SUMMARY: The FDA on August 16, 2018, approved LENVIMA® (Lenvatinib) for first-line treatment of patients with unresectable HepatoCellular Carcinoma (HCC). The American Cancer Society estimates that for 2018, about 42,220 new cases of primary liver cancer will be diagnosed in the US and 30,200 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. This increase has been attributed to the higher rate of Hepatitis C virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and type II diabetes have also likely contributed to the trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide.
NEXAVAR® (Sorafenib) was approved by the FDA in 2007 for the treatment of unresectable HepatoCellular Carcinoma (HCC) and is the only approved agent for the first line treatment of unresectable HCC. LENVIMA® is an oral multitargeted TKI which targets Vascular Endothelial Growth Factor Receptor (VEGFR) 1-3, Fibroblast Growth Factor Receptor (FGFR) 1-4, Rearranged during Transfection tyrosine kinase receptor (RET), c-KIT, and Platelet Derived Growth Factor Receptor (PDGFR). LENVIMA® differs from other TKIs with antiangiogenesis properties by its ability to inhibit FGFR-1, thereby blocking the mechanisms of resistance to VEGF/VEGFR inhibitors. In addition, it controls tumor cell growth by inhibiting RET, c-KIT, and PDGFR beta and influences tumor microenvironment by inhibiting FGFR and PDGFR beta. Based on the activity of LENVIMA® in unresectable HCC in a phase II trial, the efficacy of LENVIMA® was evaluated comparing this agent with NEXAVAR® in treatment naïve patients with unresectable HCC.
This present approval by the FDA was based on an international, multicenter, randomized, open-label, noninferiority trial (REFLECT study) in which 954 patients with previously untreated, metastatic or unresectable HCC were randomized in a 1:1 ratio to receive LENVIMA® 12 mg orally once daily for patients with a baseline body weight of 60 kg or more and 8 mg orally once daily for patients with a baseline body weight of less than 60 kg (N=478) or NEXAVAR® 400 mg orally twice daily (N=476). Treatment was continued until radiological disease progression or unacceptable toxicity. Patients had one or more measurable target lesions, Barcelona Clinic Liver Cancer (BCLC) Stage B or C, Child-Pugh Class A, ECOG PS of 1 or less, and no prior systemic therapy. Baseline characteristics were similar in both treatment groups. The median age was 62 years, the most common Child-Pugh class was A (99%) and 79% of patients had BCLC stage C disease. Twenty percent (20%) of patients had 3 or more sites of disease involvement, and 50% of patients had underlying Hepatitis B infection. The median baseline AFP level was 133 ng/mL in the LENVIMA® group and 71 ng/mL in the NEXAVAR® group. The Primary endpoint of this study was noninferiority for Overall Survival (OS). Secondary efficacy endpoints included Progression Free Survival (PFS), Time to Progression (TTP) and Objective Response Rate (ORR).
In this study, LENVIMA® was noninferior, but not statistically superior to NEXAVAR® for Overall Survival (HR=0.92). The median OS in the LENVIMA® arm was 13.6 months and 12.3 months in the NEXAVAR® arm. There was however a statistically significant improvement in Progression Free Survival with LENVIMA® when compared to NEXAVAR®, with a median PFS of 7.3 months in the LENVIMA® group 3.6 months in the NEXAVAR® arm (HR=0.64; P<0.0001). The Objective Response Rate was higher for the LENVIMA® group as compared to NEXAVAR® group – 40.6% versus 12.4% per modified RECIST assessment (P<0.0001). The median TTP in this review was 8.9 months with LENVIMA® versus 3.7 months for NEXAVAR® (HR=0.60; P<0.0001). More patients in the LENVIMA® group experienced hypertension, decreased weight, proteinuria and decreased platelet count, whereas Palmar Plantar Erythrodysesthesia and diarrhea were more common in the NEXAVAR® group.
It was concluded that LENVIMA® is noninferior to NEXAVAR® in OS, and achieves statistically significant and clinically meaningful improvements in PFS, TTP, and ORR as first line therapy, for patients with HepatoCellular Carcinoma. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Kudo M, Finn RS, Qin S, et al. The Lancet 2018;391:1163-1173
