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Journal of Clinical Oncology, Vol 26, No 11 (April 10), 2008: pp. 1886-1892 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.2614 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
From the Regional Center of Lung Diseases, Oncology Department, Pozna
Corresponding author: Rodryg Ramlau, MD, PhD, Lung Disease Centre, Oncology Department, ul.Szamarzewskiego, Pozna
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.
Lung cancer is the leading cause of death among smokers worldwide.1 Treatment outcomes for advanced non–small-cell lung cancer (NSCLC) using chemotherapeutic agents are disappointing: The 5-year overall survival remains steadily at 15%, despite the use of various combination chemotherapy doublets in the first-line treatment of NSCLC and recent therapeutic advances.2-7 New treatments with novel mechanisms of action, including agents that target angiogenesis and regulation of gene expression by retinoids have been explored.8-13
Retinoids play a critical role in cellular growth modulation, division, induction of differentiation, and activation of apoptosis. Bexarotene is a selective retinoid X receptor (RXR) modulator approved for treatment of cutaneous T-cell lymphoma.9 Bexarotene has been shown to selectively bind and activate various RXR subtypes, including In early trials, bexarotene demonstrated both satisfactory safety and promising efficacy.13,14 Encouraging survival results were observed in phase I monotherapy trials in chemotherapy-refractory patients who had experienced treatment failure with other therapies.15 In a first-line metastatic NSCLC phase I/II study, bexarotene plus cisplatin/vinorelbine showed disease stabilization with median survival of 13.7 months. (Table 1)15 Dose- and time-dependent hyperlipidemia, primarily hypertriglyceridemia, observed in these early studies was expected because of known effects of retinoids on lipid metabolism.16 On the basis of these results, two phase III trials in advanced NSCLC were conducted to evaluate the efficacy and safety of bexarotene plus standard cisplatin/vinorelbine regimen (ST1571 Prospective International Randomised Trial [SPIRIT I], reported herein) or the doublet carboplatin/paclitaxel (SPIRIT II). The primary end point was overall survival, and the secondary end point was 2-year survival. Population pharmacokinetics as well as biochemical and genetic biomarkers were also investigated.
Eligibility Criteria Inclusion criteria included histologically or cytologically confirmed NSCLC (stage IIIB with pleural effusion or stage IV), no prior chemotherapy for NSCLC, at least one measurable or assessable NSCLC lesion, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, anticipation of completion of at least four cycles of cisplatin/vinorelbine chemotherapy, no known brain metastasis, and acceptable organ function. Informed consent was obtained before prestudy assessments. The study protocol was approved by the institutional review board or ethics committee of each participating center in agreement with the regulatory requirements of each country.
Trial Design Eligible patients were randomly assigned to one of two treatment arms (Fig 1). They received vinorelbine 25 mg/m2 infused intravenously (IV) over 10 to 20 minutes once weekly. Once every 4 weeks, vinorelbine infusion was followed by cisplatin 100 mg/m2 infused IV over 30 to 60 minutes. Patients were scheduled for at least four cycles of chemotherapy (one every 4 weeks). Bexarotene (75 mg capsules) was administered at 400 mg/m2/d orally, daily, beginning on day 1. The dosage level was reduced by steps of 100 mg/m2/d if triglyceride levels increased more than 800 mg/dL or temporarily suspended for triglyceride levels greater than 1,200 mg/dL. Bexarotene patients also received an antilipid agent beginning on or before day 1. Doses of antilipid agents could be adjusted upwards if triglyceride levels rose above 400 mg/dL.
Statistical Analysis The statistical design of this study aimed to detect at least 30% survival benefit in the bexarotene arm with 80% power at a two-sided 5%  level using the log-rank test. A 600-patient accrual (300 in each arm) was planned to achieve the target of 456 death events; 623 patients (311 bexarotene, 312 control) were actually enrolled and were in the intention-to-treat (ITT) population. The median follow-up period was 24.5 months (range, 18.9 to 37.8 months). Primary efficacy analysis was a log-rank test for overall survival between arms in ITT patients, stratifying for stage and sex. The secondary efficacy end point was 2-year survival rate. Other end points included median survival, 1-year survival, median progression-free survival (PFS), and safety evaluations. The Cox regression method was used in additional survival analyses. Safety evaluation was based on all patients who were exposed to at least one dose of any study medication. Unplanned and retrospective analyses were carried out on hypertriglyceridemia subgroups in the bexarotene arm to further evaluate bexarotene effects on a special segment of NSCLC patients. All statistical analyses were performed using SAS Software (version 9.1.3; SAS Institute, Cary, NC).
Assessments
Patients The study enrolled patients from Eastern Europe (33%), Western Europe/Israel (19%), South America (17%), Russia (16%), North America (11%), and Australia (4%). Patient demographics (Table 2) show that populations in both arms were well-balanced, although significantly fewer patients with 6-month prior weight loss less than 5% were enrolled in the bexarotene arm(P < .05). In total, 623 patients were enrolled, with 613 receiving at least one dose of any one study drug: 308 patients in the bexarotene arm and 305 patients in the control arm. Chemotherapy exposure was similar between the two arms. Mean number of cycles of cisplatin/vinorelbine received in each arm was comparable: 3.2 cycles in the bexarotene arm and 3.3 cycles in the control arm. The average dose of cisplatin was also comparable: 93.1 mg/m2 (total dose, 288.2 mg/m2) and 93.4 mg/m2 (total dose, 306.4 mg/m2) in the bexarotene and control arms, respectively. The average dose of vinorelbine was 23.3 mg/m2 (total dose, 233.9 mg/m2) and 23.7 mg/m2 (total dose, 255.1 mg/m2), respectively. Subsequent anticancer therapies received were also similar between the two treatment arms (Table A1, online only).
The overall bexarotene mean daily dose was 323 mg/m2; 60% of patients received higher than the mean, whereas 40% received less than the mean. Patients in the bexarotene arm received the following antilipid agents before or at day 1: atorvastatin (56%), other statins (14%), fenofibrate (23%), ciprofibrate (9%) other antilipid agents (4%). Some patients received several agents during the study.
Efficacy Survival in the bexarotene arm was also analyzed with respect to antilipids, to rule out the possibility that the type of agent used might have affected survival. Median survival was 8.1 months in 189 patients treated with statins and 9.7 months in 106 patients treated with fibrates (P = .9). Patients in the bexarotene arm had an overall tumor response rate of 16.7% compared with 24.4% in control patients (P = .0224). Disease stabilization was achieved in 37% and 35.3% patients in the bexarotene and control arms, respectively.
Hypertriglyceridemia Subgroup Analysis
A hazard ratio analysis showed that baseline triglyceride level did not correlate with patient survival, regardless of the treatment patients received. However, it must be noted that patients were required to have normal or normalized triglyceride levels before study initiation. Furthermore, the analysis of the 6% of patients receiving any antilipid agents before random assignment did not show any survival benefit compared with patients not treated with antilipid agents. A survival hazard ratio analysis assessing several parameters showed that bexarotene-treated patients who experienced grade 3/4 hypertriglyceridemia had a better outcome compared with patients in the control arm (Fig A3, online only). In particular, patients within this subgroup who were male, had stage IV disease, prior 6-month weight loss of at least 5%, or were smokers had significantly longer survival than patients in the control arm, thus demonstrating a benefit for NSCLC patients who typically have an unfavorable prognosis. A univariate Cox regression analysis in the ITT population showed that the baseline prognostic factors were not different among the treatment groups. A time-dependent multivariate analysis revealed that regardless of subgroup criteria, bexarotene-treated patients who experienced high-grade triglyceride elevation had a survival advantage and a more favorable overall response to treatment. Further analysis of the potential role of statins and other antilipemic therapy on survival outcomes shows that no difference in survival was seen among patients receiving statins versus fibrates, two classes of drugs that lower lipids by distinctly different cellular mechanisms. Mean doses of statins received by patients across the first five cycles of treatment were not different for those patients in the upper third of triglyceride elevations with substantial survival benefit and those in the middle third who had no survival benefit compared with the upper third bexarotene arm or the chemotherapy alone group. Bexarotene-treated patients with grade 3/4 hypertriglyceridemia also had higher rates of skin rash and hypothyroidism compared with bexarotene-treated patients who did not experience these toxicities, suggesting that other systems known to be affected by rexinoids, not just lipid metabolism, had differential sensitivity to the effects of bexarotene.
Safety and Tolerability
The most common reason for early withdrawal from both study arms was disease progression, which was higher in the bexarotene arm (30.8% v 22.6%; P < .05). An equal number of patients (n = 55) withdrew from the study because of adverse events in each arm during the first four cycles. Overall, across all cycles, 20.8% of patients in the bexarotene arm discontinued because of bexarotene related toxicity, the most frequent of which was hypertriglyceridemia (12.3%).
In our study, no survival benefit, including overall survival and PFS, was associated with bexarotene treatment in the ITT study population. Interestingly, an exploratory retrospective analysis has demonstrated a significant prolonged survival, exceeding 12 months, in approximately one third (  32%) of patients who experienced grade 3/4 hypertriglyceridemia in response to bexarotene added to the cisplatin/vinorelbine doublet. Such prolonged survival duration has been observed only in one other phase III clinical trial in advanced NSCLC.8 These results may support the concept that sensitivity to bexarotene, as ascertained by degree of induced hypertriglyceridemia, defines subpopulations of patients that are likely to have distinct survival rates showing either benefit, detriment, or no impact. The SPIRIT II trial, despite differences in chemotherapeutic regimens and geographical study sites, showed a similar survival benefit and patient distribution in relation to triglyceride responses.18 The same correlation between bexarotene-induced hypertriglyceridemia and survival has been noted in several other bexarotene studies. In the two first-line phase I/II studies that led to the conduct of the SPIRIT trials,15,19 retrospective analyses demonstrated either significant or numeric correlation between bexarotene-induced hypertriglyceridemia and improved survival (manuscript in preparation). More recently, a significant correlation between bexarotene-induced hypertriglyceridemia and survival was reported in a phase II bexarotene monotherapy trial in chemotherapy-refractory advanced NSCLC patients.20 In our study, bexarotene treatment appeared to most benefit patients with an unfavorable prognosis who are male, have stage IV disease, are smokers, or had at least a 5% weight loss in the 6 months preceding study entry. The search for useful biomarkers in oncology to identify population of patients most likely to benefit has been intense in recent years. No specific biomarker has yet been identified to select those patients who would derive the most survival benefit in NSCLC trials. The present study suggests potential usefulness of a different (biochemical) type of biomarker that could serve as an indicator of response to treatment. High-grade hypertriglyceridemia associated with high sensitivity to bexarotene, led to the formulation of a new hypothesis, namely, that grade 3/4 hypertriglyceridemia correlates with survival advantage in this NSCLC patient population. Interestingly, preliminary results from a study in which the expression of other biomarkers was assessed in tumor tissue from bexarotene-treated NSCLC patients indicate that tissues with higher concentrations of bexarotene were more likely to demonstrate repression of cyclin D1 and Ki-67, consistent with the in vitro data and suggestive of a reduction in cell proliferation in response to bexarotene.15,21 A recent abstract by Petty et al suggests that hypertriglyceridemia correlates with increased tumor concentrations of bexarotene.22 Two possible explanations may help understand these findings. First, a study of RXR-receptor (RXR-R) levels in a subset of patients from both the SPIRIT I and SPIRIT II studies showed that those patients with higher levels of RXR-R at baseline had better survival,23 corroborating and expanding earlier observations of Brabender et al.11 It is conceivable that those patients expressing higher levels of RXR-R showed better responses on activation by bexarotene, as shown by higher triglyceride levels and other markers of receptor activation (hypothyroidism, skin rash) and as a result, derived better survival. A second complementary explanation is drawn from the observation that a number of patients, particularly those in the upper third of triglyceride responses had, at baseline, clear evidence of metabolic syndrome, as reported recently in a retrospective analysis of patients in both SPIRIT I and II.24 This observation suggests that these patients have background alterations in lipid metabolism and, perhaps, genetic polymorphisms that can predispose them to have differential responses and survival outcomes when lipid metabolism and the downstream metabolic pathways are activated by agents such as bexarotene. It is also interesting to speculate that statins, which have been reported to be associated with reduced risk of lung cancer,25 as well as other cancers, may reflect their use in a subpopulation of patients with hyperlipidemias (a major component of metabolic syndrome) that may already be predisposed to better outcomes in NSCLC as a result of their underlying metabolic syndrome dysfunction. In this and the companion study18 statins or fibrates were not correlated with better survival, whereas high hypertriglyceridemia induced by bexarotene clearly was. The correlation between elevated triglycerides and the survival is quite novel. Whether hypertriglyceridemia has a predictive or a prognostic value cannot be definitively concluded from the study, and several questions are still open to discussion and interpretation. In conclusion, the addition of bexarotene to cisplatin/vinorelbine chemotherapy did not improve survival compared with chemotherapy alone in the first-line treatment of NSCLC. A subpopulation analysis revealed that high-grade hypertriglyceridemia in bexarotene-treated patients may correlate with longer survival. Additional ongoing biochemical and genetic marker analyses are being conducted to optimize a biomarker approach that could help identify determinants of survival and provide a basis for patient selection in future confirmatory studies. Further research to identify appropriate biomarkers and/or to utilize hypertriglyceridemia as a predictive factor to select the most appropriate patient populations for bexarotene treatment is warranted.
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: Rosa Negro-Vilar, Ligand (C); Samia Rahal, Ligand (C); Joseph K. Zhang, Ligand (C); Andres Negro-Vilar, Ligand Pharmaceuticals (C); Zofia E. Dziewanowska, Ligand Pharmaceuticals (C) Consultant or Advisory Role: Paul Schwarzenberger, Amgen (C), Johnson & Johnson (C) Stock Ownership: Rosa Negro-Vilar, Ligand; Joseph K. Zhang, Ligand Pharmaceuticals; Andres Negro-Vilar, Ligand Pharmaceuticals Honoraria: None Research Funding: Petr Zatloukal, PPD, Ligand Pharmaceuticals; Paul Schwarzenberger, Ligand Pharmaceuticals; Sergei V. Orlov, Ligand Pharmaceuticals; Guillermo Temperley, Ligand Pharmaceuticals Expert Testimony: None Other Remuneration: None
Conception and design: Andres Negro-Vilar, Zofia E. Dziewanowska Financial support: Zofia E. Dziewanowska Administrative support: Rosa Negro-Vilar, Andres Negro-Vilar, Zofia E. Dziewanowska Provision of study materials or patients: Rodryg A. Ramlau, Jacek Jassem, Sergei V. Orlov, Maya Gottfried, José Rodrigues Pereira, Guillermo Temperley, Rosa Negro-Vilar, Zofia E. Dziewanowska Collection and assembly of data: Rodryg A. Ramlau, Petr Zatloukal, Paul Schwarzenberger, Sergei V. Orlov, Maya Gottfried, José Rodrigues Pereira, Rosa Negro-Vilar, Zofia E. Dziewanowska Data analysis and interpretation: Rodryg A. Ramlau, Samia Rahal, Joseph K. Zhang, Zofia E. Dziewanowska Manuscript writing: Rodryg A. Ramlau, Jacek Jassem, Samia Rahal, Zofia E. Dziewanowska Final approval of manuscript: Rodryg A. Ramlau, Jacek Jassem, Paul Schwarzenberger, Maya Gottfried, José Rodrigues Pereira, Rosa Negro-Vilar, Samia Rahal, Joseph K. Zhang, Andres Negro-Vilar, Zofia E. Dziewanowska
We thank the following principal investigators for participating in this study: Jorge Ayub; New Hope Cancer Centers; Frida Barak, Barzilai Medical Center, Department of Oncology; Stephen Begbie, Port Macquarie Base Hospital; David Blake, Medical Associates Health Centers; Cesar Blajman, ISIS Clinica Especializada; Larisa Bolotina, Scientific Research Institute of Oncology, n.a. Hertzen; Vasily Borisov, City Oncology Clinical Center; Demosthenes Bouros, District General University Hospital of Alexandroupolis; Mark Bower, Department of Oncology, Chelsea & Westminster Hospital; Denis Braun, Centre Hospitalier General Francois Maillot, Service de Pneumologie A; Jean-Luc Breton, Centre Hospitalier General de Belfort, Service de Pneumologie; Ivana Bustova, Nemocnice Ceske Budejovice, Oddeleni klinicke a radiacni onkologie; Mikhail Byakhov, Central Clinical Hospital n.a. Semashko; Michael Chia, Burnside War Memorial Hospital; Pandora Christaki-Koukourikou, G. Papanikolaou Hospital; Philip Clingan, Southern Medical Daycare Centre; Edit Csada, Csongrad megyei Onkormanyzat Mellkasi Betegsegek Szakkorhaza; Arnold Cyjon, Assaf-Harofe Hospital, Department of Oncology; Didier Debieuvre, Centre Hospitalier Intercommunal de la Haute-Soane, Service de Pneumologie et Allergologie; Carlos Delfino, Hospital Privado de la Comunidad; Susan Dent, Ottawa Regional Cancer Centre; Agnes Devai, Uzsoki Street Hospital; Luis Fein, Centro Oncologico de Rosario; Luke Dreisbach, Desert Hematology-Oncology Medical Group, Inc.; Angela Barreira Diogenes, Hospital do Cancer, Instituto do Cancer do Ceara; Stephen Falk, Bristol Hematology and Oncology Centre; Silvia Ferrandini, Hospital de Clinicas Jose de San Martin; Bruno Ferrari, Hospital Mater Dei; Jitendra Gandhi, University Oncology and Hematology; Harinder Garewal, Southern Arizona V.A. Health Care System; Alexandria Gerogianni, seventh Pneumonology Clinic, Sotiria Hospital for Diseases of the Chest; Vera Gorbunova, Russian Oncology Research Center n.a. Blokhin; Maya Gottfried, Institute of Oncology, Meir Hospital; Jayne Gurtler, Metairie, Louisiana; John Hankins, Brookwood Oncology/Hematology Associates; Peter Harper, Guy's and St. Thomas' Cancer Centre; William Horvath, Hematology-Oncology Associates of Ohio and Michigan; Haralabos Kalofonos, University Hospital of Patras; Ali Khojasteh, Capitol Comprehensive Cancer Care Clinic; Jacek Jassem, Katedra i Klinika Onkologii i Radioterpii, Akademii Medycznej w Gdansku; Erzsebet Juhasz, Koranyi National Institute for Pulmonology; Mark Levitt, Institute of Oncology, Sheba Medical Center; Mikhail Lichinitser, Russian Oncology Research Center n.a. Blokhin; Ray Lowenthal, Royal Hobart Hospital; Pal Magyar, Semmelweis Egyetem, Pulmonologiai Klinika; Tariq Mahmood, Midwest city, Oklahoma; Anatoliy Makhson, City Oncology Center #62; Georgiy Manikhas, City Oncology Center; Suzete Mayo, Complexo Hospitalar Heliopolis; Joe McKendrick, Box Hill Hospital; Vladimir Moiseyenko, Research Institute of Oncology n.a. Petrov; Wojciech Morzycki, QEII Health Sciences Centre, Nova Scotia Cancer Centre; Sri Navaratnam, Cancer Care Manitoba; Igor Nemirovski, Hadassah Medical Center; Marianne Nicolson, Aberdeen Royal Infirmary; Sergei Orlov, St. Petersburg Pavlov State Medical University, Laboratory of Thoracic Oncology; Jose Pereira; Instituto do Cancer Arnaldo Vierira Carvalho; Allan Price, University of Edinburgh, Western General Hospital; Rodryg Ramlau, Oddzial Onkologii, Wielkopolskie Centrum Chorob Pluc i Gruzlicy; Eduardo Richardet, Hospital Italiano de Cordoba; Janusz Rolski, Klinika Chemioterapii Collegium Medicum; Paul Schwarzenberger, Clinical Oncology Research Associates, LLC; William Solomon, SUNY Downstate Medical Center; Lynn Steinbrenner, VA Western New York Healthcare System; Guillermo Temperley, Hospital de Oncologia Curie; Hakaru Tadokoro, Universidade Federal de Sao Paulo-UNIFESP; Gillian Thomas, Leicester Royal Infirmary; Michael Toumbis, sixth Pneumonology Department, "Sotiria" Hospital for Diseases of the Chest; Craig Underhill, Border Medical Oncology, Murray Valley Private Hospital & Cancer Treatment Centre; Jeferson Vinholes, Irmandade Santa Casa de Misericordia de Porto Alegre; Jiri Votruba, Plicni oddeleni, Nemocnice Na Homolce; Olga Vtoraya, Arkhangelsk Regional Oncology Center, Chemotherapy Department; Marek Wojtukiewicz, Oddzial Chemioterapii Nowotworow i Chorob Wewnetrznych, Biolostocki Osrodek Onkologiczny im. M. Sklodowskiej-Curie; Nise Yamaguchi, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo; and Desmond Yip, The Canberra Hospital; Petr Zatloukal, Klinika pneumologie a hrudni chirurgie, Fakultni nemocnice Na Bulovce.
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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Brabender J, Metzger R, Salonga D, et al: Comprehensive expression analysis of retinoic acid receptors and retinoid X receptors in non-small cell lung cancer: Implications for tumor development and prognosis. Carcinogenesis 26:525-530, 2005 13. Miller VA, Benedetti FM, Rigas JR, et al: Initial clinical trial of a selective retinoid X receptor ligand, LGD1069. J Clin Oncol 15:790-795, 1997 14. Rizvi NA, Marshall JL, Dahut W, et al: A phase I study of LGD1069 in adults with advanced cancer. Clin Cancer Res 5:1658-1664, 1999 15. Khuri FR, Rigas JR, Figlin RA, et al: Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non-small-cell lung cancer. J Clin Oncol 19:2626-2637, 2001 16. Rottman JN, Widom RL, Nadal-Ginard B, et al: A retinoic acid-responsive element in the apolipoprotein AI gene distinguishes between two different retinoic acid response pathways. Mol Cell Biol 11:3814-3820, 1991 17. Rigas JR, Dragnev KH: Emerging role of rexinoids in non-small cell lung cancer: Focus on bexarotene. Oncologist 10:22-33, 2005 18. Blumenschein GR Jr, Khuri FR, von Pawel J, et al: 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. J Clin Oncol 26:1879-1885, 2008 19. Rizvi N, Hawkins MJ, Eisenberg PD, et al: Placebo-controlled trial of bexarotene, a retinoid X receptor agonist, as maintenance therapy for patients treated with chemotherapy for advanced non-small-cell lung cancer. Clin Lung Cancer 2:210-215, 2001[Medline] 20. Govindan R, Crowley J, Schwartzberg L, et al: Phase II trial of bexarotene capsules in patients with advanced non-small cell lung cancer (NSCLC) after failure of tw or more previous therapies. J Clin Oncol 24:4848-4854, 2006 21. Rigas JR, Dragnev KH, Petty WJ, et al: A proof-of-principle trial of bexarotene in patients (pts) with resectable non-small cell lung cancer (NSCLC). J Clin Oncol 23:654s, 2005 (suppl; abstr 7136)[CrossRef] 22. Petty WJ, Dragnev KH, Memoli VA, et al: Proof-of-principle clinical trial of bexarotene for the treatment of non-small cell lung cancer. Chest 128:312S, 2005[Abstract] 23. Negro-Vilar A, Gatzemeier U, Ramlau R, et al: Biomarker correlates of survival in NSCLC: Role of RXRβ and PPAR 24. Dziewanowska Z, Zhang J, Sun S, et al: Components of metabolic syndrome correlate with longer survival in NSCLC in bexarotene-treated patients with high hypertriglyceridemia in SPIRIT I and II trials: A retrospective analysis. J Clin Oncol 24:398s, 2006 (suppl; abstr 7137) 25. Khurana V, Bejjanki HR, Caldito G, et al: Statins reduce the risk of lung cancer in humans: A large case-control study of US veterans. Chest 131:1282-1288, 2007[CrossRef][Medline] 26. 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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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, Poland; Charles University, Postgraduate Medical School, Prague, Czech Republic; Medical University of Gda
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ABSTRACT
INTRODUCTION
(Fig A1, online only). The expression of retinoid receptors, including RXRβ, is decreased in some NSCLC biopsy specimens, and increased RXRβ expression has been associated with better survival in NSCLC patients.
5x the upper limit of normal), with the most rapid increases occurring during the first 3 to 4 weeks of therapy. These patients consequently underwent dose reductions of bexarotene, resulting in an average bexarotene dose of 274 mg/m2/d in this patient subpopulation. The second group comprised patients who experienced grade 0 to 2 serum triglyceride elevations and who did not require similar bexarotene dose reductions; the mean bexarotene dose in these patients was 347 mg/m2/d (
