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Assessment of clinical activity of E7080, a multitargeted kinase inhibitor, in patients with advanced melanoma treated in two phase I trials.

8527 Background: E7080 is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In phase I studies of E7080, DLTs were hypertension and proteinuria and common toxicities included grade 1-2 fatigue, anorexia, nausea, weight loss and diarrhea. MTD for E7080 once daily (QD) is 25 mg and for twice daily (BID) is 20 mg (i.e.10 mg BID).


METHODS
From 7/2005 to 10/2008, 82 patients (pts) with advanced solid tumors including 14 with advanced melanoma were enrolled into a phase I study of escalating doses of E7080 QD. From 7/2005 to 8/2009, 77 pts with advanced solid tumors including 29 with advanced melanoma were enrolled into a second phase I study of escalating doses of E7080 BID. 25/29 pts receiving E7080 BID underwent pretreatment biopsy for molecular analysis of tumor vascular and melanoma cell components. Those results are reported separately. Clinical outcomes for melanoma pts treated with E7080 in phase I trials are reported.


RESULTS
35/43 pts received E7080 doses of ≥ 20 mg/day. 5/14 pts receiving E7080 QD had tumor reductions of 20% to 85%, including 2 confirmed PRs. Median progression free survival (PFS) was 7 months. 6 mo PFS was 58%. 7/29 pts receiving E7080 BID, had tumor reductions of 20% to 85% including 3 confirmed PRs. Median PFS for this group was 3.6 months, 6 mo PFS was 25%. For all pts treated in both trials median PFS was 4 mo (95% CI: 3.4-7.1). 6 mo PFS was 35%. Median duration of PR was 15 mo (range: 5-23 mo).


CONCLUSIONS
E7080 administered to pts with advanced melanoma in two phase I studies achieved PRs and prolonged tumor regression in a subset of patients. Pts receiving QD doses of E7080 ≥20 mg/day appear to have longer PFS compared to pts receiving QD E7080 doses <20 mg/day. A phase II trial is currently ongoing to determine the magnitude of the treatment effect in molecularly defined populations and to identify the molecular features of E7080 responsive melanomas.