In updated phase III results, lenvatinib continued to be noninferior in overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, and achieved significant improvements in progression-free survival, time to progression, and objective response rate compared with sorafenib.
Richard S. Finn, MD
In updated phase III results, lenvatinib (Lenvima) continued to be noninferior in overall survival (OS) compared with sorafenib (Nexavar) for patients with unresectable hepatocellular carcinoma (HCC), and achieved significant improvements in progression-free survival (PFS), time to progression, and objective response rate (ORR) compared with sorafenib.
In the randomized, open-label, noninferiority study, 954 patients were enrolled to receive lenvatinib (n = 478) or sorafenib (n = 476) at 400 mg twice daily. The patients in this study had greater than 1 target lesion, Barcelona Clinic Liver Cancer stage B or C, Child-Pugh class A, an ECOG performance score of 0 or 1, and no prior systemic therapy.
The primary endpoint of this study was noninferiority, with secondary efficacy endpoints including PFS, time to progression, and ORR.
The median OS with lenvatinib compared with sorafenib was 13.6 months and 12.3 months, respectively (HR, 0.92; 95%; CI, 0.79-1.06). The hazard ratio was estimated with a stratified Cox proportional hazard model. The median PFS was 7.4 months with lenvatinib compared with 3.7 months for sorafenib (HR, 0.66; 95%; CI, 0.57-0.77;P< .00001). The median treatment duration for lenvatinib was 5.7 months versus 3.7 months for sorafenib. The ORR was 24.1% with lenvatinib versus 9.2% with sorafenib (odds ratio, 3.13%; 95% CI, 2.15-4.56;P<.00001) .
“The positive data with lenvatinib being noninferior to sorafenib is now being disseminated but we’re still waiting for regulatory approval,” states study investigator Richard Finn, MD, an associate professor of medicine at the David Geffen School of Medicine of UCLA. “Lenvatinib met its primary endpoint and the side effect profile is manageable. We anticipate the drug being approved globally, providing a new option for patients.”
A similar number of patients on both arms of this study saw treatment-emergent adverse events (AEs). The most common AEs experienced on the lenvatinib arm include hypertension (42%), diarrhea (39%), decreased appetite (34%), decreased weight (31%), and fatigue (30%). Drug discontinuations due to AEs were needed in 13% and 9% of the lenvatinib arm and sorafenib arm, respectively.
Sorafenib is currently the only approved agent for unresectable HCC in the first-line setting, leading to the increasing interest for the use of lenvatinib as another option for patients.
“Many of us are interested in trying to further differentiate the 2 compounds to identify the patients who might do better with one [drug] or the other. That will be based on further analyses of the clinical data and subgroups, as well as the ongoing effort in biomarkers to help identify a potential subgroup of patients who might benefit from receiving 1 regimen over the other,” Finn explained.
Future analyses of the data will help to better understand the remaining questions with this research, such as how to sequence these agents and the best way to integrate new biologic agents.
“After 10 years, we have not had a new option for patients with liver cancer in the frontline setting,” Finn added. “Now challenges for us will be how to integrate this into our management guidelines, especially in the context of the data earlier this year with regorafenib (Stivarga), a second-line treatment after sorafenib, and the evolving data with PD-1 inhibitors.”
The treatment landscape for patients with HCC has undergone several changes recently starting with the April 2017 FDA approval of the multikinase inhibitor regorafenib in the second-line setting following sorafenib. Similarly, the PD-1 inhibitor, nivolumab (Opdivo), has shown promise in a phase II study; the agent was granted a priority review designation by the FDA in May 2017.
Lenvatinib has been approved as a treatment for patients with recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer and following VEGF therapy in combination with everolimus (Afinitor) for patients with renal cell carcinoma (RCC).
Cheng A-L, Finn RS, Qin S, et al. Phase III trial of lenvatinib (LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC).J Clin Oncol. 2017;35 (suppl; abstr 4001).