Lenvatinib combined with dacarbazine versus dacarbazine alone as first-line treatment in patients with stage IV melanoma

Michele Maio, Jessica Cecile Hassel, Michele Del Vecchio, Alessandro Testori, Paolo Antonio Ascierto, Ernie Marshall, Hiliary Glen, Paul Lorigan, Elaine Meek, Song Liou, Jeff Paul Hodge, Fabrina Bologna, Harish P. Dave

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    Background: Lenvatinib (E7080; LEN) is an oral, receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ . In a phase I study qd dosing of >/= 20mg LEN demonstrated PRs and prolonged SD in patients (pts) with advanced melanoma. Dacarbazine (DTIC) upregulates the proangiogenic factor VEGF and has been shown to confer resistance in melanoma cell lines (Lev, JCO 2004; 22:2092-2100). Treatment of melanoma pts with LEN + DTIC may potentiate the therapeutic effects of DTIC. Methods: This was a phase II study in pts with metastatic melanoma randomized 1:1 to receive LEN (20 mg QD) + DTIC (1000 mg/m2 Q 21 d) or DTIC (1000 mg/m2Q 21 d). Pts were stratified by LDH level and stage IV subclass. Eligible pts were ECOG PS 0/1 and had no prior systemic therapies. BRAF status was determined from circulating tumor DNA. The primary endpoint was PFS by independent assessment. Results: In a modified ITT analysis,a total of 78 of 81 pts were evaluable for efficacy; 59% were male, 59% were Stage IV M1c, 22% had elevated LDH, 29% had prior adjuvant therapy and 49% BRAF wild-type (wt). Most common AEs in the LEN + DTIC arm were hypertension (48%), nausea (38%), constipation (33%), and diarrhea (31%). Most common Grade 3/4 AEs in LEN + DTIC were hypertension (26%) and neutropenia (10%). There were no deaths due to an AE. Median PFS increased in LEN + DTIC compared to DTIC alone (see Table). An improvement in median PFS was observed in BRAFwt pts on the combination. Conclusions: A 2.7-fold increase in the median PFS was observed in pts administered LEN + DTIC compared to single agent DTIC. A 2.5 fold increase in the median PFS was observed in the combination arm in pts with BRAFwt melanoma. The AE profile observed with the LEN + DTIC was consistent with observed LEN monotherapy studies. These data suggest further evaluation of LEN + DTIC in BRAFwt melanoma is warranted. Clinical trial information: NCT01133977.
    Original languageUndefined
    JournalJournal of Clinical Oncology
    Issue number15
    Publication statusPublished - 2013


    • Melanoma
    • skin cancers

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