Roy Baynes, MD, PhD
Japan’s Pharmaceuticals and Medical Devices Agency has approved lenvatinib mesylate (Lenvima) for the frontline treatment of patients with unresectable hepatocellular carcinoma (HCC).
The approval was based on data from the phase III REFLECT trial, in which overall survival (OS) was noninferior for lenvatinib versus sorafenib (Nexavar). 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.
In a press release, Merck (MSD) and Eisai, the developers of lenvatinib, noted that this is the first approval worldwide for the multiple receptor tyrosine kinase inhibitor in this indication and the first new systemic therapy to be approved in Japan for frontline HCC in a decade.
“Today’s approval is an important first for Lenvima and a significant first regulatory event under our collaboration with Eisai,” Roy Baynes, MD, PhD, senior vice president, head of clinical development, and chief medical officer, Merck Research Laboratories, said in a statement. “We congratulate Eisai on the approval of this new indication and look forward to working together to bring this important treatment option to patients.”
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 complete response 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%).
Merck and Eisai announced in September 2017 that the US FDA had accepted a supplemental new drug application for frontline lenvatinib in HCC.
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).