FDA Extends Review Period for Lenvatinib in Hepatocellular Carcinoma

The review period for lenvatinib as a first-line treatment for patients with unresectable hepatocellular carcinoma has been extended by the FDA. According to Eisai and Merck, the companies codeveloping the drug, this will allow ample time to review the application. 

Masatoshi Kudo, MD

The review period for lenvatinib (Lenvima) as a first-line treatment for patients with unresectable hepatocellular carcinoma (HCC) has been extended by the FDA. According to Eisai and Merck, the companies codeveloping the drug, this will allow ample time to review the application.

The new action date for the supplemental new drug application (sNDA) has been set as August 24, 2018.

The sNDA submitted for lenvatinib was based on data from the phase III REFLECT trial published in theLancetin February 2018. In the trial, The multikinase inhibitor lenvatinib showed noninferiority to the frontline standard of care, sorafenib (Nexavar) in this trial. According to an investigator review, median overall survival (OS) with lenvatinib was 13.6 months versus 12.3 months for sorafenib (HR, 0.92; 95% CI, 0.79-1.06).

Adding to these results, by investigator review, lenvatinib was superior to sorafenib for progression-free survival (PFS) and time-to-progression (TTP). The median PFS was 7.4 versus 3.7 months for lenvatinib and sorafenib, respectively (HR, 0.66; 95% CI: 0.57-0.77;P<.0001). TTP was 8.9 months for lenvatinib compared with 3.7 months for sorafenib (HR, 0.63; 95% CI, 0.53-0.73;P<.0001).

Lead author Masatoshi Kudo, MD, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan, said the results represented the first positive OS results from a first-line phase III study for HCC in over a decade. “Based on our results, lenvatinib might be a potential new treatment option for advanced hepatocellular carcinoma," he added.

The REFLECT study randomized 954 patients with unresectable HCC to lenvatinib (n = 478) or sorafenib (n = 476). Lenvatinib was administered to patients 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 dose twice daily. Primary endpoint of the study was OS noninferiority.

Baseline characteristics were similar between the 2 groups, with a median age of approximately 62 years and a predominant ECOG performance status of 0 (63%). The most common Child-Pugh class was A (99%) and 79% of patients had BCLC stage C disease. Also, 20% of the patients had ≥3 sites of disease involvement, and half of the patients had underlying hepatitis B infection. The median baseline AFP level was 133.1 ng/mL and 71.2 ng/mL in the lenvatinib and sorafenib arms, respectively.

According to the investigator review, the objective response rate (ORR) was 24.1% with lenvatinib versus 9.2% with sorafenib (odds ratio [OR], 3.13; 95% CI, 2.15-4.56;P<.00001). The complete response (CR) rate was 1.3% in the lenvatinib group and 0.4% with sorafenib. Median duration of response was 5.7 months with lenvatinib and 3.7 months for sorafenib.

By masked independent imaging review, the median PFS was 7.3 versus 3.6 months for lenvatinib and sorafenib, respectively (HR, 0.64; 0.55-0.75;P<.0001). The median TTP in this review was 7.4 months with lenvatinib versus 3.7 months for sorafenib (HR, 0.60; 95% CI, 0.51-0.71;P<.0001).

The improvement in ORR was more dramatic in the independent assessment using modified RECIST criteria, at 40.6% with lenvatinib versus 12.4% for sorafenib (OR, 5.01; 95% CI, 3.59-7.01;P<.0001). The CR rate was 2.1% with lenvatinib compared with 0.8% for sorafenib in this analysis. By the RECIST v1.1 criteria, however, the independently reviewed ORR was 18.8% for lenvatinib versus 6.5% for sorafenib (OR, 3.34; 95% CI, 2.17-5.14;P<.0001).

Dose reductions due to treatment-emergent adverse events (TEAEs) were recorded in 37% of the patinets from the lenvatinib arm and 38% from the sorafenib group. Drug discontinuations due to TRAEs were needed for 9% and 7% of those in the lenvatinib and sorafenib groups, respectively.

Between lenvatinib and sorafenib, the most common all-grade TEAEs were palmar-plantar erythrodysesthesia (27% vs 52%, respectively), diarrhea (39% vs 46%), and hypertension (42% vs 30%). Grade ≥3 TEAEs were more common with lenvatinib versus sorafenib (57% vs 49%, respectively). There were more serious treatment-related TEAEs in the lenvatinib arm (18%) compared with sorafenib (10%).

The most common grade 3/4 TRAEs with lenvatinib and sorafenib, respectively, were hypertension (23% vs 14%), decreased weight (8% vs 3%), increased blood bilirubin (7% vs 5%), proteinuria (6% vs 2%), decreased platelet count (5% 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 is currently approved for treatment of 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.


Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial [published online February 9, 2018].Lancet. doi:10.1016/S0140-6736(18)30207-1.