Frontline Lenvatinib Shows Promising Results in Phase III HCC Trial

Lenvatinib was shown to be noninferior to standard therapy with sorafenib in the frontline treatment of patients with unresectable hepatocellular carcinoma.

Lenvatinib (Lenvima) was shown to be noninferior to standard therapy with sorafenib (Nexavar) in the frontline treatment of patients with unresectable hepatocellular carcinoma (HCC), according to Eisai, the developer of the multikinase inhibitor.

In a phase III trial, known as Study 304, overall survival (OS) outcomes with lenvatinib were noninferior to OS results with sorafenib, meeting the study’s primary endpoint. The findings also demonstrated statistically significant improvements with lenvatinib for secondary endpoints, including progression-free survival, time to progression, and objective response rate (ORR). Eisai reported that it intends to present the full data at an upcoming scientific meeting and will also discuss the findings with the FDA and global regulatory authorities.

“Although much progress has been made in cancer research, there remains a great need for more options in the treatment of unresectable hepatocellular carcinoma,” Alton Kremer, MD, PhD, chief clinical officer and chief medical officer, Oncology Business Group at Eisai, said in a statement. “The findings from this phase III trial represent an important development for previously untreated patients with unresectable hepatocellular carcinoma who unfortunately face a poor prognosis.”

The international, multicenter, open-label, noninferiority Study 304 randomized 954 patients with unresectable HCC to frontline treatment with lenvatinib at either 8 mg or 12 mg once per day based on body weight (n = 478) or sorafenib at 400 mg twice daily (n = 476). Patients received treatment until progression or unacceptable toxicity.

The most frequently reported all-grade adverse events in the lenvatinib group were hypertension, diarrhea, decreased appetite, weight loss, and fatigue. These toxicities are in line with previous side-effect results reported for lenvatinib.

Results from a phase II study of lenvatinib in patients with advanced HCC were published last year in theJournal of Gastroenterology. The study enrolled 46 patients between July 2010 and June 2011 at locations across Japan and Korea. Patients were not eligible for surgery or local therapy.

Lenvatinib was administered at 12 mg orally once daily in 28-day cycles. The primary endpoint was time to progression (TTP). Secondary endpoints included OS, ORR, and disease control rate.

The median TTP was 7.4 months (95% CI, 5.5-9.4). The ORR was 37%, comprising all partial responses (n = 17). Nineteen patients (41%) had stable disease and the disease control rate was 78%. The median OS was 18.7 months (95% CI, 12.7-25.1).

The most common all-grade adverse events (AEs) included hypertension (76 %), palmar-plantar erythrodysesthesia syndrome (65 %), decreased appetite (61%), and proteinuria (61%). Seventy-four percent of patients (n = 34) required dose reductions related to AEs and 22% of patients (n = 10) discontinued treatment due to AEs. Lower body weight was associated with a higher incidence of early (<30 days) dose withdrawal or reduction.

Lenvatinib is an oral, multitargeted receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFR. It is FDA-approved for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, as well as for use in combination with everolimus for patients with advanced renal cell carcinoma who were previously treated with an antiangiogenic therapy.


Ikeda K, Kudo M, Kawazoe S, et al. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma [published online October 4, 2016].J Gastroenterol. doi:10.1007/s00535-016-1263-4.