Lenvatinib HCC Data Published as FDA Considers Approval


Lenvatinib (Lenvima) was noninferior for overall survival while improving progression-free survival compared with sorafenib (Nexavar) for the frontline treatment of patients with unresectable hepatocellular carcinoma.

Masatoshi Kudo, MD

Lenvatinib (Lenvima) was noninferior for overall survival (OS) while improving progression-free survival (PFS) compared with sorafenib (Nexavar) for the frontline treatment of patients with unresectable hepatocellular carcinoma (HCC), according to findings from the phase III REFLECT trial now published online in the Lancet.1

Based on these pivotal findings, the FDA is considering an application for lenvatinib in the first-line HCC setting. In the phase III multicenter, open-label, randomized, global, REFLECT trial, median OS results for lenvatinib were noninferior compared with sorafenib (13.6 vs 12.3 months; HR, 0.92; 95% CI, 0.79-1.06). Lenvatinib was superior for median PFS (7.4 vs 3.7 months; HR, 0.66; 95% CI: 0.57-0.77; P <.0001) and median time-to-progression (TTP; 8.9 vs 3.7 months; HR, 0.63; 95% CI, 0.53-0.73; P <.0001).

“To our knowledge, our study is the first global phase III trial in 10 years to show a treatment effect on overall survival [in this setting], and the first ever positive trial against an active control,” first author Masatoshi Kudo, MD, Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan, and coinvestigators wrote. “Based on our results, lenvatinib might be a potential new treatment option for advanced hepatocellular carcinoma.”

REFLECT randomized 954 patients at 154 trial sites in 20 countries enrolled from March 2013 through July 2015. Investigators randomly assigned patients to 12 mg of lenvatinib once daily for those weighing ≥60 kg or 8 mg once daily for those weighing <60 kg (n = 478), or 400 mg of twice-daily sorafenib (n = 476). Treatment was continued until disease progression or unacceptable toxicity. OS was the primary endpoint. Secondary efficacy endpoints were PFS, TTP, and overall response rate (ORR).

Baseline characteristics were similar between the groups, with a median age of 62 years (range, 20-88) 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.

Beyond PFS, lenvatinib also demonstrated a significantly higher ORR (24.1% vs 9.2%; odds ratio, 3.13; 95% CI, 2.15-4.56; P <.0001). 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.

The most common any-grade AEs associated with lenvatinib were hypertension (42%), diarrhea (39%), decreased appetite (34%), and decreased weight (31%). Palmar-plantar erythrodysaesthesia (52%) was the most common AE associated with sorafenib, followed by diarrhea (46%), hypertension (30%), and decreased appetite (27%).

Grade ≥3 TEAEs were more common with lenvatinib versus sorafenib (75% vs 67%). 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 (5% vs 3%), elevated AST levels (5% vs 8%), decreased appetite (5% vs 1%), diarrhea (4% vs 4%), and palmar-plantar erythrodysesthesia (3% vs 11%).

Writing in an accompanying editorial, María Reig, PhD, and Jordi Bruix, MD, both with the Barcelona Clinic Liver Cancer Group, noted that these data clearly shows that lenvatinib treatment is equal to sorafenib. However, it is not clear that this result will affect clinical practice.2

“Sorafenib has been available for the past 10 years, and many physicians have acquired the needed experience to properly prescribe and follow up patients so that adverse events are detected early and adequately managed,” they wrote. “Additionally, patients who tolerate sorafenib and present with progression now have regorafenib as an effective second-line option, whereas there are no data about any effective option beyond lenvatinib.

“Real-life experience and further data will inform us about the effect of lenvatinib in the treatment landscape. Although it is great to have a new drug in the repertoire, only time will tell if lenvatinib has changed real-life systemic treatment for hepatocellular carcinoma patients.”


  1. 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.
  2. Reig M, Bruix J. Lenvatinib: can a non-inferiority trial change clinical practice? [published online February 9, 2018]. Lancet. doi: 10.1016/S0140-6736(18)30208-3.
Related Videos
Pamela L. Kunz, MD, associate professor, internal medicine (medical oncology), Yale School of Medicine; director, Center for Gastrointestinal (GI) Cancers, chief, GI Medical Oncology, Smilow Cancer Hospital, Yale Cancer Center
Suneel Kamath, MD
Suneel Kamath, MD
Jennifer R. Eads, MD, physician lead, GI Cancer Research, director, National Clinical Trials Network, Abramson Cancer Center, University of Pennsylvania, associate professor, clinical medicine (hematology-oncology), Penn Medicine, Perelman Center for Advanced Medicine
Olivia Aranha, MD, PhD
Michael Iglesia, MD, PhD
Petros Grivas, MD, PhD; and Chandler Park, MD, MSc, FACP
Arndt Vogel, MD
Daniel M. Halperin, MD, associate professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center
Haeseong Park, MD, MPH