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Randomized Phase III Trial Comparing Bexarotene (L1069-49)/Cisplatin/Vinorelbine With Cisplatin/Vinorelbine in Chemotherapy-Naïve Patients With Advanced or Metastatic Non–Small-Cell Lung Cancer: SPIRIT I

Rodryg Ramlau, Petr Zatloukal, Jacek Jassem, Paul Schwarzenberger, Sergei V. Orlov, Maya Gottfried, Jose Rodrigues Pereira, Guillermo Temperley, Rosa Negro-Vilar, Samia Rahal, Joseph K. Zhang, Andres Negro-Vilar, Zofia E. Dziewanowska

From the Regional Center of Lung Diseases, Oncology Department, Pozna, Poland; Charles University, Postgraduate Medical School, Prague, Czech Republic; Medical University of Gdask, Department of Oncology and Radiotherapy, Gdask, Poland; Gulf Coast Minority-Based Community Clinical Oncology Program, Mobile, AL; Saint Petersburg Pavlov State Medical University, Laboratory of Thoracic Oncology, Saint Petersburg, Russia; Meir Hospital, Institute of Oncology, Kfar Saba, Israel; Arnaldo Vieira de Carvalho Cancer Institute, São Paulo, Brazil; Marie Curie Cancer Hospital, Internal Medicine, Buenos Aires, Argentina; and Ligand Pharmaceuticals, San Diego, CA

Corresponding author: Rodryg Ramlau, MD, PhD, Lung Disease Centre, Oncology Department, ul.Szamarzewskiego, Pozna, Poland 60-569; e-mail: rramlau{at}wcchpig.pl

Purpose This study evaluated whether the combination of the synthetic rexinoid bexarotene with first-line cisplatin/vinorelbine therapy provides additional survival benefit in patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods Patients with stage IIIB with pleural effusion or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to open-label bexarotene 400 mg/m²/d with cisplatin/vinorelbine or to cisplatin/vinorelbine alone. Antilipid agents were initiated on or before day 1 in the bexarotene arm. Primary efficacy end point was overall survival. Primary, secondary and supportive efficacy analyses were conducted.

Results A total of 623 patients (312 control, 311 bexarotene) were enrolled. Overall, no significant difference in survival occurred between the two treatment groups. However, an unplanned retrospective analysis showed that a subpopulation of bexarotene patients (n = 98 of 306) who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had longer median survival compared with control patients (12.3 v 9.9 months; log-rank P = .08). Within that subgroup, those who benefited the most included males, smokers, those with stage IV disease, and those with a 6-month prior weight loss of 5% or more. Incidence, type and severity of grade 3/4 adverse events were comparable between arms, except for leukopenia (higher in chemotherapy arm) and hyperlipemia, hypothyroidism, dyspnea, and headache (higher in chemotherapy/bexarotene arm).

Conclusion The addition of bexarotene to first-line chemotherapy did not increase survival in patients with advanced NSCLC. However, a subgroup (32%) of bexarotene-treated patients developing high-grade hypertriglyceridemia appeared to have better survival (12.3 months) than controls; thus triglyceride response may be a biomarker of survival benefit with bexarotene.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL, and at 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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