HDAC Inhibitor Plus Checkpoint Blocker Tested in Advanced Lung Cancer Trial

Immune checkpoint inhibitors like durvalumab have transformed cancer treatment, but many patients still fail to respond. One emerging strategy is to combine checkpoint blockade with epigenetic drugs that can reprogram tumor cells to become more visible to the immune system. This trial explored that approach in patients with advanced cancers, including non-small cell lung cancer.

The study combined mocetinostat, an orally administered HDAC inhibitor developed by Mirati Therapeutics, with durvalumab, a monoclonal antibody targeting PD-L1. HDAC inhibitors work by altering chromatin structure and gene expression, potentially upregulating immune-activating signals on tumor cells. The hypothesis was that this epigenetic priming could sensitize tumors to checkpoint blockade and improve response rates.

The phase 1/2 trial enrolled 83 participants and evaluated three escalating doses of mocetinostat — 50 mg, 70 mg, and 90 mg — in combination with durvalumab. The study began in June 2016 and was designed to assess safety, tolerability, and preliminary efficacy across advanced solid tumor types, with a specific focus on NSCLC.

The trial was terminated in December 2019 before reaching its planned completion. No detailed efficacy or safety results are available from the abstract alone. The early termination may reflect challenges with tolerability, lack of efficacy signals, or strategic decisions by the sponsor rather than a definitive negative result.

Despite the termination, this trial contributes to the growing body of evidence on HDAC inhibitor and checkpoint inhibitor combinations. The approach remains scientifically compelling, and other combinations in this class continue to be investigated. Clinicians and researchers should note that epigenetic priming strategies require careful patient selection and dose optimization to realize their potential in immuno-oncology.