Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.
BACKGROUND
Several studies have shown the efficacy, tolerability, and ease of administration of pemetrexed-an antifolate antineoplastic agent-in patients with advanced non-small-cell lung cancer. We assessed pemetrexed as maintenance therapy in patients with this disease.


METHODS
This randomised double-blind study was undertaken in 83 centres in 20 countries. 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed (500 mg/m(2), day 1) plus best supportive care (n=441) or placebo plus best supportive care (n=222) in 21-day cycles until disease progression. Treatment was randomised with the Simon and Pocock minimisation method. Patients and investigators were masked to treatment. All patients received vitamin B(12), folic acid, and dexamethasone. The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00102804.


RESULTS
All randomly assigned participants were analysed. Pemetrexed significantly improved progression-free survival (4.3 months [95% CI 4.1-4.7] vs 2.6 months [1.7-2.8]; hazard ratio [HR] 0.50, 95% CI 0.42-0.61, p<0.0001) and overall survival (13.4 months [11.9-15.9] vs 10.6 months [8.7-12.0]; HR 0.79, 0.65-0.95, p=0.012) compared with placebo. Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group (21 [5%] vs three [1%]). Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (70 [16%] vs nine [4%]; p<0.0001), specifically fatigue (22 [5%] vs one [1%], p=0.001) and neutropenia (13 [3%] vs 0, p=0.006). No pemetrexed-related deaths occurred. Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs 149 [67%]; p=0.0001).


CONCLUSIONS
Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer.


BACKGROUND
Eli Lilly.
Ciuleanu
Tudor
T
Oncological Institute Ion Chiricuta, Cluj, Romania.
Brodowicz
Thomas
T
Zielinski
Christoph
C
Kim
Joo Hang
JH
Krzakowski
Maciej
M
Laack
Eckart
E
Wu
Yi-Long
YL
Bover
Isabel
I
Begbie
Stephen
S
Tzekova
Valentina
V
Cucevic
Branka
B
Pereira
Jose Rodrigues
JR
Yang
Sung Hyun
SH
Madhavan
Jayaprakash
J
Sugarman
Katherine P
KP
Peterson
Patrick
P
John
William J
WJ
Krejcy
Kurt
K
Belani
Chandra P
CP
D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005971:Glutamates / Q000009:adverse effects / Q000627:therapeutic use*; D006147:Guanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced; D000068437:Pemetrexed; D011379:Prognosis; D016016:Proportional Hazards Models; D015996:Survival Rate; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine