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The Differential Efficacy of Pemetrexed According to NSCLC Histology: A Review of Two Phase III Studies

^aThoracic Oncology Unit, University of Turin, San Luigi Hospital, Orbassano (Torino), Italy; ^bIndiana University, Indianapolis, Indiana, USA; ^cMD Anderson Cancer Center, Houston, Texas, USA; ^dEli Lilly and Company, Indianapolis, Indiana, USA; ^eEli Lilly and Company, Bad Hamburg, Germany; ^fEli Lilly and Company, Toronto, Ontario, Canada; ^gPrincess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada

Key Words. Non-small cell lung cancer • Pemetrexed • Nonsquamous histology • Adenocarcinoma • Squamous cell carcinoma • Large cell carcinoma • Thymidylate synthase

Correspondence: Correspondence: Giorgio Scagliotti, M.D., Ph.D., University of Torino, Department of Clinical and Biological Sciences, San Luigi Hospital, Regione Gonzole, 10, Orbassano (Torino) 10043, Italy. Telephone: (39) 011-9026414; Fax: (39) 011-9038616; e-mail: giorgio.scagliotti{at}unito.it.

Received October 23, 2008; accepted for publication February 3, 2009.

Disclosures

Giorgio Scagliotti: Honoraria: Eli Lilly and Company, Sanofi Aventis, Roche, GlaxoSmithKline; Nasser Hanna: Honoraria: Eli Lilly; Frank Fossella: None; Katherine Sugarman: Employment/leadership position: Eli Lilly and Company; Johannes Blatter: Employment/leadership position: Eli Lilly and Company; Patrick Peterson: Employment/leadership position: Eli Lilly and Company; Lorinda Simms: Employment/leadership position: Eli Lilly and Company; Frances A. Shepherd: Honoraria: Eli Lilly and Company; Ownership interest: Eli Lilly and Company. These studies were sponsored by Eli Lilly and Company.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by independent peer reviewers.

Background. Recent studies of pemetrexed have identified a predictive role for non-small cell lung cancer (NSCLC) histology. We further reviewed the differential efficacy of pemetrexed according to histology in two large, phase III NSCLC trials.

Methods. One study tested pemetrexed versus docetaxel in previously treated patients (n = 571) and the other tested cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy-naive patients (n = 1,725) with advanced NSCLC. Cox proportional hazard models were used to test for covariate-adjusted treatment-by-histology interactions (THIs) for overall survival (OS) and progression-free survival (PFS). For each histologic subgroup, the Kaplan–Meier method was used to estimate unadjusted within-arm medians, and Cox models were used to estimate covariate-adjusted between-arm hazard ratios (HRs).

Results. In both studies, treatment arms were well balanced for histology. THIs were statistically significant (p < .005) for both OS and PFS. Nonsquamous patients treated with pemetrexed-based therapy experienced longer survival than the comparators (HR, 0.78 and 0.84, respectively), whereas squamous patients had shorter survival (HR, 1.56 and 1.23, respectively). Whereas the efficacy of pemetrexed regimens differed according to histology, it did not differ for docetaxel or for cisplatin plus gemcitabine. Pemetrexed was well tolerated across histologic groups.

Conclusions. The consistency of these results across studies confirms the predictive effect of histology for pemetrexed and the survival advantage for pemetrexed in patients with nonsquamous histology. These analyses suggest pemetrexed should not be recommended for the treatment of squamous cell carcinoma, but, because of efficacy and safety advantages, pemetrexed may be preferable to other agents for treatment of patients with nonsquamous NSCLC.

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