Axitinib in combination with radiotherapy for advanced hepatocellular carcinoma: a phase I clinical trial

Kai-Lin Yang,Hui-Ling Ko,Su-Chen Huang,Yi-Ying Huang,Mau-Shin Chi,Kwan-Hwa Chi,Yu-Min Lin

doi:10.1186/s13014-020-01742-w

Abstract

BackgroundTo investigate maximum tolerated dose (MTD) of axitinib, a selective vascular endothelial growth factor receptor 1–3 inhibitor, in combination with radiotherapy (RT) for advanced hepatocellular carcinoma (HCC).MethodsThis phase I study followed the rule of traditional 3 + 3 design. Major eligibility included: (1) patients with advanced HCC unsuitable for surgery, radiofrequency ablation or transarterial chemoembolization, or who failed after prior local–regional treatment; (2) failure on sorafenib or no grant for sorafenib from health insurance system. Eligible patients with advanced HCC received axitinib for total 8 weeks during and after RT. Three cohorts with axitinib dose escalation were planned: 1 mg twice daily (level I), 2 mg twice daily (level II) and 3 mg twice daily (level III). The prescribed doses of RT ranged from 37.5 to 67.5 Gy in 15 fractions to liver tumor(s) and were determined based on an upper limit of mean liver dose of 18 Gy (intended isotoxic RT for normal liver). The primary endpoint was MTD of axitinib in combination with RT. The secondary endpoints included overall response rate (ORR), RT in-field response rate, acute and late toxicities, overall survival (OS) and progression free survival (PFS).ResultsTotal nine eligible patients received axitinib dose levels of 1 mg twice daily (n = 3), 2 mg twice daily (n = 3) and 3 mg twice daily (n = 3). Dose-limiting toxicity (DLT) did not occur in the 3 cohorts; the MTD was defined as 3 mg twice daily in this study. ORR was 66.7%, including 3 complete responses and 3 partial responses, at 3 months after treatment initiation. With a median follow-up of 16.6 months, median OS was not reached, 1-year OS was 66.7%, and median PFS was 7.4 months.ConclusionsAxitinib in combination with RT for advanced HCC was well tolerated with an axitinib MTD of 3 mg twice daily in this study. The outcome analysis should be interpreted with caution due to the small total cohort.Trial registration ClinicalTrials.gov (Identifier: NCT02814461), Registered June 27, 2016—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02814461

Highlights

To investigate maximum tolerated dose (MTD) of axitinib, a selective vascular endothelial growth factor receptor 1–3 inhibitor, in combination with radiotherapy (RT) for advanced hepatocellular carcinoma (HCC)
Patients with advanced HCC unsuitable for resection, liver transplantation, radiofrequency ablation (RFA) or transarterial chemoembolization (TACE), or who failed after prior local–regional treatment were eligible
Our study successfully proved that axitinib in combination with RT is safe at least up to the dose of axitinib 3 mg twice daily, which was considered as the MTD in this study

Summary

Introduction

To investigate maximum tolerated dose (MTD) of axitinib, a selective vascular endothelial growth factor receptor 1–3 inhibitor, in combination with radiotherapy (RT) for advanced hepatocellular carcinoma (HCC). Intensity-modulated radiotherapy (IMRT) has improved conformity of tumor dose and can spare critical normal organs better, while imageguided radiotherapy (IGRT) and breathing motion management allow accurate RT delivery by reducing setup error and effect of breathing cycle on liver location [25, 26]. These together lead to an emerging role of stereotactic ablative body radiotherapy (SABR) in HCC [27]. A treatment strategy combining RT with systemic therapy may be indicated

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