longer median OS was also observed among patients with Child-Pugh A liver disease who received regorafenib as a second- or later-line therapy after sorafenib compared with findings from the RESORCE study.

REFINE (NCT03289273) had a broader patient population compared with RESORCE, which reflects the less stringent inclusion criteria of the real-world study. More patients were included who had Child-Pugh B liver disease, and more patients had an ECOG performance status of ≥ 2, as well as more sorafenib-intolerant patients. However, the safety findings appeared consistent with that of the RESORCE trial, and no unexpected safety signals were observed in this study.

The primary end point of this study was to evaluate the safety of regorafenib, which was assessed in terms of incidence of treatment-emergent adverse events (TEAEs). Secondary end points include OS and progression-free survival (PFS).

Among the 500 patients who had enrolled to the study and were observed for at least 4 months, 498 received regorafenib treatment and were evaluable for the study. Child-Pugh class A liver disease was observed in the majority of patients (67%), while Child-Pugh class B occurred in 11% and class C disease in 1% of patients. The Child-Pugh score, however, was missing or not evaluable in 21% of patients. The majority of patients had an ECOG performance status of 0 (42%), while 40% had a status of 1 and 5% had a status of 2 through 4. The ECOG performance status was missing or not evaluable in 13%.

The majority of patients in the study had received prior systemic therapy (98%), and 97% had received prior sorafenib. Regorafenib was the second-line therapy for 81% of patients, while it was used in the third line or later in 17% of patients and as frontline therapy in 2%. Overall, 99% of the patients who received regorafenib in the second-line setting had received sorafenib previously.

The median OS was 14.8 months (95% CI, 12.9-18.4) among those who received regorafenib in the second line after prior sorafenib. The median OS was 13.2 among those receiving regorafenib in any line (95% CI, 11.4-16.3) and 13.9 months among those who received regorafenib in any line after sorafenib (95% CI, 11.4-16.3). The median OS was 8.3 months for those receiving regorafenib in the third or later line (95% CI, 6.7-12.3).

Investigators also evaluated the OS by Child-Pugh class and ALBI grade at study entry in the patients who had received sorafenib previously. The median OS was 16.0 months among the Child-Pugh class A group (95% CI, 13.1-18.8) versus 8.0 months among the Child-Pugh class B group (95% CI, 5.2-not evaluable [NE]). The median OS among those with ALBI grades 1, 2, and 3, respectively, were 19.6 months (95% CI, 14.8-19.6), 10.5 (95% CI, 8.7-16.0), and 3.1 months (95% CI, 1.6-8.7).

Regorafenib is an FDA-approved treatment for patients with HCC who have previously received sorafenib, and the oral multikinase inhibitor received its approval on the basis of the RESORSE study. The median OS in the RESORCE study was 10.6 months with regorafenib compared with 7.8 months with placebo (HR, 0.62; 95% CI, 0.50-0.78; P <.0001). The most common grade 3/4 TEAEs included hypertension, hand-foot skin reaction, increased blood bilirubin, and fatigue. To be included in the RESORCE study, patients had to have tolerated sorafenib and received their last dose of sorafenib within 10 weeks of randomization. Patients were enrolled to REFINE if they had unresectable HCC and had previously made the decision to move forward with regorafenib with their treating physician prior to enrollment to the study.

Reference

Merle P, Lim HY, Finn RS, et al. Sequential treatment with sorafenib followed by regorafenib in patients with unresectable hepatocellular carcinoma: interim analysis of the observational REFINE study. Presented at: 2020 ILCA Virtual Conference; September 11–13, 2020; Virtual. Abstract P-115.