A phase II pharmacodynamic study of erlotinib in patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy.
OBJECTIVE
To examine potential markers of clinical benefit and the effects of erlotinib on the epidermal growth factor receptor (EGFR) signaling pathway in advanced non-small cell lung cancer patients refractory to platinum-based chemotherapy.


METHODS
Patients were given erlotinib (150 mg/d). Tumor biopsies were done immediately before treatment and in a subgroup of patients after 6 weeks' treatment.


RESULTS
Of 73 evaluable patients, 7 (10%) had partial response and 28 (38%) had stable disease. In 53 patients with baseline tumor samples, no relationship was observed between pretreatment levels of EGFR, phosphorylated (p)-EGFR, p-AKT, p-mitogen-activated protein kinase (MAPK), or p27 and clinical benefit (i.e., response, or stable disease >/=12 weeks). Tumors from 15 of 57 patients had high EGFR gene copy number, assessed using fluorescence in situ hybridization (FISH positive), 10 of whom had clinical benefit, compared with 5 of 42 FISH-negative patients. FISH-positive patients had longer median progression-free [137 versus 43 days, P = 0.002; hazard ratio (HR), 0.37] and overall (226 versus 106 days, P = 0.267; HR, 0.70) survival than FISH-negative patients. In paired biopsy samples from 14 patients, p-EGFR (P = 0.002), p-MAPK (P = 0.001), and Ki-67 (P = 0.025) levels were significantly reduced after 6 weeks' treatment. Apoptosis was significantly increased in patients with clinical benefit (P = 0.029), and may be a marker of clinical benefit.


CONCLUSIONS
In this study, EGFR FISH-positive status was associated with improved outcome after erlotinib therapy. Erlotinib led to reduced levels of p-EGFR, p-MAPK, and Ki-67, and stimulated apoptosis in tumor samples from patients with clinical benefit.
Felip
Enriqueta
E
Medical Oncology Service and Pathology Service, Vall d'Hebron University Hospital, Barcelona, Spain.
Rojo
Federico
F
Reck
Martin
M
Heller
Astrid
A
Klughammer
Barbara
B
Sala
Gemma
G
Cedres
Susana
S
Peralta
Sergio
S
Maacke
Heiko
H
Foernzler
Dorothee
D
Parera
Marta
M
Möcks
Joachim
J
Saura
Cristina
C
Gatzemeier
Ulrich
U
Baselga
José
J
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D018450:Disease Progression; D000069347:Erlotinib Hydrochloride; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018773:Genes, erbB-1; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D017671:Platinum Compounds / Q000008:administration & dosage*; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
D017671:Platinum Compounds; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride