Elsevier

The Lancet

Volume 391, Issue 10126, 24–30 March 2018, Pages 1163-1173
The Lancet

Articles
Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial

https://doi.org/10.1016/S0140-6736(18)30207-1Get rights and content

Summary

Background

In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1–3, FGF receptors 1–4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma.

Methods

This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice–web response system—with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors—to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266.

Findings

Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1–14·9) was non-inferior to sorafenib (12·3 months, 10·4–13·9; hazard ratio 0·92, 95% CI 0·79–1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib.

Interpretation

Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed.

Funding

Eisai Inc.

Introduction

Hepatocellular carcinoma is the most common type of liver cancer, which is the third leading cause of cancer deaths worldwide, causing nearly 745 000 deaths each year.1 The disease usually occurs in people with chronic liver disease, particularly cirrhosis, which limits the feasibility of surgical resection.2, 3 Sorafenib, an oral multikinase inhibitor, is the only systemic therapy proven to extend overall survival when used as a first-line treatment, showing a median improvement of 2·8 months compared with placebo (10·7 months vs 7·9 months; hazard ratio [HR] 0·69; p<0·001), despite a low response rate of 2%.4 In patients from the Asia-Pacific region taking sorafenib, the median improvement in overall survival compared with placebo was 2·3 months (6·5 months vs 4·2 months; HR 0·68; p=0·014).5

Drug development for hepatocellular carcinoma in the past 10 years has been marked by four failed global phase 3 trials (of sunitinib, brivanib, linifanib, and erlotinib plus sorafenib) that did not show non-inferiority6, 7, 8 or superiority9 to sorafenib in terms of overall survival in first-line treatment of hepatocellular carcinoma. No approved first-line systemic treatments are available for advanced unresectable hepatocellular carcinoma other than sorafenib. Only regorafenib and nivolumab are approved as second-line systemic treatments for patients who do not respond to sorafenib.10 Otherwise, best supportive care or participation in clinical trials is recommended in the second-line setting by treatment guidelines.11 Therefore, because of the paucity of systemic treatment options for patients with advanced hepatocellular carcinoma, a need exists to develop new drugs for effective management of this disease.

Lenvatinib is an oral multikinase inhibitor that targets VEGF receptors 1–3, FGF receptors 1–4, PDGF receptor α, RET, and KIT.12, 13, 14, 15 Lenvatinib monotherapy is approved for treatment of radioiodine-refractory differentiated thyroid cancer.16 Lenvatinib and everolimus are approved as a combined treatment for advanced renal cell carcinoma following one previous antiangiogenic therapy.17 In a phase 2 study of patients with advanced hepatocellular carcinoma, 12 mg lenvatinib once-daily showed clinical activity and had an acceptable safety profile.18 Based on dose adjustments depending on bodyweight and pharmacokinetic modelling data,19 a starting dose of lenvatinib was adopted (12 mg for patients ≥60 kg and 8 mg for patients <60 kg once-daily) for further clinical development in hepatocellular carcinoma. Given the efficacy signal observed in this phase 2 study,18 we did a phase 3 randomised, open-label, non-inferiority study to compare the efficacy and safety of lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma.

Research in context

Evidence before this study

We searched PubMed from inception up to March 16, 2017 using the search terms “phase 3” [Title/Abstract] OR “phase III” [Title/Abstract] AND “hepatocellular carcinoma” [MeSH Terms]. The search was restricted to clinical trials in English language only and yielded 65 reports. Of these publications, 21 described the use of targeted drugs for treatment of hepatocellular carcinoma, 11 were studies of single-drug sorafenib treatment, and three were studies of sorafenib in combination with another drug. Five trials investigated targeted agents following treatment with sorafenib and four trials investigated first-line treatment of hepatocellular carcinoma with sorafenib as the comparator. None of these four trials met their primary endpoints of non-inferiority or superiority over sorafenib in terms of overall survival.

Added value of this study

To our knowledge, this is the first global phase 3 trial in 10 years to meet its primary endpoint of non-inferiority in terms of overall survival against sorafenib as a first-line treatment for hepatocellular carcinoma. Furthermore, lenvatinib showed statistically significant and clinically meaningful improvement in terms of all secondary endpoints (progression-free survival, time to progression, and objective response rate) with a reasonable safety profile.

Implications of all the available evidence

The results of this study support lenvatinib as a first-line treatment option for patients with unresectable hepatocellular carcinoma.

Section snippets

Study design and participants

This multicentre, phase 3, randomised, open-label, non-inferiority study was done at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions (China, Hong Kong, Japan, South Korea, Malaysia, Philippines, Singapore, Taiwan, Thailand, Belgium, Canada, France, Germany, Israel, Italy, Poland, Russia, Spain, UK, and USA).

Eligible patients had unresectable hepatocellular carcinoma, with diagnoses confirmed histologically or cytologically, or confirmed clinically in

Results

Between March 1, 2013, and July 30, 2015, 1492 patients were recruited. 954 eligible patients from 20 countries were randomly assigned to receive lenvatinib (n=478) or sorafenib (n=476, figure 1).

Patient baseline characteristics were similar between treatment groups, except for baseline hepatitis C aetiology and α-fetoprotein concentrations (table 1). At the time of data cutoff (Nov 13, 2016, at 701 deaths), the median duration of follow-up was 27·7 months (IQR 23·3–32·8) in the lenvatinib

Discussion

To our knowledge, our study is the first global phase 3 trial in 10 years to show a treatment effect on overall survival, and the first ever positive trial against an active control. Our study showed lenvatinib to be non-inferior to sorafenib—the current standard of care in hepatocellular carcinoma—for overall survival. Lenvatinib showed statistically significant clinically meaningful improvement for all secondary efficacy endpoints (progression-free survival, time to progression, and objective

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