Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma.

Abstract

BACKGROUND:

The efficacy and safety of axitinib, a potent and selective vascular endothelial growth factor receptors 1-3 inhibitor, combined with best supportive care (BSC) was evaluated in a global, randomized, placebo-controlled phase II trial in patients with locally advanced or metastatic hepatocellular carcinoma (HCC).

PATIENTS AND METHODS:

Patients with HCC and Child-Pugh Class A who progressed on or were intolerant to one prior antiangiogenic therapy were stratified by tumour invasion (presence/absence of extrahepatic spread and/or vascular invasion) and region (Asian/non-Asian) and randomized (2:1) to axitinib/BSC (starting dose 5 mg twice-daily) or placebo/BSC. The primary end point was overall survival (OS).

RESULTS:

The estimated hazard ratio for OS was 0.907 [95% confidence interval (CI) 0.646-1.274; one-sided stratified P = 0.287] for axitinib/BSC (n = 134) versus placebo/BSC (n = 68), with the median (95% CI) of 12.7 (10.2-14.9) versus 9.7 (5.9-11.8) months, respectively. Results of prespecified subgroup analyses in Asian versus non-Asian patients or presence versus absence of tumour invasion were consistent with the overall population. Improvements favouring axitinib/BSC (P < 0.01) were observed in secondary efficacy end point analyses [progression-free survival (PFS), time to tumour progression (TTP), and clinical benefit rate (CBR)], and were retained among Asian patients in the prespecified subgroup analyses. Overall response rate did not differ significantly between treatments and patient-reported outcomes favoured placebo/BSC. Most common all-causality adverse events with axitinib/BSC were diarrhoea (54%), hypertension (54%), and decreased appetite (47%). Baseline serum analyses identified potential new prognostic (interleukin-6, E-selectin, interleukin-8, angiopoietin-2, migration inhibitory factor, and c-MET) or predictive (E-selectin and stromal-derived factor-1) factors for survival.

CONCLUSIONS:

Axitinib/BSC did not improve OS over placebo/BSC in the overall population or in stratification subgroups. However, axitinib/BSC resulted in significantly longer PFS and TTP and higher CBR, with acceptable toxicity in patients with advanced HCC.

TRIAL REGISTRATION:

ClinicalTrials.gov, NCT01210495.

• Authors: Y-K Kang, T Yau, J-W Park, H Y Lim, T-Y Lee, S Obi, S L Chan, Sk Qin, R D Kim, M Casey, C Chen, H Bhattacharyya, J A Williams, O Valota, D Chakrabarti, M Kudo
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 26 Issue 12 Pg. 2457-63 (Dec 2015) ISSN: 1569-8041 [Electronic] England
• PMID: 26386123 (Publication Type: Clinical Trial, Phase II, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Imidazoles
• Indazoles
• Axitinib

Topics

• Adult
• Aged
• Aged, 80 and over
• Axitinib
• Carcinoma, Hepatocellular (mortality, therapy)
• Double-Blind Method
• Female
• Humans
• Imidazoles (therapeutic use)
• Indazoles (therapeutic use)
• Liver Neoplasms (mortality, therapy)
• Male
• Middle Aged
• Neoplasm Invasiveness (pathology)
• Palliative Care (methods, trends)
• Survival Rate (trends)
• Treatment Outcome