1. Phase I trial of everolimus in combination with thoracic radiotherapy in non-small-cell lung cancer
- Author
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M. Angokai, C. Hennequin, Rastislav Bahleda, Laura Faivre, A. Levy, Yungan Tao, J.P. Pignon, Jean-Charles Soria, Désirée Deandreis, Eric Deutsch, C. Le Pechoux, Sofia Rivera, Eric Angevin, and Benjamin Besse
- Subjects
Male ,Oncology ,Lung Neoplasms ,Time Factors ,medicine.medical_treatment ,Administration, Oral ,Phases of clinical research ,Kaplan-Meier Estimate ,Risk Factors ,Carcinoma, Non-Small-Cell Lung ,Antineoplastic Combined Chemotherapy Protocols ,Non-Small-Cell Lung ,Conformal ,TOR Serine-Threonine Kinases ,Vinorelbine ,Radiotherapy Dosage ,Chemoradiotherapy ,Hematology ,Middle Aged ,Chemotherapy regimen ,Treatment Outcome ,Administration ,Disease Progression ,Female ,France ,medicine.drug ,Oral ,Adult ,medicine.medical_specialty ,Maximum Tolerated Dose ,Urology ,Vinblastine ,Disease-Free Survival ,Drug Administration Schedule ,Phase I ,Internal medicine ,medicine ,Humans ,Everolimus ,Concomitant combination ,Non-small-cell lung cancer ,Thoracic radiotherapy ,Aged ,Cisplatin ,Neoplasm Staging ,Protein Kinase Inhibitors ,Radiotherapy, Conformal ,Lung cancer ,Chemotherapy ,Radiotherapy ,business.industry ,Carcinoma ,medicine.disease ,Radiation therapy ,Concomitant ,business - 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.
- Published
- 2015