A Phase I/II Multicenter Study of Single-Agent Foretinib as First-Line Therapy in Patients with Advanced
Thomas C C Yau1, Riccardo Lencioni2, Wattana Sukeepaisarnjaroen3
1Department of Medicine, The University of Hong Kong, Hong Kong, China.
Abstract:
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 patients.Experimental Design: In the phase I part, advanced hepatocellular carcinoma patients were dose escalated on foretinib (30-60 mg) every day 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 every day. The most frequent adverse events were hypertension, decreased appetite, ascites, and pyrexia. When dosed at 30 mg every day in the first-line setting, foretinib demonstrated promising antitumor activity. According to the modified 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 antitumor activity and good tolerability in the first-line setting in Asian advanced hepatocellular carcinoma patients. Baseline plasma levels of IL6 or IL8 might predict the response to foretinib. Clin Cancer Res; 23(10); 2405-13. ©2016 AACR.
Insights
Foretinib showed promising antitumor activity and good tolerability in first-line advanced hepatocellular carcinoma patients. Interleukin-6 (IL6) and Interleukin-8 (IL8) may predict treatment response.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Advanced hepatocellular carcinoma (HCC) presents a significant unmet need for effective first-line therapies.
- Multikinase inhibitors offer a targeted approach to HCC treatment by inhibiting key signaling pathways involved in tumor growth and angiogenesis.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of foretinib, a multikinase inhibitor, as a first-line treatment for advanced HCC.
- To determine the maximum tolerated dose (MTD) of foretinib in this patient population.
- To identify potential biomarkers correlating with clinical outcomes.
Main Methods:
- Phase I/II, single-arm study involving dose escalation of foretinib (30-60 mg daily) to determine the MTD.
- An expansion cohort of 32 patients received foretinib at the MTD for efficacy and safety assessment.
- Exploratory biomarker analyses were performed to identify predictors of response and survival.
Main Results:
- The MTD of foretinib was established at 30 mg daily. Common adverse events included hypertension, decreased appetite, ascites, and pyrexia.
- Foretinib demonstrated promising antitumor activity: objective response rate (22.9%), disease stabilization rate (82.9%), median duration of response (7.6 months).
- Median time to progression was 4.2 months, and median overall survival (OS) was 15.7 months. IL6 and IL8 were identified as independent predictors of OS.
Conclusions:
- Foretinib exhibits promising antitumor activity and favorable tolerability as a first-line treatment for advanced HCC in Asian patients.
- Baseline plasma levels of IL6 or IL8 may serve as predictive biomarkers for foretinib response in HCC.
- Further investigation into foretinib's role in HCC treatment is warranted, considering its potential efficacy and biomarker associations.
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