Epigenetic Therapy Shows Potential in Advanced Lung Cancer || NCI Cancer Bulletin for November 15, 2011 - National Cancer Institute

 

Epigenetic Therapy Shows Potential in Advanced Lung Cancer

Treatment with drugs that target epigenetic changes in genes—chemical modifications that influence gene expression but do not involve changes in the sequence of DNA—showed promise in a small clinical trial of patients with advanced non-small cell lung cancer (NSCLC), researchers reported last week. The phase I/II trial is believed to be the first to demonstrate successful treatment of a solid tumor with epigenetic therapy. Findings from the trial, led by researchers from the Johns Hopkins University, were published November 9 in Cancer Discovery.

In the trial, 45 patients with metastatic NSCLC whose tumors had returned after previous treatment received low doses of azacitidine (Vidaza) and entinostat, two drugs that target epigenetic changes involved in silencing gene activity. Median survival among trial participants was 6.4 months, which is similar to what was seen in the clinical trials that led the Food and Drug Administration (FDA) to approve the targeted therapy erlotinib (Tarceva) for patients with advanced NSCLC. (The FDA approved azacitidine for the treatment of myelodysplastic syndromes in 2004.)

Among the patients who completed at least one cycle of treatment with the two drugs, median survival was 8.6 months. Seven patients from the trial are still alive, including two who began treatment approximately 4 years ago. The trial, which was sponsored in part by NCI’s Cancer Therapy Evaluation Program, did not include a comparison group of patients who did not receive the investigational therapy.

The treatment approach takes advantage of the fact that, unlike genetic mutations, epigenetic changes are potentially reversible. High doses of the drugs used in earlier trials were too toxic for patients, so the researchers used low concentrations that were sufficient to reverse epigenetic changes but that had limited toxic side effects, explained the study’s senior author, Dr. Charles Rudin, during a press briefing.

The two drugs “were well tolerated,” Dr. Rudin said, and the researchers were surprised to see tumor responses in two patients, including one complete response that lasted 14 months. Another 10 patients had stable disease. But he cautioned that the results need to be confirmed in a larger study population.

Patients whose tumors responded to the therapy improved gradually over several months of treatment, which suggested that the treatment was indeed working via an epigenetic mechanism, study co-author Dr. Malcolm Brock noted. After stopping treatment with the two drugs, 19 patients went on to receive at least one round of chemotherapy, other targeted therapies, or both. In four of these patients, including the two longer-term survivors, tumors shrank substantially after the additional therapy.

The findings should encourage continued research on epigenetic cancer treatments, including tests of epigenetic drugs in combination with standard therapies and identification of subsets of patients most likely to respond, Dr. Jeffrey Engelman of Harvard Medical School said during the briefing. Dr. Engelman was not involved in the study.

A small, multi-institution trial has been launched to test the same drug combination as a post-surgical, or adjuvant, treatment in patients with stage I lung cancer, Dr. Brock said.
NCI Cancer Bulletin for November 15, 2011 - National Cancer Institute