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Phase III Trial Comparing Carboplatin, Paclitaxel, and Bexarotene With Carboplatin and Paclitaxel in Chemotherapy-Naïve Patients With Advanced or Metastatic Non–Small-Cell Lung Cancer: SPIRIT II

George R. Blumenschein, Jr, Fadlo R. Khuri, Joachim von Pawel, Ulrich Gatzemeier, Wilson H. Miller, Jr, Robert M. Jotte, Jacques Le Treut, Show-Li Sun, Jinkun K. Zhang, Zofia E. Dziewanowska, Andres Negro-Vilar

From Department of Thoracic/Head & Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Clinical and Translational Research, Winship Cancer Institute at Emory University, Atlanta, GA; Ligand, San Diego, CA; US Oncology, Rocky Mountain Cancer Centers, Houston, TX; Zentralkrankenhaus Gauting, Abteilung Onkologie, Gauting bei Muenchen; Grosshansdorf Hospital, Grosshansdorf; Zentralkrankenhaus, Gauting, Germany; Department of Oncology, Sir Mortimer B. Davis - Jewish General Hospital, Montreal, Quebec, Canada; and Groupe Français de Pneumo Cancérologie, Aix en Provence, France

Corresponding author: George R. Blumenschein Jr, MD, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 432, Houston, TX 77030; e-mail: gblumens{at}mdanderson.org

Purpose: The purpose of this study was to determine whether addition of the synthetic rexinoid bexarotene (Targretin; Eisai Inc, Woodcliff Lake, NJ) to standard first-line carboplatin and paclitaxel therapy provides additional survival benefit in patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods: Patients with stage IIIB disease with pleural effusion, or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1, were randomly assigned to bexarotene 400 mg/m²/d combined with carboplatin and paclitaxel, or assigned to carboplatin and paclitaxel alone. Bexarotene patients also received lipid-lowering agents on or before day 1. The primary efficacy end point was overall survival; secondary efficacy and supportive analyses were also conducted.

Results: A total of 612 patients (306 per arm) were enrolled onto the study. In the intent-to-treat population, no significant difference in survival occurred between the two arms. However, a subpopulation (approximately 40%) of bexarotene-treated patients who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had significantly longer median survival than control patients (12.4 v 9.2 months; log-rank, P = .014). Bexarotene-treated patients with grade 3/4 hypertriglyceridemia who received the most benefit included those who were male, were smokers, experienced 6-month prior weight loss 5%, and had stage IV disease. The incidence and severity of most adverse events were similar between arms, although hyperlipidemia, neutropenia, fatigue, leukopenia, arthralgia, and diarrhea were more frequent in the bexarotene arm.

Conclusion: Although the addition of bexarotene to chemotherapy did not improve survival in the overall study population, occurrence of high-grade hypertriglyceridemia in bexarotene-treated patients strongly correlated with increased survival, suggesting that bexarotene may benefit a segment of first-line NSCLC patients.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; and the 11th World Conference on Lung Cancer, July 3-6, 2005, Barcelona, Spain.

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

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