Originally published as JCO Early Release 10.1200/JCO.2008.20.8793 on May 26 2009

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Japanese-US Common-Arm Analysis of Paclitaxel Plus Carboplatin in Advanced Non–Small-Cell Lung Cancer: A Model for Assessing Population-Related Pharmacogenomics

From the Southwest Oncology Group, San Antonio, TX; University of California Davis Cancer Center, Sacramento; and University of Southern California Norris Cancer Center, Los Angeles, CA; Cancer Research and Biostatistics, Seattle, WA; Japan Multinational Trial Organization, Kobe; National Kinki-chuo Chest Medical Center, Sakai; Kyoto University Hospital, Kyoto; National Cancer Center Hospital, Tokyo; National Cancer Center Hospital East, Kashiwa, Chiba; and Kinki University School of Medicine, Osakasayama, Osaka, Japan; University of Kansas, Kansas City, MO; University Hospital, Bern, Switzerland; and University of North Carolina, Chapel Hill, NC.

Corresponding author: David R. Gandara, MD, University of California Davis Cancer Center, 4501 X St, Suite 3017, Sacramento, CA 95817-2229; e-mail: david.gandara{at}ucdmc.ucdavis.edu.

Purpose To explore whether population-related pharmacogenomics contribute to differences in patient outcomes between clinical trials performed in Japan and the United States, given similar study designs, eligibility criteria, staging, and treatment regimens.

Methods We prospectively designed and conducted three phase III trials (Four-Arm Cooperative Study, LC00-03, and S0003) in advanced-stage, non–small-cell lung cancer, each with a common arm of paclitaxel plus carboplatin. Genomic DNA was collected from patients in LC00-03 and S0003 who received paclitaxel (225 mg/m²) and carboplatin (area under the concentration-time curve, 6). Genotypic variants of CYP3A4, CYP3A5, CYP2C8, NR1I2-206, ABCB1, ERCC1, and ERCC2 were analyzed by pyrosequencing or by PCR restriction fragment length polymorphism. Results were assessed by Cox model for survival and by logistic regression for response and toxicity.

Results Clinical results were similar in the two Japanese trials, and were significantly different from the US trial, for survival, neutropenia, febrile neutropenia, and anemia. There was a significant difference between Japanese and US patients in genotypic distribution for CYP3A4*1B (P = .01), CYP3A5*3C (P = .03), ERCC1 118 (P < .0001), ERCC2 K751Q (P < .001), and CYP2C8 R139K (P = .01). Genotypic associations were observed between CYP3A4*1B for progression-free survival (hazard ratio [HR], 0.36; 95% CI, 0.14 to 0.94; P = .04) and ERCC2 K751Q for response (HR, 0.33; 95% CI, 0.13 to 0.83; P = .02). For grade 4 neutropenia, the HR for ABCB1 3425CT was 1.84 (95% CI, 0.77 to 4.48; P = .19).

Conclusion Differences in allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese and US patients. In an exploratory analysis, genotype-related associations with patient outcomes were observed for CYP3A4*1B and ERCC2 K751Q. This common-arm approach facilitates the prospective study of population-related pharmacogenomics in which ethnic differences in antineoplastic drug disposition are anticipated.

Supported in part by Public Health Service Cooperative Agreement Grants. No CA32102, CA38926 CA46441, CA58416, CA46282, CA35261, CA58658, CA35431, CA45807, CA58882, CA35119, CA12644, CA67663, CA63844, CA45808, CA35128, CA20319, CA42777, CA16385, CA45377, CA52654, CA67575, CA22433, CA35192, CA46113, CA35176, CA74647, CA37981, CA74811, CA11083, CA14028, CA27057, CA58861, CA45461, CA35090, CA5686, GM63340 (all awarded by the National Cancer Institute, Department of Health and Human Services); and by the Hope Foundation.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA; the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA; and the 43rd Annual Meeting of the American Society of Clinical Oncology, May 29-June 2, 2007, Chicago, IL.

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

Clinical Trials repository link available on JCO.org.

Clinical trial information can be found for the following: NCT00006484.

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