A phase I/II study in HCC shows that the HDAC inhibitor belinostat safely leads to disease stabilization.

  • Major finding: A phase I/II study in HCC shows that the HDAC inhibitor belinostat safely leads to disease stabilization.

  • Clinical relevance: RAD23B expression may be a generally useful biomarker for predicting HDAC inhibitor response.

  • Impact: These findings support further study of the antitumor activity of belinostat in HCC.

Patients with unresectable hepatocellular carcinoma (HCC) have a poor prognosis due to advanced stage of disease and frequent concomitant chronic liver disease. Because epigenetic abnormalities are commonly observed in HCC and epigenetic therapies have shown efficacy in preclinical models of HCC, Yeo and colleagues conducted a multicenter phase I/II trial to assess the safety and activity of the histone deacetylase (HDAC) inhibitor belinostat in patients with unresectable HCC. In the phase I dose-escalation study, the plasma concentration of belinostat increased linearly with the dosage and safely reached levels predicted to increase histone acetylation and be efficacious based on preclinical models. In the phase II trial, the primary endpoint was progression-free survival, and the main secondary endpoints were response according to Response Evaluation Criteria in Solid Tumors and overall survival. Additionally, pretreatment tumor samples from 38 of the 42 patients enrolled in the phase II trial were used for an exploratory analysis to determine whether expression of RAD23 homolog B (RAD23B, or HR23B), a putative biomarker of HDAC inhibitor sensitivity, could predict belinostat response. Belinostat was well tolerated, with grade 3 or 4 toxicities occurring in only 10% of patients. The median progression-free survival was 2.64 months and median overall survival was 6.6 months. One patient (2.4%) experienced a partial response, 19 patients (45.2%) had stable disease, and 22 patients' (52.4%) disease progressed. Notably, of the patients whose tumors expressed high levels of RAD23B, 58% achieved disease stabilization compared with only 14% of the patients with low-RAD23B tumors. Although this trial was not placebo controlled and thus does not definitively show that belinostat has single-agent antitumor activity, these results suggest that belinostat can safely stabilize unresectable HCC and that RAD23B expression may be a useful predictor of belinostat response.

Yeo W, Chung HC, Chan SL, Wang LZ, Lim R, Picus J, et al. Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma: a multicenter phase I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase II Consortium and the Cancer Therapeutics Research Group. J Clin Oncol 2012 Aug 20 [Epub ahead of print].