Phase I dose-escalation study of the multikinase inhibitor lenvatinib in patients with advanced solid tumors and in an expanded cohort of patients with melanoma
Mené sur 77 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la toxicité et l'activité antitumorale du lenvatinib
Purpose: This "3+3" phase I study evaluated the safety, biologic, and clinical activity of lenvatinib, an oral multikinase inhibitor, in patients with solid tumors. Experimental Design: Ascending doses of lenvatinib were administered po bid in 28-day cycles. Safety and response were assessed for all patients. Angiogenic and apoptotic factors were tested as possible biomarkers in an expanded melanoma cohort. Results: Seventy-seven patients were treated in 3 cohorts: 18 with intermittent bid dosing (7 days on, 7 days off) of 0.1-3.2 mg; 33 with bid dosing of 3.2-12 mg; and 26 with bid dosing of 10 mg (expanded melanoma cohort). Maximum tolerated dose was established at 10 mg po bid. Prominent drug-related toxicities included hypertension (43%), fatigue (42%), proteinuria (39%), and nausea (25%); dose-limiting toxicities included hypertension, fatigue, and proteinuria. Twelve patients (15.6%) achieved partial response (PR, n=9) or unconfirmed PR (uPR, n=3), and 19 (24.7%) achieved stable disease (SD) ≥23 weeks. Total PR/uPR/SD≥23 weeks was 40.3% (n=31). Responses (PR/uPR) by disease were: melanoma, 5/29 patients (includes 1 patient with NRAS mutation); thyroid, 3/6; pancreatic, 1/2; lung, 1/1; renal, 1/1; endometrial, 1/4; and ovarian, 1/5. AUC0-24 and Cmax increased dose-proportionally. In multivariate Cox proportional hazard model analyses, increased baseline systolic blood pressure and decreased angiopoietin-1 ratio (2 hours:baseline) were associated with longer progression-free survival (PFS) in the expanded melanoma cohort (P=0.041 and P=0.03, respectively). Conclusions: The toxicity profile, pharmacokinetics, and antitumor activity of lenvatinib are encouraging. Decreases in the angiopoietin-1 ratio correlated with longer PFS in melanoma patients.