title: Phase I trial of everolimus in combination with thoracic radiotherapy in non-small-cell lung cancer.
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).
  
  
  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.
  
  
  CONCLUSIONS
  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.
  2007-001698-27.
authors.affiliation: Department of Radiation Oncology; Drug Development Department (DITEP), Gustave Roussy, Paris-Sud University, Villejuif; Paris-Sud University, Kremlin-Bicêtre Medical University, DHU TORINO, SIRIC SOCRATES, LABEX LERMIT; INSERM 1030 Molecular Radiotherapy, Cancer research institute, Villejuif. Electronic address: eric.deutsch@gustaveroussy.fr.
authors.forename: E
authors.initials: E
authors.lastname: Deutsch
authors.affiliation: Department of Radiation Oncology; Institut d'Oncologie Thoracique (IOT).
authors.forename: C
authors.initials: C
authors.lastname: Le Péchoux
authors.affiliation: Departments of Biostatistics.
authors.forename: L
authors.initials: L
authors.lastname: Faivre
authors.affiliation: Department of Radiation Oncology; Drug Development Department (DITEP), Gustave Roussy, Paris-Sud University, Villejuif.
authors.forename: S
authors.initials: S
authors.lastname: Rivera
authors.affiliation: Department of Radiation Oncology; Drug Development Department (DITEP), Gustave Roussy, Paris-Sud University, Villejuif.
authors.forename: Y
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Departments of Biostatistics.
authors.forename: J-P
authors.initials: JP
authors.lastname: Pignon
authors.affiliation: Departments of Biostatistics.
authors.forename: M
authors.initials: M
authors.lastname: Angokai
authors.affiliation: Drug Development Department (DITEP), Gustave Roussy, Paris-Sud University, Villejuif.
authors.forename: R
authors.initials: R
authors.lastname: Bahleda
authors.affiliation: Nuclear Medicine, Gustave Roussy, Villejuif.
authors.forename: D
authors.initials: D
authors.lastname: Deandreis
authors.affiliation: Drug Development Department (DITEP), Gustave Roussy, Paris-Sud University, Villejuif.
authors.forename: E
authors.initials: E
authors.lastname: Angevin
authors.affiliation: Department of Radiation Oncology, Saint Louis Hospital, Paris.
authors.forename: C
authors.initials: C
authors.lastname: Hennequin
authors.affiliation: Institut d'Oncologie Thoracique (IOT); Department of Medicine, Gustave Roussy, Villejuif, France.
authors.forename: B
authors.initials: B
authors.lastname: Besse
authors.affiliation: Department of Radiation Oncology; Drug Development Department (DITEP), Gustave Roussy, Paris-Sud University, Villejuif; INSERM 1030 Molecular Radiotherapy, Cancer research institute, Villejuif; Institut d'Oncologie Thoracique (IOT).
authors.forename: A
authors.initials: A
authors.lastname: Levy
authors.affiliation: Drug Development Department (DITEP), Gustave Roussy, Paris-Sud University, Villejuif; Paris-Sud University, Kremlin-Bicêtre Medical University, DHU TORINO, SIRIC SOCRATES, LABEX LERMIT; Institut d'Oncologie Thoracique (IOT).
authors.forename: J-C
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D059248:Chemoradiotherapy / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D002945:Cisplatin / Q000008:administration & dosage; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005602:France; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000201:enzymology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011879:Radiotherapy Dosage; D020266:Radiotherapy, Conformal / Q000009:adverse effects / Q000401:mortality; D012307:Risk Factors; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D047428:Protein Kinase Inhibitors; D014747:Vinblastine; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin; D000077235:Vinorelbine
keywords: concomitant combination; everolimus; non-small-cell lung cancer; phase I; thoracic radiotherapy