Originally published as JCO Early Release 10.1200/JCO.2007.15.0375 on May 27 2008

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Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non–Small-Cell Lung Cancer

Giorgio Vittorio Scagliotti, Purvish Parikh, Joachim von Pawel, Bonne Biesma, Johan Vansteenkiste, Christian Manegold, Piotr Serwatowski, Ulrich Gatzemeier, Raghunadharao Digumarti, Mauro Zukin, Jin S. Lee, Anders Mellemgaard, Keunchil Park, Shehkar Patil, Janusz Rolski, Tuncay Goksel, Filippo de Marinis, Lorinda Simms, Katherine P. Sugarman, David Gandara

From the University of Torino, Orbassano; San Camillo-Forlanini Hospitals, Rome, Italy; Tata Memorial Hospital, Mumbai; Nizam's Institute of Medical Sciences, Hyderabad; Bangalore Institute of Oncology, Bangalore, India; Asklepios-Fachkliniken Munchen, Gauting; Heidelberg University Medical Center, Mannheim; Hospital Grosshansdorf, Grosshansdorf, Germany; Jeroen Bosch Ziekenhuis, 's-Hertogenbosch, the Netherlands; University Hospital Gasthuisberg, Leuven, Belgium; Specjalistyczny Szpital Im, Szczecin; Maria Sklodowska-Curie Memorial Institute, Krakow, Poland; National Cancer Institute-Brazil, Rio de Janeiro, Brazil; National Cancer Center, Goyang; Samsung Medical Center, Seoul, South Korea; Herlev University Hospital, Herlev, Denmark; Ege University, Izmir, Turkey; Eli Lilly & Co, Canada, Toronto, Ontario Canada; Eli Lilly & Co, Indianapolis, IN; University of California Davis Cancer Center, Sacramento, CA

Corresponding author: Giorgio Vittorio Scagliotti, MD, University of Torino, Department of Clinical and Biological Sciences, S. Luigi Hospital, Regione Gonzole, 10, Orbassano (Torino), Italy 10043; e-mail: giorgio.scagliotti{at}unito.it

Purpose Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting.

Patients and Methods This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m² on day 1 and gemcitabine 1,250 mg/m² on days 1 and 8 (n = 863) or cisplatin 75 mg/m² and pemetrexed 500 mg/m² on day 1 (n = 862) every 3 weeks for up to six cycles.

Results Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.

Conclusion In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

published online ahead of print at www.jco.org on May 27, 2008.

Supported by Eli Lilly & Co, Indianapolis, IN.

Presented at the 12th World Conference on Lung Cancer, September 1-6, 2007, Seoul, South Korea; and the 14th European Cancer Conference, September 23-26, 2007, Barcelona, Spain.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on www.JCO.org.

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