Epigenetic Therapy With Belinostat Stabilizes HCC

David J. Kerr, MD


January 15, 2013

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Hello. I am David Kerr, Professor of Cancer Medicine at University of Oxford and past President of ESMO, the European Society for Medical Oncology. Today I want to discuss an interesting paper published recently in Journal of Clinical Oncology about epigenetic therapy for unresectable hepatocellular cancer (HCC).[1]

We know that important epigenetic changes are driving the cancer phenotype in HCC and that these consist mainly of methylation or of histone acetylation. This new trial was led by Winnie Yeo as part of the Mayo Phase 2 Trials Consortium that is based predominantly in southern China. They looked at the histone deacetylase (HDAC) inhibitor belinostat and designed a phase 1 trial to determine the appropriate dose of 1400 mg/m2 given by a short IV infusion daily for 5 days and repeated every 3 weeks. For the phase 2 expansion cohort, the investigators recruited another 42 patients in reasonable shape, with a performance status of 2 or better, all with unresectable but measurable disease and Child stage A or B. Although the response rate was only 2.4%, around 43% achieved disease stabilization, with progression-free survival of 2-2.5 months and overall survival of 6.6 months. In terms of stabilization of disease, this is a readout that looks pretty interesting.

Perhaps more interesting, however, the investigators took things a step further and looked at nuclear expression of a potential biomarker of chemosensitivity for HDAC inhibitors called HR23B. They found that those patients with HCC who had high levels of nuclear staining for the sensitivity biomarker HR23B had a 58% disease-stabilization rate, compared with those patients who had a low level of HR23B expression, who had a disease stabilization rate of only 14%.

This presents us with 2 important take-home messages: Epigenetic therapy is worth considering, to see how we could build that forward into large, well-designed, randomized trials in HCC. We need more drugs in our therapeutic armamentarium for this disease -- of that, there is no question whatsoever. But tantalizingly, should we be selecting HCC patients on the basis of nuclear expressive straining of HR23B, a biomarker that does appear to have very real potential in terms of selecting patients who are sensitive to this class of HDAC inhibitors? Of course, this was shown for belinostat only, but other data in the Proceedings of the National Academy of Sciences[2] and basic science data suggest that this may be a class effect. Would we dare to design a prospective trial in which we select patients with high expression of the HR23B biomarker and recruit those patients for a placebo-controlled, randomized trial, perhaps as second line, in HCC?

Interesting times, and well worth watching the evolution of both the drug and the potential biomarker in the treatment of this difficult disease. So, Medscapers, ahoy! Thanks for listening.