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

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

Abstract

Background: 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).

Methods: This 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).

Results: Total 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.

Conclusions: Axitinib 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://ichgcp.net/clinical-trials-registry/NCT02814461.

Keywords: Advanced hepatocellular carcinoma; Axitinib; Maximum tolerated dose; Radiotherapy.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Waterfall plot for percentage change in tumor size at 3 months after treatment initiation. The dashed line at 20% means the cut-off value for progressive disease, and the dashed line at -30% for determination of means the cut-off value for partial response. a Overall tumor response of individual patients. b RT in-field tumor response of individual patients
Fig. 2
Fig. 2
A case presentation (complete response, long-term alive, no recurrence). A 72-year-old man, with liver cirrhosis Child–Pugh class A (non-HBV, non-HCV related), was diagnosed as having a 12-cm HCC in left lobe of liver with classical enhancement pattern and involvement of left portal vein by CT scan in August 2016, clinically staged as cT3bN0M0, BCLC stage C. High alpha-fetoprotein (AFP) up to 160.1 ng/ml was noted. TACE failed with only partial obliteration of tumor vessels. He was then eligible for this phase I trial. He received RT with 45 Gy in 15 fractions plus axitinib 1 mg twice daily for 2 months. The patient tolerated the treatment well. At 3 months after RT initiation, follow-up CT scan revealed complete response of the tumor, and AFP decreased to 1.9 ng/ml. In 2020, the patient is still regularly followed up without recurrence
Fig. 3
Fig. 3
Overall survival
Fig. 4
Fig. 4
Progression-free survival

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