Randomized Double-Blind Placebo-Controlled Trial of Marimastat in Patients with Small Cell Lung Cancer Following Response to First-Line Chemotherapy: an NCIC-CTG and EORTC Study
Frances A. Shepherd, M.D. National Cancer Institute of Canada-Clinical Trials Group, Toronto, Ontario, Canada
Summary: A Phase III trial of the metalloproteinase inhibitor marimastat for the treatment of small cell lung cancer showed that the agent had no effect on tumor progression. The severe musculoskeletal toxicity accompanying use of the drug has led to a halt of further studies of this agent against lung cancer.
As the first orally administered matrix metalloproteinase inhibitor, marimastat has attracted interest as a possible treatment for several types of cancer. The latest Phase III trial of the drug in the treatment of small cell lung cancer, however, demonstrated no effect on survival compared with placebo. Use of the drug was associated with severe musculoskeletal toxicity, and researchers have halted further development of the agent for treatment of lung cancer.
Marimastat is a general inhibitor of proteolytic matrix enzymes. Excessive expression of these enzymes in cancers such as small cell lung cancer is a poor prognostic sign, associated with metastases and poorly differentiated histologic appearance.
Small cell lung cancer typically responds well to first-line therapy but has a high rate of relapse, which was the reason it was chosen as the model to test potential tumoristatic effects of marimastat.
The Phase III trial included 555 patients with small cell lung cancer that had responded to first-line therapy. After completion of chemotherapy, patients were subsequently treated with oral marimastat or placebo for up to 2 years. There was no statistically significant difference in progression-free survival (4.32 months in the marimastat group and 4.44 months in the placebo group). The difference in overall survival (9.4 months with marimastat and 9.7 months with placebo) was also without statistical significance.
Musculoskeletal toxicity occurred in 63% of patients and required discontinuation of the drug in one third of those affected. Pain scores for overall pain and shoulder pain after 3 and 6 months were also significantly increased. At 6 months, patients on marimastat also reported significantly increased fatigue and worsened quality of life.
Dr. Shepherd stated that the trial's results--- showing that marimastat did not improve time to progression or overall survival and was associated with severe musculoskeletal toxicity adversely affecting quality of life and drug compliance---are considered definitive. Further development of marimastat as an agent for lung cancer has been halted, although it is still being tested for gastrointestinal tumors.
2001 by DOL Inc. All rights reserved.