News Release: Research, School of Medicine, Winship Cancer Institute
Jun. 2, 2009
New Treatment Strategy Enhances Outcome for Lung Cancer
A new strategy for treating non-small cell lung cancer increases the effectiveness of standard chemotherapy in patients with advanced stage disease, according to results presented at the American Society of Clinical Oncology meeting in Orlando.
Addition of vorinostat, a histone deacetylase (HDAC) inhibitor, to a standard chemotherapy regimen of carboplatin and paclitaxel increased response rates from 12.5 percent to 34 percent in a phase II clinical trial of 94 patients with metastatic non-small cell lung cancer. It also demonstrated favorable trends for progression-free survival and overall survival.
This placebo-controlled, randomized phase II study was conducted across a consortium of academic institutions, supported by the National Cancer Institute, and was chaired by Dr. Suresh Ramalingam, associate professor of Hematology and Medical Oncology at Emory University's Winship Cancer Institute.
The objective response rate, the primary endpoint of the study, was 34 percent for patients who received vorinostat in combination with chemotherapy compared to 12.5 percent for those treated with placebo with chemotherapy plus placebo.
"Advanced non-small cell lung cancer is a very challenging form of cancer to treat," says Ramalingam.
"These results confirm our pre-clinical observations with this novel combination and the provocative data from our earlier phase I clinical trial," he says. "This will have to be further evaluated in confirmatory phase III studies before they can be adopted in routine use.
"These results also open the door to evaluate other drugs that belong to this class of compounds for the treatment of NSCLC, many of which are in early clinical development," says Ramalingam.
"HDAC inhibitors can now be considered among the leading targeted agents under evaluation for the treatment of lung cancer," says states Dr. Chandra P. Belani, the study co-chair and deputy director and Miriam Beckner Professor of Medicine at the Penn State Hershey Cancer Institute.
Vorinostat or placebo were given in cycles of two weeks on, one week off, while carboplatin and paclitaxel were given on day three of each cycle for up to six cycles. Median progression-free survival (the amount of time from the start of treatment until a patient's tumor started growing again) was six months vs. 4.1 months for placebo. The median survival was 13 months and 9.7 months respectively, for patients treated with vorinostat and placebo.
However, these differences were not statistically significant, as the study was not powered to detect differences in progression-free or overall survival. The side effects noted more frequent with the use of vorinostat included fatigue, hyponatremia and low platelet count.
Vorinostat is part of an emerging class of anti-tumor agents that interfere with enzymes known as histone deacetylases. Inhibiting these enzymes increases the level of acetylation, a reversible chemical modification, on proteins in the cell. Vorinostat is sold by Merck as Zolinza and was approved by the FDA in 2006 to treat cutaneous T cell lymphoma. A similar randomized study conducted worldwide was stopped early by the independent data monitoring committee and is in the process of being analyzed.
Vorinostat may be affecting histones, abundant spool-like proteins around which the cell's DNA is wound, and other proteins important for cell division such as tubulin. Scientists believe these effects could enhance the DNA-damaging and cell division-inhibiting effects of carboplatin and paclitaxel, respectively.
Emory University, University of Chicago, City of Hope Cancer Center, University of Pittsburgh Medical Center, University of California Davis Cancer Center and Penn State Hershey Cancer Institute participated in the study, which was supported by the Cancer Therapy Evaluation Program of the National Cancer Institute.
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