1. Phase I trial of everolimus in combination with thoracic radiotherapy in non-small-cell lung cancer.
- Author
-
Deutsch E, Le Péchoux C, Faivre L, Rivera S, Tao Y, Pignon JP, Angokai M, Bahleda R, Deandreis D, Angevin E, Hennequin C, Besse B, Levy A, and Soria JC
- Subjects
- Administration, Oral, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Chemoradiotherapy adverse effects, Chemoradiotherapy mortality, Cisplatin administration & dosage, Disease Progression, Disease-Free Survival, Drug Administration Schedule, Everolimus adverse effects, Female, France, Humans, Kaplan-Meier Estimate, Lung Neoplasms enzymology, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Staging, Protein Kinase Inhibitors adverse effects, Radiotherapy Dosage, Risk Factors, TOR Serine-Threonine Kinases antagonists & inhibitors, TOR Serine-Threonine Kinases metabolism, Time Factors, Treatment Outcome, Vinblastine administration & dosage, Vinblastine analogs & derivatives, Vinorelbine, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Carcinoma, Non-Small-Cell Lung therapy, Chemoradiotherapy methods, Everolimus administration & dosage, Lung Neoplasms therapy, Protein Kinase Inhibitors administration & dosage, Radiotherapy, Conformal adverse effects, Radiotherapy, Conformal mortality
- Abstract
Background: This phase I study evaluated the safety and efficacy of the oral mTOR inhibitor everolimus in combination with thoracic radiotherapy followed by consolidation chemotherapy in locally advanced or oligometastatic untreated non-small-cell lung cancer (NSCLC)., Patients and Methods: Everolimus dose was escalated in incremental steps [sequential cohorts of three patients until the occurrence of dose-limiting toxicity (DLT)] and administered orally weekly (weekly group: dose of 10, 20 or 50 mg) or daily (daily group: 2.5, 5 or 10 mg), 1 week before, and during radiotherapy until 3.5 weeks after the end of radiotherapy. Two cycles of chemotherapy (cisplatin-navelbine) were administrated 4.5 weeks after the end of radiotherapy., Results: Twenty-six patients were included in two centers, 56% had adenocarcinoma and 84% had stage III disease. In the weekly group (12 assessable patients), everolimus could be administered safely up to the maximum planned weekly dose of 50 mg; however, one patient experienced a DLT of interstitial pneumonitis at the weekly dose level of 20 mg. In the daily group (9 assessable patients): one DLT of interstitial pneumonitis with a fatal outcome was observed at the daily dose level of 2.5 mg; two other DLTs (one grade 3 esophagitis and one bilateral interstitial pneumonitis) were found at the daily dose level of 5 mg. Overall there were five patients with G3-4 interstitial pneumonitis related to treatment. Among 22 assessable patients for response, there were 9 (41%) partial response and 7 (32%) stable disease. At a median follow-up of 29 months, the 2-year overall survival and progression-free survival actuarial rates were 31% and 12%, respectively., Conclusion: In previously untreated and unselected NSCLC patients, the recommended phase II dose of everolimus in combination with thoracic radiotherapy is 50 mg/week. Pulmonary toxicity is of concern and should be carefully monitored to establish the potential role of mTOR inhibitor with concomitant radiotherapy., Eudract N: 2007-001698-27., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2015
- Full Text
- View/download PDF