FDA Accepts Lenvatinib Application for Advanced HCC

Kenichi Nomoto, PhD

The FDA has accepted a supplemental new drug application for lenvatinib (Lenvima) as a frontline systemic treatment for patients with advanced hepatocellular carcinoma (HCC), according to a statement from the company developing the therapy, Eisai. Under a standard review, the FDA will render a decision within 10 months.

UPDATE 8/16/2018: FDA Approves Lenvatinib for Frontline HCC >>>

The application for lenvatinib was based on findings from the phase III REFLECT trial, in which overall survival (OS) was noninferior for lenvatinib versus sorafenib. Median OS with lenvatinib was 13.6 versus 12.3 months for sorafenib (HR, 0.92; 95% CI, 0.79-1.06). Lenvatinib was also associated with improvements in progression-free survival (PFS), time to progression (TTP) and objective response rate (ORR) compared with sorafenib.

"Patients with advanced liver cancer face a debilitating, life-threatening disease and additional treatment options are needed for these patients," Kenichi Nomoto, PhD, chief scientific officer, Oncology Business Group, Eisai, said in a statement. "Given the importance of the REFLECT study results, in which lenvatinib was the first first-line systemic therapy to demonstrate positive results when compared to sorafenib in a phase III trial in patients with HCC in more than a decade, we will work closely with the FDA in hopes of bringing a new treatment option to patients living with advanced liver cancer."

In the REFLECT study, 954 patients with unresectable HCC were randomized to lenvatinib (n = 478) or sorafenib (n = 476). Lenvatinib was given at 8 mg per day for those weighing <60 kg and at 12 mg per day for those weighing ≥60 kg. Sorafenib was given at a 400 mg twice daily dose. The primary endpoint of the study was OS noninferiority.

Baseline characteristics were similar between the groups, with a median age of approximately 61 years and a predominant ECOG performance status of 0 (64%). The most common Child-Pugh class was A (99%) and approximately 80% of patients had BCLC stage C disease. Nearly a fifth of patients had ≥3 sites of disease involvement, and half of patients had underlying hepatitis B infection. The median baseline AFP level was 133.1 ng/mL in the lenvatinib arm and 71.2 ng/mL in the sorafenib group.

The median PFS with lenvatinib was 7.4 versus 3.7 months with sorafenib (HR, 0.66; 95% CI, 0.57-0.77; P <.00001). The median TTP was 8.9 months with lenvatinib and 3.7 months with sorafenib (HR, 0.63; 95% CI, 0.53-0.73; P <.00001). 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 CR rate was 1.3% in the lenvatinib group and 0.4% with sorafenib.

The median duration of treatment with lenvatinib was 5.7 versus 3.7 months with sorafenib. Dose reductions due to treatment-emergent adverse events (TEAEs) were required for 37% of those in the lenvatinib arm and for 38% of those in the sorafenib group. Drug discontinuations due to TRAEs were needed for 9% and 7% of those in the lenvatinib and sorafenib groups, respectively.

Grade ≥3 TEAEs were more common with lenvatinib versus sorafenib (57% vs 49%, respectively). The most common grade 3/4 TRAEs with lenvatinib and sorafenib, respectively, were hypertension (23% vs 14%), decreased weight (8% vs 3%), decreased platelet count (6% vs 3%), elevated aspartate aminotransferase (5% vs 8%), decreased appetite (5% vs 1%), diarrhea (4% vs 4%), and palmar-plantar erythrodysesthesia (3% vs 11%).

“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,” study investigator Richard Finn, MD, an associate professor of medicine at the David Geffen School of Medicine of UCLA, told OncLive. “Now, the challenge for us will be how to integrate this into our management guidelines, especially in the context of the data earlier this year with regorafenib, 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 in the past year, starting with the approval of the multikinase inhibitor regorafenib in the second-line setting following sorafenib. Similarly, the PD-1 inhibitor nivolumab (Opdivo) was approved as a second-line therapy on September 22, based on findings from the phase I/II CheckMate 040 study.

Lenvatinib is currently 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 for patients with advanced renal cell carcinoma.

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).