Researchers from the Johns Hopkins Medical Institute and the Lovelace Respiratory Research Institute have reported that the combination of Vidaza® (5-azacitidine) and entinostat (SNDX-275) has significant activity in patients with advanced relapsed non–small cell lung cancer (NSCLC). The details of this study were presented at the 2009 meeting of the American Society of Clinical Oncology.[1] 

Vidaza is an inhibitor of DNA methytransferase (DNMT) and is approved by the U.S. Food and Drug Administration for the treatment of myelodysplasia. Vidaza also is effective in patients with acute myeloid leukemia.

Entinostat is an oral inhibitor of histone deacetylase (HDAC) that was apparently first developed in Japan in the late 1990s and has subsequently been evaluated in several academic institutions including the National Cancer Institute. Entinostat is currently being evaluated by Syndax, which acquired the commercial rights in 2007 from Bayer Schering Pharma AG.

Entinostat is an oral drug with a 100-hour half life that is given weekly or biweekly. Laboratory studies suggest activity against a wide variety of tumor cell lines in-vitro including resistant cell lines. Phase I studies of entinostat by researchers from the University of Maryland showed that treatment of patients with relapsed or refractory acute leukemia resulted in induced increase in protein and histone H3/H4 acetylation, p21 expression, and caspase-3 activation.[2] Although no responses were seen, there were promising laboratory results, which justify further testing in combination with other agents. A Phase I study in patients with refractory solid tumors and lymphomas established a tolerable dose and schedule of administration.[3] Two of 27 treated patients, including a patient with melanoma, had a partial response. The responding patient with melanoma has been stable on therapy for over five years. Prolonged disease stabilization was observed in an additional six patients.

A recent study combined entinostat with Vidaza for the treatment of patients with MDS and AML.[4] This study failed to find correlates between laboratory tests and clinical response to this drug combination. This was not an efficacy trial, so randomized trials will be needed to determine if this drug combination is better than Vidaza alone.

At ASCO 2009 in-vitro data were presented that showed the combination of entinostat and erlotinib (Tarceva®) or lapatinib (Tykerb®) was active against resistant HER2-positive cell lines of breast cancer, NSCLC, and head and neck cancer.[5] 

The concept behind the current testing of entinostat with Vidaza in lung cancer is that “epigenetic gene silencing mediated through aberrant DNA methylation and histone deacetylation is a key contributior to lung carcinogensis.” This study included 25 patients with NSCLC who had failed one or more prior chemotherapy regimens. One patient had a complete response and remains on therapy at 14 months. She had a second lung cancer, which was successfully removed surgically, and remains disease-free at 20 months. Two patients had stable disease; one for more than 16 months and one for four months. All other patients progressed. These authors are currently attempting to identify patients with lung cancer who may benefit from this approach.

Comments: These studies suggest that there may be a role for entinostat in combination with other agents for the treatment of a wide variety of tumors. The concept of histone deacetylase inhibition appears to be very sound; there is a lot of preclinical data to document this. We therefore can expect many more studies of entinostat combinations in cancer therapy.

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