Saiama N Waqar1, Clifford Robinson2, Jeffrey Bradley2, Boone Goodgame3, Melissa Rooney1, Kristina Williams1, Feng Gao4, Ramaswamy Govindan5. 1. Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO. 2. Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO. 3. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX. 4. Division of Biostatistics, Washington University School of Medicine, St Louis, MO. 5. Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO. Electronic address: rgovinda@dom.wustl.edu.
Abstract
BACKGROUND: The addition of targeted agents to thoracic radiation has not improved outcomes in patients with locally advanced non-small-cell lung cancer (NSCLC). To improve cure rates in locally advanced NSCLC, effective targeted therapies need to be identified that can be given safely with radiation therapy. Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) pathway and has single-agent activity in lung cancer. Inhibition of the mTOR pathway has been found to augment the cytotoxic effect of radiation in preclinical studies. There is scant clinical experience with mTOR inhibitors and radiation. PATIENTS AND METHODS: This was a phase I study evaluating the combination of temsirolimus with thoracic radiation in patients with NSCLC. RESULTS: Ten patients were enrolled in the study. The dose-limiting toxicities included sudden death, pneumonitis, and pulmonary hemorrhage. The maximum tolerated dose of temsirolimus that could be administered safely with concurrent radiotherapy (35 Gy in 14 daily fractions) was 15 mg intravenously weekly. Of the 8 evaluable patients, 3 had a partial response and 2 had stable disease. CONCLUSION: The combination of temsirolimus 15 mg weekly and thoracic radiation is well tolerated and warrants further investigation, perhaps in a molecularly defined subset of patients.
BACKGROUND: The addition of targeted agents to thoracic radiation has not improved outcomes in patients with locally advanced non-small-cell lung cancer (NSCLC). To improve cure rates in locally advanced NSCLC, effective targeted therapies need to be identified that can be given safely with radiation therapy. Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) pathway and has single-agent activity in lung cancer. Inhibition of the mTOR pathway has been found to augment the cytotoxic effect of radiation in preclinical studies. There is scant clinical experience with mTOR inhibitors and radiation. PATIENTS AND METHODS: This was a phase I study evaluating the combination of temsirolimus with thoracic radiation in patients with NSCLC. RESULTS: Ten patients were enrolled in the study. The dose-limiting toxicities included sudden death, pneumonitis, and pulmonary hemorrhage. The maximum tolerated dose of temsirolimus that could be administered safely with concurrent radiotherapy (35 Gy in 14 daily fractions) was 15 mg intravenously weekly. Of the 8 evaluable patients, 3 had a partial response and 2 had stable disease. CONCLUSION: The combination of temsirolimus 15 mg weekly and thoracic radiation is well tolerated and warrants further investigation, perhaps in a molecularly defined subset of patients.
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