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Originally published as JCO Early Release 10.1200/JCO.2008.19.5560 on October 20 2008 © 2008 American Society of Clinical Oncology.
In Reply
University of Torino, Orbassano, Italy
Eli Lilly & Co, Indianapolis, Indiana Drs Janku and Bird expressed interest in our study and we appreciate their detailed review of other studies of pemetrexed in patients with advanced non–small-cell lung cancer (NSCLC). In response, we would like to discuss the significance of the histology results in these trials, supporting our recommendation that cisplatin/pemetrexed be used as a reference regimen in future studies for patients with nonsquamous NSCLC. A retrospective analysis1 of the randomized phase III study in patients (N = 571) with previously treated advanced NSCLC2 identified a statistically significant improvement in overall survival (OS) for nonsquamous patients treated with pemetrexed, compared with docetaxel (median OS, 9.3 v 8.0 months, respectively; hazard ratio [HR], 0.778, P = .048). Based on these results, as well as supporting preclinical evidence,3 analyses were prespecified in two subsequent phase III studies investigating pemetrexed as first-line and maintenance treatment in order to examine efficacy according to NSCLC histology.4,5 Results from our phase III study (N = 1,725), the largest ever performed in first-line NSCLC, confirmed a statistically significant survival advantage for nonsquamous patients treated with cisplatin/pemetrexed, compared with cisplatin/gemcitabine (median OS 11.8 v 10.4 months, respectively; HR, 0.81; P = .005).4 Our study used cisplatin/gemcitabine as the comparator based on the results of phase III studies that concluded that this regimen is as effective as several other platinum doublets.6,7 It is important to note that the histology analysis was prospectively planned, and the size of the nonsquamous patient population in this trial (n = 1,000) provided sufficient statistical power for the observed difference. The results from our trial demonstrate that cisplatin/pemetrexed is superior to cisplatin/gemcitabine for the first-line treatment of advanced nonsquamous NSCLC. In both phase III trials, statistically significant treatment by histology interactions were observed for pemetrexed (P = .001 for the previously treated NSCLC trial, and P = .0011 for our first-line NSCLC trial).1,4 More recently, results from a third phase III study investigating pemetrexed as maintenance treatment for advanced NSCLC (N = 663) were presented at the 2008 American Society of Clinical Oncology Annual Meeting. Results from this study demonstrated improved efficacy after four cycles of a platinum-based regimen for nonsquamous patients receiving maintenance pemetrexed, compared with placebo (preliminary median OS 14.4 v 9.4 months, respectively; P = .005).5 We agree that, historically, published results from chemotherapy studies have not identified a strong prognostic or predictive role for NSCLC histology; this is confirmed by a recent review of the literature.8 However, in the case of pemetrexed, the current clinical evidence is strong and supported by multiple studies.1,4,5,9 In these studies, pemetrexed consistently demonstrated a differential effect by histology, with improved efficacy in nonsquamous NSCLC compared with squamous cell carcinoma. The predictive role for histology in pemetrexed studies is further supported by statistically significant treatment by histology interactions, confirming that this is a real effect that is unique to pemetrexed versus active comparators.1,4 The evolution of personalized medicine is the future of cancer care, and our results demonstrate that histology is an important factor for patients and physicians to consider in treatment decisions. The strong statistical evidence supports this conclusion, demonstrating that the significant treatment by histology effects for pemetrexed across multiple trials are not the result of a statistical aberration. In conclusion, we believe that the clinical benefit of pemetrexed treatment in patients with advanced nonsquamous NSCLC has been consistently confirmed across three randomized, phase III trials, and future studies should consider a pemetrexed-based regimen as a reference regimen. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Katherine P. Sugarman, Eli Lilly & Co (C) Consultant or Advisory Role: Giorgio V. Scagliotti, Eli Lilly & Co (C) Stock Ownership: Katherine P. Sugarman, Eli Lilly & Co Honoraria: Giorgio V. Scagliotti, Eli Lilly & Co, Hoffman-La Roche Inc, Sanofi-aventis Research Funding: None Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on October 20, 2008 REFERENCES 1. Peterson P, Park K, Fossella F, et al: Is pemetrexed more effective in adenocarcinoma and large cell carcinoma than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC). J Thorac Oncol 2:S851, 2007 (suppl 4; abstr P2-238)[CrossRef] 2. Hanna N, Shepherd FA, Fossella FV, et al: Randomized phase III trial of pemetrexed versus docetaxel in patients with non–small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589-1597, 2004 3. Ceppi P, Volante M, Saviozzi S, et al: Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer 107:1589-1596, 2006[CrossRef][Medline] 4. Scagliotti GV, Parikh P, von Pawel J, et al: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543-3551, 2008 5. Ciuleanu TE, Brodowicz T, Belani CP, et al: Maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC: A phase III study. J Clin Oncol 26:426s, 2008 (suppl, abstr 8011) 6. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002 7. Scagliotti GV, De Marinis F, Rinaldi M, et al: Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 20:4285-4291, 2002 8. Hirsch FR, Spreafico A, Novello S, et al: The prognostic and predictive role of histology in advanced non-small cell lung cancer: A literature review. J Thorac Oncol (in press) 9. Ohe Y, Ichinose Y, Nakagawa K, et al: Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer. Clin Cancer Res 14:4206-4212, 2008
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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