Interim analysis of a phase II trial of 5-azacitidine (5AC) and entinostat (SNDX-275) in relapsed advanced lung cancer (NSCLC)

8055 Background: Epigenetic gene silencing mediated through aberrant DNA methylation and histone deacetylation is a key contributor to lung carcinogenesis. Pre-clinical studies suggest that combining inhibitors of DNA methyltransferase (DNMT) with inhibitors of histone deacetylase (HDAC) synergistically induce re-expression of epigenetically-silenced tumor suppressor genes. Clinical studies at our institution combining the DNMT inhibitor, 5AC, with the HDAC inhibitor, entinostat, in hematologic malignancies have shown remarkable clinical activity. We hypothesized a similar effect would be seen in lung cancer. This study aims to assess the response rate and time to progression of 5AC and entinostat in NSCLC. Methods: Patients (pts) include adults with histologically confirmed recurrent NSCLC and progressive disease after ≥1 prior chemotherapy regimen. 40 mg/m 2 of 5AC is administered SQ days 1–6 and 8–10 with 7 mg of entinostat PO days 3 and 10 of a 28 day cycle. A standard Simon two stage design is being used. The sample size is calculated with a power of 90% and a two-sided type 1 error allowance of 5%. Stage 1 included 18 pts, with subsequent expansion to a total of 32. Results: 25 pts have enrolled to date. Demographic characteristics include: mean age (range) - 63 (46- 80); M:F - 1:2; 80% former smokers; 80% adenocarcinomas; mean # of previous therapies - 3. One pt. has had a complete response. She remained on therapy for 14 m and came off therapy due to a new nodule which was resected. Molecular analysis suggests a second primary stage I NSCLC. She remains disease free at 20 m. Another man has stabilization of disease (SD) for ≥16 m with marked symptomatic improvement. Another pt had SD for 4 months. The remaining pts have progressed after 2 cycles of therapy. Main toxicities included injection site reactions, nausea/vomiting, constipation, fatigue, and hematologic toxicities. Conclusions: The combination of 5AC and entinostat is safe and well tolerated in advanced NSCLC pts. 2 pts have had durable benefit from treatment, including a complete response. Pharmacodynamic and pharmacokinetic analyses are being conducted to identify characteristics of the subset of pts responding to this novel therapy. [Table: see text]