Lenvatinib for Advanced BRAF Wild-Type Melanoma

Chicago—At a minimum of 15 months follow-up, patients with unresectable, metastatic BRAF wild-type melanoma who received 24 mg of lenvatinib once daily had a median progression-free survival of 3.7 months and a median overall survival of 9.5 months, according to a phase 2 trial. The investigational agent was also associated with a manageable safety profile, according to the trial’s authors.

Results were presented at the ASCO meeting during a poster session. The poster was titled A Phase 2 Study of the Multitargeted Kinase Inhibitor Lenvatinib in Patients with Advanced BRAF Wild-Type Melanoma.

Lenvatinib is an oral multitargeted tyrosine kinase inhibitor being tested in several cancers, including melanoma. The authors noted that melanoma is the most frequently fatal skin malignancy and that it is expected to be associated with approximately 9480 deaths in the United States this year. They added that although BRAF V600E mutations are found in approximately half of cutaneous melanomas, the FDA has not approved any targeted therapies to treat BRAF wild-type melanoma. In addition, despite the fact that BRAF inhibitors are associated with a significant clinical and survival benefit, the authors said that nearly all of the patients eventually develop resistance to the drugs and experience disease progression.

In this study, the authors included patients with unresectable stage III or IV melanoma whose disease progressed after taking up to 2 systemic anticancer treatment regimens. Patients also had not received prior BRAF-targeted therapy, had an Eastern Cooperative Oncology Group performance status score of 0 or 1, had adequately controlled blood pressure, and had adequate renal, hepatic, bone marrow, and blood coagulation functions.

Exclusion criteria included melanoma of intraocular origin, leptomeningeal metastases or brain metastases, significant cardiovascular impairment, prolonged QTc interval, and bleeding or thrombotic disorders requiring anticoagulant therapy.

The 93 patients each received 24 mg of lenvatinib once daily during 28-day cycles until they had disease progression, unacceptable toxicity, or withdrew consent. Median age was 64 years, 69% of patients were male, and 95% of patients had stage IV disease based on American Joint Committee on Cancer staging criteria. At baseline, median time since first diagnosis of melanoma was 10.3 months and median time from last disease progression was 6.0 months.

Of the patients, 97.8% had treatment-related, treatment-emergent adverse events, with 64.5% experiencing grade 3 or 4 events. The most common events were hypertension (59.1% of patients), fatigue (58.1%), nausea (44.1%), decreased appetite (37.6%), vomiting (29.0%), dysphonia (26.9%), headache (25.8%), and proteinuria (25.8%). In addition, 45.2% of patients had an adverse event leading to dose reduction, 47.3% had an adverse event leading to dose interruption, and 17.2% had an adverse event leading to withdrawal of the study drug.

Further, the objective response rate was 8.6%, the median duration of response was 9.1 months, and 23.7% of patients achieved durable stable disease.

The authors also noted that previous studies had found that serum angiopoietin-2 (Ang-2) levels were a biomarker for melanoma progression and metastasis and correlated with tumor load and overall survival. In this study, they found that patients with low Ang-2 levels at baseline had significantly longer progression-free survival and significantly longer overall survival compared with patients who had high Ang-2 levels at baseline.

Eisai Inc. provided funding for the study.