Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1.
OBJECTIVE
The purpose of this study was to determine whether the addition of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE) to standard first-line gemcitabine and cisplatin provides clinical benefit over gemcitabine and cisplatin alone in patients with advanced or metastatic non-small-cell lung cancer (NSCLC). Gefitinib has demonstrated encouraging efficacy in advanced NSCLC in phase II trials in pretreated patients, and a phase I trial of gefitinib in combination with gemcitabine and cisplatin showed favorable tolerability.


METHODS
This was a phase III randomized, double-blind, placebo-controlled, multicenter trial in chemotherapy-naive patients with unresectable stage III or IV NSCLC. All patients received up to six cycles of chemotherapy (cisplatin 80 mg/m(2) on day 1 and gemcitabine 1,250 mg/m(2) on days 1 and 8 of the 3-week cycle) plus either gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. Daily gefitinib or placebo was continued until disease progression. End points included overall survival (primary), time to progression, response rates, and safety evaluation.


RESULTS
A total of 1,093 patients were enrolled. There was no difference in efficacy end points between the treatment groups: for the gefitinib 500 mg/d, gefitinib 250 mg/d, and placebo groups, respectively, median survival times were 9.9, 9.9, and 10.9 months (global ordered log-rank [GOLrank] P =.4560), median times to progression were 5.5, 5.8, and 6.0 months (GOLrank; P =.7633), and response rates were 49.7%, 50.3%, and 44.8%. No significant unexpected adverse events were seen.


CONCLUSIONS
Gefitinib in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced NSCLC did not have improved efficacy over gemcitabine and cisplatin alone. The reasons for this remain obscure and require further preclinical testing.
Giaccone
Giuseppe
G
Vrije Universiteit Medical Center, Department of Oncology, De Boelelaan 1117, 1081 Amsterdam, the Netherlands. g.giaccone@vumc.nl
Herbst
Roy S
RS
Manegold
Christian
C
Scagliotti
Giorgio
G
Rosell
Rafael
R
Miller
Vincent
V
Natale
Ronald B
RB
Schiller
Joan H
JH
Von Pawel
Joachim
J
Pluzanska
Anna
A
Gatzemeier
Ulrich
U
Grous
John
J
Ochs
Judith S
JS
Averbuch
Steven D
SD
Wolf
Michael K
MK
Rennie
Pamela
P
Fandi
Abderrahim
A
Johnson
David H
DH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage*; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D011336:Probability; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage*; D012016:Reference Values; D016019:Survival Analysis; D016896:Treatment Outcome; D000093542:Gemcitabine
D011799:Quinazolines; D003841:Deoxycytidine; D002945:Cisplatin; D000077156:Gefitinib; D000093542:Gemcitabine