Abstract LB-411: A phase II study of combination epigenetic therapy in advanced non-small cell lung cancer Conference Paper uri icon

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abstract

  • Abstract Background: Epigenetic gene silencing is a key contributor to carcinogenesis. Pre-clinical studies suggest that combined inhibition of DNA methyltransferase and of histone deacetylase activity can synergistically re-express aberrantly silenced genes. Clinical studies combining 5-azacitidine (5AC) 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 II study in patients (pts) with advanced, recurrent non-small cell lung cancer (NSCLC). This was just completed under the aegis of a Stand up to Cancer (SU2C) project. Methods: Subjects included adults with recurrent metastatic NSCLC and progressive disease after ≥1 prior chemotherapy regimen. Pts were given 5AC 40 mg/m2 SQ 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. Results: 42 pts were enrolled on study, of whom, 32 completed 2 cycles and were evaluable for response. Mean # of previous therapies was 3. Treatment was well tolerated, with local injection site reactions being the most common toxicity. A complete response was observed in a pt with 3 prior therapies that also had the highest 5AC exposure by pharmacokinetic analysis. She remained on therapy for 14 months (m) and discontinued due to what proved to be a genetically distinct second primary lung cancer. This was resected, and she remained disease free off treatment for 12 m. A second pt with 3 prior therapies and metastases to the liver had a partial response for 8 m, including complete resolution of his liver disease. He also developed an independent primary, treated with chemoradiotherapy, and has been progression-free for over 18 m off epigenetic therapy. 9 pts had disease stabilization (SD) over multiple cycles, including 2 with SD for 14 m and 18 m, respectively, with marked symptomatic improvement. Median time to progression was 8 weeks and median overall survival was 8 m, comparing favorably with currently FDA approved drugs for this clinical context. Biomarker assessments included serial analysis of circulating tumor DNA methylation in plasma (loci: APC, RASSF1A, HCAD). 17 pts had ≥ 2 methylated loci detectable. 8 pts (47%) showed decreasing signal at all detectable loci of which 6 had SD or better, including both pts with RECIST criteria response. Conclusions: The combination of 5AC and entinostat is safe and well tolerated in advanced NSCLC pts. Durable patient benefit has been observed in this extensively pretreated population, including major objective responses. Correlative analyses are ongoing to identify characteristics of pts benefitting from this novel therapy. Based on these data, related studies are being initiated in colon, breast, and early stage NSCLC pts under the aegis of the SU2C. Supported by NCI, FAMRI, and AACR/SU2C. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-411. doi:10.1158/1538-7445.AM2011-LB-411

authors

  • Juergens, Rosalyn
  • Vendetti, Frank
  • Wrangle, John
  • Coleman, Barbara
  • Sebree, Rosa
  • Rudek-Renaut, Michelle
  • Belinsky, Steven
  • Brock, Malcolm
  • Herman, James
  • Baylin, Stephen
  • Rudin, Charles

publication date

  • April 15, 2011