FDA Delays Decision on Lenvatinib for HCC

Masatoshi Kudo, MD

The FDA has extended the review period for lenvatinib (Lenvima) as a first-line treatment for patients with unresectable hepatocellular carcinoma (HCC), to allow ample time to review the application, according to Eisai and Merck, the companies codeveloping the drug. The new action date for the supplemental new drug application (sNDA) is August 24, 2018.

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

The sNDA submitted for lenvatinib was based on data from the phase III REFLECT trial, which were published in February 2018 in the Lancet. In the trial, the multikinase inhibitor lenvatinib showed noninferiority to the established first-line standard of care, sorafenib (Nexavar). The median overall survival (OS) by investigator review with lenvatinib was 13.6 months compared with 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).

When the findings were published in the Lancet, first 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 in nearly a decade from a frontline global phase III study for patients with HCC. “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 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 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. Twenty percent 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 objective response rate (ORR) by investigator review 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. The 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 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.

The most common all-grade TEAEs between lenvatinib and sorafenib 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%).

In addition to the pending HCC indication, 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.

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.