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Epigenetic therapy improved PFS, OS in NSCLC
Juergens RA. Cancer Discov. 2011;doi:10.1158/2159-8290.CD-11-0214.
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Patients with recurrent, metastatic non–small cell lung cancer who received inhibitors of DNA methylation and histone deacetylation demonstrated a longer median survival compared with existing therapeutic options, according to researchers from Johns Hopkins University.
In addition, the researchers observed that after the epigenetic therapy, a number of patients demonstrated stronger responses to additional treatment with standard chemotherapies.
“This raises the possibility that the epigenetic treatment is having a delayed effect, or is even sensitizing patients’ tumors in a way that makes them more vulnerable to subsequent therapies,” study researcher Stephen B. Baylin, MD, deputy director of the Kimmel Cancer Center at Johns Hopkins University, said during a press conference.
The phase 1/2 trial included 45 patients with recurrent, metastatic NSCLC who had been extensively pretreated.
In the phase 1 portion of the study, three patients received 30 mg/m2/day azacitidine (Vidaza, Celgene) and seven patients received 40 mg/m2/day azacitidine. All patients received entinostat (Syndax Pharmaceuticals) 7 mg on days 3 and 10 of each cycle. None of the patients experienced dose-limiting toxicities.
The phase 2 portion of the trial included 42 patients who received 40 mg/m2 azacitidine on days 1 to 6 and 8 to 10, as well as 7 mg entinostat on days 3 and 10 of each 28-day cycle. In an intent-to-treat analysis, the median PFS was 7.4 weeks and the median OS was 6.4 months.
The researchers also examined promoter methylation status in DNA in patient plasma collected before therapy and after one cycle of therapy. Ten patients had at least two methylated target genes before therapy and a decrease in the level of these genes after treatment. The OS was 10.42 months for patients with this methylation signature vs. 6.54 months for patients without this methylation signature.
Disclosure: Dr. Baylin reports consulting for and receiving research support from MDxHealth.
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This is a groundbreaking paper, showing that by modifying the epigenetics of cancer cells, we can get impressive responses in lung cancer. Getting real responses in lung cancer is difficult, and responses like those seen in a couple of the patients on this trial catch our attention. As with most groundbreaking studies, these findings raise many exciting questions as to how we can make these therapies more effective for patients with lung cancer. We need to know how to identify which patients will respond to these therapies. The investigators have done a great job of working to identify biomarkers that may inform which patients will be directed to these therapies. These patient responses are reminiscent of results of other targeted therapy studies in lung cancer, when responses were observed in only a fraction of patients, but we did not know why. For example, when EGFR inhibitors were introduced into the clinic, there was just a small subset of patients who had tremendous responses, and following up those observations led to the identification of EGFR mutations that predict response to these agents. I have great confidence that investigators will follow up these initial findings to figure out exactly which patients are most likely to respond to epigenetic modifiers. I also anticipate that we will learn how to use such agents more effectively, and potentially in combination with other therapies, to increase their impact on lung cancer.
– Jeffrey A. Engelman, MD, PhD
Director, Center for Thoracic Oncology, Massachusetts General Hospital
Disclosure: Dr. Engelman reports no relevant financial disclosures.