A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma
Mené sur des patients asiatiques atteints d'un carcinome hépatocellulaire de stade avancé, cet essai de phase I/II évalue les caractéristiques pharmacocinétiques et pharmacodynamiques, l'activité antitumorale, la dose maximale tolérée, la toxicité et l'efficacité, du point de vue du taux de réponse objective, du forétinib, un inhibiteur multikinase, en traitement de première ligne
Purpose: This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the first-line setting in advanced hepatocellular carcinoma (HCC) patients.
Experimental Design: In the phase I part, advanced HCC patients were dose-escalated on foretinib (30-60 mg) once daily (QD) using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety. Exploratory analyses were conducted to assess potential biomarkers that might correlate with clinical efficacy and survival.
Results: The MTD of foretinib was established as 30 mg QD. The most frequent adverse events were hypertension, decreased appetite, ascites, and pyrexia. When dosed at 30 mg QD in the first-line setting, foretinib demonstrated promising anti-tumor activity. According to the modified Response Evaluation Criteria in Solid Tumors (mRECIST), the objective response rate was 22.9%, the disease stabilization rate 82.9% and the median duration of response 7.6 months. The median time to progression was 4.2 months and the median overall survival (OS) was 15.7 months. Fifteen candidate biomarkers whose levels in the circulation were significantly altered in response to foretinib treatment were elucidated. Multivariate analyses identified IL6 and IL8 as independent predictors of OS.
Conclusions: Foretinib demonstrated promising anti-tumor activity and good tolerability in the first-line setting in Asian advanced HCC patients. Baseline plasma levels of IL6 or IL8 might predict response to foretinib.
http://clincancerres.aacrjournals.org/content/clincanres/early/2016/11/05/1078-0432.CCR-16-1789.full.pdf
Clinical Cancer Research , résumé, 2015