Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer.
BACKGROUND
Preclinical studies have demonstrated that the inhibition of the PI3K/Akt/mTOR pathway restores gefitinib sensitivity in resistant cancer cell lines. A phase 1 study was conducted of the combination of everolimus, an mTOR inhibitor, and gefitinib to determine a daily dose of everolimus with gefitinib in patients with advanced nonsmall-cell lung cancer (NSCLC).


METHODS
Oral everolimus and gefitinib were both administered daily to patients with progressive NSCLC. Patients were enrolled in 3-patient cohorts at everolimus dose levels of 5 and 10 mg daily. All patients received gefitinib 250 mg daily.


RESULTS
Ten patients were enrolled. The maximum tolerated dose of everolimus was 5 mg when administered daily with gefitinib 250 mg. Two patients who were treated at the 10 mg dose level of everolimus experienced dose-limiting toxicity, including grade 5 hypotension and grade 3 stomatitis. Pharmacokinetic studies demonstrated no consistent, significant interaction on the t(max), C(max), and AUC(0-8h) of either agent. Two partial radiographic responses were identified among the 8 response-evaluable patients.


CONCLUSIONS
For further study, everolimus at a dose of 5 mg daily in combination with daily gefitinib 250 mg is recommended. The 2 radiographic responses identified are encouraging. A phase 2 trial in patients with NSCLC is under way.
Milton
Daniel T
DT
Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, New York, USA.
Riely
Gregory J
GJ
Azzoli
Christopher G
CG
Gomez
Jorge E
JE
Heelan
Robert T
RT
Kris
Mark G
MG
Krug
Lee M
LM
Pao
William
W
Pizzo
Barbara
B
Rizvi
Naiyer A
NA
Miller
Vincent A
VA
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D015996:Survival Rate; D014481:United States / Q000453:epidemiology
D011799:Quinazolines; D000068338:Everolimus; D000077156:Gefitinib; D020123:Sirolimus