Targeting epigenetic changes in non-small cell lung cancer.

摘要

Epigenetic gene silencing is a key contributor to carcinogenesis. Pre-clinical studies suggest that combined inhibition of DNA methyltransferase and histone deacetylase activity can synergistically re-express aberrantly silenced genes. Clinical studies combining 5-azacitidine and entinostat have shown activity in leukemia. We hypothesized that a similar effect might be seen in patients with solid tumors. As a first test of this hypothesis, we conducted a phase I/II study with embedded biologic correlates in patients with advanced, recurrent non-small-cell lung cancer.;Subjects included adults with metastatic lung cancer and progressive disease after at least one prior chemotherapy regimen. Patients were given 5-azacitidine 40 mg/m² subcutaneously days 1-6 and 8-10, and entinostat 7 mg days 3 and 10, on a 28 day cycle. A standard Simon two stage design was used.;Forty-two patients were enrolled on study. Thirty-two completed two cycles and were evaluable for response. Mean number of previous therapies was three. Treatment was well tolerated, with local injection site reactions being the most common toxicity. Two patients had objective responses with stability off therapy over one year. Nine patients had disease stabilization over multiple cycles, including two with stable disease for 14 and 18 months, respectively, and with marked symptomatic improvement. Median time to progression was 7.4 weeks. Median overall survival was 6.3 months, comparing favorably with currently approved drugs for this clinical context. Biomarker assessments included serial analysis of circulating tumor DNA methylation in plasma (loci: APC , CDH13, CDKN2A, RASSF1A ). Twenty-six patients had two or more methylated loci detectable. Ten patients (38%) showed decreasing signal at all detectable loci of which eight had stable disease or better, including both patients with an objective response.;The combination of 5-azacitidine and entinostat is safe and well tolerated in advanced lung cancer patients. Durable patient benefit was observed in this extensively pretreated population, including major objective responses. Correlative analyses have identified a predictive panel based on changes in methylation status of key genes in the serum which may be useful to select responding patients early on during treatment. Based on these data, related studies are being initiated in colon, breast, and early stage lung cancer.