Updated Survival Follow-Up for Phase Ib Trial of the Histone Deacetylase Inhibitor Abexinostat With Pazopanib in Patients With Solid Tumor Malignancies.

Abstract

Histone deacetylase (HDAC) inhibition downregulates hypoxia-inducible factor-1α and modulates multiple metabolomic pathways relevant in cancer. Here we report a potential novel biomarker to predict exceptional responders (>3 years) in patients receiving HDAC and vascular endothelial growth factor (VEGF) inhibition. Patients with solid tumor malignancies were enrolled in this phase Ib trial of abexinostat (4/7 ×21 days) and pazopanib (28/28 days), with a dose expansion in renal cell carcinoma (RCC). Plasma was analyzed for metabolomics and peripheral blood mononuclear cells (PBMCs) for VEGF and HDAC2 expression levels. Fifty-one patients were enrolled: n = 36 patients in dose escalation and n = 15 in dose expansion. After the initial report in 2017, six patients had remained on study: four with RCC and one each with medullary thyroid and thymic neuroendocrine carcinoma. One patient with RCC remains on treatment for >11 years after progression on five systemic therapies. Overall, the median duration of therapy measured 5.6 (1-133) months. The median duration of therapy in exceptional responders measured 44.1 (39.8-133+) months. The median overall survival in patients with high PBMC HDAC2 expression versus low HDAC2 was 32.3 versus 9.2 months (<i>P</i> = .004) for all patients and 43.3 versus 25.1 months for patients with RCC (<i>P</i> = .09). Exceptional responders had lower kynurenine levels both pre- and post-treatment (<i>P</i> = .002, <i>P</i> < .001, respectively). HDAC2 and kynurenine expression levels were inversely correlated (<i>P</i> = .02). Abexinostat added to pazopanib shows extended tolerability and long-term responses and survival. PBMC HDAC2 levels, the abexinostat target, are relevant predictors of response. In addition, metabolomic assessment points to kynurenine as a predictor for exceptional response to combined VEGF plus HDAC inhibition.