On August 16, 2018, lenvatinib (Lenvima) was approved for the first-line treatment of patients with unresectable hepatocellular carcinoma.^1,2

Supporting Efficacy Data

Approval was based on the findings of a phase III open-label noninferiority trial (REFLECT), in which 954 patients with previously untreated metastatic or unresectable hepatocellular carcinoma were randomly assigned to receive oral lenvatinib at 12 mg once daily for patients weighing ≥ 60 kg and 8 mg once daily for those weighing < 60 kg (n = 478) or oral sorafenib (Nexavar) at 400 mg twice daily (n = 476).^2,3 Treatment continued until radiologic disease progression or unacceptable toxicity. The primary endpoint was overall survival.

The median age of patients was 62 years (range = 20–88 years), 84% were male, 69% were Asian and 29% were white, 63% had an Eastern Cooperative Oncology Group performance status of 0, 69% weighed ≥ 60 kg, 70% had macroscopic portal vein invasion or extrahepatic disease spread or both, 79% had Child-Pugh A and Barcelona Clinic Liver Cancer (BCLC) stage C disease and 21% had Child-Pugh A and BCLC stage B disease, and 75% had radiographic evidence of cirrhosis. Among 590 patients with at least a single site of documented distant metastatic disease, 52% had lung metastasis, 45% had lymph node metastasis, and 16% had bone metastasis.

The median overall survival in the lenvatinib group was noninferior to but not superior to that in the sorafenib group (13.6 vs 12.3 months, hazard ratio [HR] = 0.92, 95% confidence interval = 0.79–1.06). The median progression-free survival was 7.3 months vs 3.6 months on modified Response Evaluation Criteria in Solid Tumors (RECIST) (HR = 0.64, P < .001) and 7.3 vs 3.6 months on RECIST v1.1 (HR = 0.65, 95% CI = 0.56–0.77). Objective response rates were 41% vs 12% on modified RECIST (P < .001) and 19% vs 7% on RECIST v1.1.

How It Works 

Lenvatinib is an inhibitor of the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). It also inhibits other kinases implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4; platelet-derived growth factor receptor alpha, KIT, and RET. Lenvatinib also exhibits antiproliferative activity in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with a concurrent inhibition of FGF-receptor substrate 2α phosphorylation. The combination of lenvatinib and everolimus (Afinitor) showed increased antiangiogenic and antitumor activity demonstrated by decreases in human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and by decreases in tumor volume in mouse xenograft models of human renal cell cancer that were greater than those with either drug alone.

How It Is Used

The recommended dose of lenvatinib in hepatocellular carcinoma is 12 mg once daily for patients weighing ≥ 60 kg and 8 mg once daily for patients weighing < 60 kg. Treatment should continue until disease progression or unacceptable toxicity.

Lenvatinib should be withheld for grade 3 hypertension, grade 3 cardiac dysfunction, grade 3 or 4 hepatotoxicity, grade 3 or 4 renal toxicity, proteinuria of 2 g or greater in 24 hours, QT prolongation, reversible posterior leukoencephalopathy syndrome, and persistent or intolerable grade 2 or 3 adverse reactions. Treatment can be resumed at a reduced dose upon resolution or recovery. Lenvatinib should be permanently discontinued for grade 4 hypertension, grade 4 cardiac dysfunction, any arterial thrombotic event, hepatic failure, nephrotic syndrome, gastrointestinal perforation, grade 3 or 4 fistula formation, and other grade 4 adverse reactions as well as for reversible posterior leukoencephalopathy syndrome, hepatotoxicity, renal toxicity, and cardiac dysfunction based on the severity and persistence of the adverse reactions.

Recommended dose reductions for adverse events in patients with hepatocellular carcinoma are stepwise to 8 mg once daily, 4 mg once daily, and 4 mg every other day in patients weighing ≥ 60 kg and to 4 mg once daily, 4 mg every other day, and treatment discontinuation in patients weighing < 60 kg.

Safety Profile

In the REFLECT trial, the most common adverse events of any grade in the lenvatinib group were hypertension (45% vs 31% in the sorafenib group), fatigue (44% vs 36%), diarrhea (39% vs 46%), decreased appetite (34% vs 27%), arthralgia/myalgia (31% vs 20%), decreased weight (31% vs 22%), and abdominal pain (30% vs 28%); others that occurred in more than 20% of patients were palmar-plantar erythrodysesthesia syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea. The most common grade 3 or 4 adverse events in the lenvatinib group included hypertension (24% vs 15%), decreased weight (8% vs 3%), fatigue (7% vs 6%), and proteinuria (6% vs 2%). The most common grade 3 or 4 laboratory abnormalities were increased gamma-glutamyltransferase (17% vs 20%), hyponatremia (15% vs 9%), and hyperbilirubinemia (13% vs 10%).

The most common serious adverse events in patients who received lenvatinib were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%). Adverse events led to dose reduction or interruption in 62%, with the most common causes being fatigue (9%), decreased appetite (8%), diarrhea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%). Adverse events led to treatment discontinuation in 20% of patients, with the most common causes being hepatic encephalopathy (2%), fatigue (1%), hyperbilirubinemia (1%), and hepatic failure (1%).

Lenvatinib carries warnings/precautions for hypertension, cardiac dysfunction; arterial thromboembolic events; hepatotoxicity; proteinuria; diarrhea, renal failure and impairment; gastrointestinal perforation and fistula formation; QT interval prolongation; hypocalcemia; reversible posterior leukoencephalopathy syndrome; hemorrhagic events; impairment of thyroid-stimulating hormone suppression/thyroid dysfunction; wound-healing complications; and embryofetal toxicity.

Patients treated with lenvatinib should be regularly monitored for blood pressure, clinical signs/symptoms of cardiac dysfunction, liver function, renal function, proteinuria, electrolyte imbalance, blood calcium levels, and thyroid function. Patients should be advised not to breastfeed when receiving lenvatinib. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves lenvatinib for unresectable hepatocellular carcinoma. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm617185.htm. Accessed November 26, 2018.

2. Lenvima (lenvatinib) capsules prescribing information. Eisai, Inc, August 2018. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206947s007lbl.pdf. Accessed November 26, 2018.

3. 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. Lancet 391:1163-1173, 2018.