FDA Accepts Supplemental NDA for Lenvatinib as Liver Cancer Treatment

Eisai announced the U.S. Food and Drug Administration (FDA) accepted for review a supplemental New Drug Application (sNDA) for lenvatinib (marketed as Lenvima) for the potential use in the first-line treatment of patients with hepatocellular carcinoma (HCC), commonly referred to as liver cancer.

"Patients with advanced liver cancer face a debilitating, life-threatening disease and additional treatment options are needed for these patients," said Kenichi Nomoto, PhD, Chief Scientific Officer, Oncology Business Group, Eisai. "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 3 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."

The sNDA submission is based on the positive results of the pivotal Phase 3 REFLECT trial. In this study, lenvatinib demonstrated a treatment effect on OS by statistical confirmation of non-inferiority to sorafenib.  This is the first positive Phase 3 study of a systemic treatment in comparison to sorafenib in this patient population. Additionally, patients experienced statistically significant and clinically meaningful improvements in the secondary efficacy endpoints of progression-free survival (PFS), time to progression (TTP) and objective response rate (ORR).

This release discusses an investigational use for an FDA-approved product. It is not intended to convey conclusions about safety or efficacy. There is no guarantee that any investigational uses of such FDA-approved product will gain FDA approval.

REFLECT was an international, multicenter, open-label, randomized, non-inferiority Phase 3 study to compare the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment in patients with unresectable HCC. Patients (n=954) at 183 trial sites in 21 countries were randomized to receive lenvatinib 12 mg or 8 mg once a day depending on body weight (≥60 kg or <60 kg) (n=478) or sorafenib 400 mg twice a day (n=476). Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint of this study was OS. The secondary efficacy endpoints of this study were PFS, TTP and ORR.

The median OS for patients treated with lenvatinib was 13.6 months compared to 12.3 months for sorafenib (HR: 0.92; 95% CI: 0.79 – 1.06). Median PFS was 7.4 months with lenvatinib with a median TTP of 8.9 months compared to median PFS of 3.7 months (HR: 0.66; 95% CI: 0.57 – 0.77; p<0.00001) and median TTP of 3.7 months on sorafenib (HR 0.63; 95% CI; 0.53 – 0.73; p<0.00001). In addition, lenvatinib demonstrated significantly higher ORR (24%) compared to sorafenib (9%) (odds ratio: 3.13; 95% CI: 2.15-4.56; p<0.00001). Endpoints were evaluated using mRECIST and determined by investigator assessment. Independent radiologic review is now complete.

In this study, the most common treatment-emergent adverse events (TEAEs) observed in the lenvatinib arm were hypertension, diarrhea, decreased appetite, decreased weight, and fatigue. In the sorafenib arm, the most common TEAEs were palmar-plantar erythrodysesthesia, diarrhea, hypertension, and decreased appetite. Patients who received lenvatinib had fewer instances of palmar-plantar erythrodysesthesia, diarrhea and alopecia, and more instances of hypertension, proteinuria, dysphonia, and hypothyroidism, than did patients who received sorafenib. Nine percent of patients treated with lenvatinib and 7% of patients treated with sorafenib discontinued treatment due to treatment-related adverse events. Forty-three percent of patients treated with lenvatinib and 30% of patients who received sorafenib experienced serious TEAEs.

Hepatocellular carcinoma is the most common type of liver cancer, accounting for about 90% of cases of primary liver cancer in the United States. In 2015, liver cancer accounted for approximately 788,000 deaths globally, making it the second leading cause of cancer-related deaths worldwide. The prevalence and mortality rate of liver cancer has been rising steadily over the past decade. This year, more than 40,710 Americans will be diagnosed and 28,920 will die from their disease. HCC patients with advanced stage disease may not be amenable for potentially curative therapeutic interventions such as a liver transplant, surgical resection or tumor ablation (typically radiofrequency ablation). Patients who cannot be treated with potentially curative approaches have a poor prognosis.