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The Oncologist, Vol. 10, No. 1, 22-33, January 2005; doi:10.1634/theoncologist.10-1-22
© 2005 AlphaMed Press

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Emerging Role of Rexinoids in Non-Small Cell Lung Cancer: Focus on Bexarotene

James R. Rigas, Konstantin H. Dragnev

Comprehensive Thoracic Oncology Program, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA

Correspondence: James R. Rigas, M.D., Comprehensive Thoracic Oncology Program, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, New Hampshire 03756, USA. Telephone: 603-650-6344; Fax: 603-650-0563; e-mail: james.r.rigas{at}dartmouth.edu


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Retinoids
 Rexinoids in the Treatment...
 Summary and Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Explain the role of retinoids in cell division, growth, differentiation, and proliferation.
  2. Discuss the phase I, II, and III data using rexinoids to extend survival in NSCLC patients.
  3. Describe the expected toxicity profile of retinoids and rexinoids.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Retinoids
 Rexinoids in the Treatment...
 Summary and Conclusions
 References
 
Although the introduction of third-generation antineoplastic agents in the treatment of non-small cell lung cancer has led to modest improvements in overall patient survival, lung cancer continues to be the leading cause of cancer-related death worldwide, and improved therapies are needed. Retinoids play a critical role in the regulation of cell division, growth, differentiation, and proliferation, and they represent an exciting new avenue for targeted therapy. Several synthetic retinoids that bind to retinoic acid receptors are currently being investigated in a variety of tumor types. However, many of these agents have been associated with cheilitis, skin reactions, severe headache, and hypertriglyceridemia. Synthetic agents that bind specifically to retinoid X receptors are called rexinoids. Bexarotene (Targretin®; Ligand Pharmaceuticals; San Diego, CA; http://www.ligand.com) is a novel, multitargeted synthetic rexinoid that is currently being investigated in the treatment of non-small cell lung cancer. Phase I and II studies have demonstrated that bexarotene is safe and well tolerated in this patient population either alone or in combination with chemotherapeutic agents. Patients treated with bexarotene experience manageable adverse events at reduced levels compared with retinoic acid receptor-specific retinoids. Bexarotene in combination with chemotherapeutic agents has demonstrated an encouraging median survival for patients with advanced non-small cell lung cancer compared with historical results with combination chemotherapy alone. Two phase III trials are currently under way to fully characterize the role of bexarotene in the treatment of this disease. The purpose of this review is to explore the rationale for rexinoids in the treatment of malignancies and to discuss the clinical profile of bexarotene in the treatment of non-small cell lung cancer.

Key Words. Bexarotene • Non-small cell lung cancer • Retinoid • Rexinoid • Targeted therapy


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Retinoids
 Rexinoids in the Treatment...
 Summary and Conclusions
 References
 
Lung cancer is the leading cause of cancer-related death in the United States, accounting for an estimated 32% of cancer deaths in men and 25% of cancer deaths in women [1]. Further, it is estimated that 173,770 new cases of lung cancer will be diagnosed in 2004 and that 160,440 people will die of the disease. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. The majority of patients with NSCLC present with advanced disease, and this aggressive tumor is associated with a poor prognosis. The 5-year survival rate for patients with advanced (stage IIIB/IV) NSCLC is <5% [2]. In this palliative care setting, the goals of chemotherapy are to improve symptoms and quality of life and prolong survival.

Common chemotherapy regimens used in the treatment of advanced NSCLC are platinum-based regimens of newer cytotoxic agents, including paclitaxel, docetaxel, vinorelbine, gemcitabine, or irinotecan. Recently, an Eastern Cooperative Oncology Group study compared four combination chemotherapy regimens in patients with stage IIIB/IV NSCLC [3]. In that study, 1,155 eligible patients were treated with cisplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel, or carboplatin/paclitaxel. The response rate and survival rate did not differ significantly between any of these treatment groups. The median overall survival for each treatment group ranged from 7.4–8.1 months, with a median overall survival for all 1,155 patients of 7.9 months. The 2-year survival for these patients ranged from 10%–13%, depending on the treatment arm. Therefore, the current treatment regimens do not substantially improve the overall outcome for these patients.

In an effort to improve the prognosis of patients with advanced NSCLC, several new targeted agents are currently being investigated (Table 1Go). The two agents furthest along in clinical development are the epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib (Iressa®; AstraZeneca, Wilmington, DE; http://www.astrazeneca-us.com) and erlotinib (Tarceva®; Genentech, Inc.; South San Francisco, CA; http://www.genentech.com). Gefitinib is approved for the treatment of NSCLC in Japan, and the U.S. Food and Drug Administration (FDA) recently granted approval for gefitinib in the third-line treatment of patients with NSCLC. However, gefitinib has recently been linked in Japan to more than 100 deaths associated with pneumonitis [4]. Further, in the first-line setting, the addition of gefitinib offered no benefit in overall survival, response rate, or time to progression (TTP) compared with carboplatin/paclitaxel or gemcitabine/cisplatin alone [3]. Erlotinib showed promising early results in NSCLC, yet two phase III trials of erlotinib plus chemotherapy in first-line NSCLC did not meet the primary efficacy end point of improving overall survival. However, a recent report has demonstrated a survival advantage with erlotinib alone compared with placebo in patients with NSCLC following failure of first- and second-line chemotherapy [5].


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  		Table 1. Novel treatment options in development for the treatment of NSCLC
 
Recently, a preliminary analysis of a phase III trial investigating the antisense oligonucleotide AffinitakTM (formerly called LY90003/ISIS 3521; Isis Pharmaceuticals, Inc.; Carlsbad, CA; http://www.isip.com) in combination with chemotherapy reported that Affinitak did not significantly improve median overall survival when combined with carboplatin and paclitaxel (10.0 months versus 9.7 months) [6]. Other promising agents under investigation in NSCLC are inhibitors of kinase signaling pathways, antiangiogenesis agents, matrix metalloproteinase inhibitors, and rexinoids. In a recent phase I/II study, the combination of bevacizumab, an antivascular endothelial growth factor monoclonal antibody in combination with erlotinib demonstrated encouraging antitumor activity in previously treated patients with NSCLC [7]. Several metalloproteinase inhibitors have been investigated in lung cancer. However, phase III trials with AG3340, BAY12-9566, and marimastat were recently halted because of a lack of efficacy [8–11]. In addition, a phase II/III study of the broad-spectrum matrix metalloproteinase inhibitor BMS-275291 plus chemotherapy failed to demonstrate an improved survival in the first-line treatment of patients with NSCLC [12].

Retinoids have been studied for several years as a promising class of agents in the treatment and prevention of cancer. The early retinoids were nonspecific for receptor binding, primarily to retinoic acid receptors (RARs). The rexinoid agent bexarotene (Targretin®; Ligand Pharmaceuticals; San Diego, CA; http://www.ligand.com) is the only FDA-approved rexinoid selective for the retinoid X receptors (RXRs) ({alpha}, ß, {gamma}), and the capsules are currently approved for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma in patients whose disease is refractory to at least one prior systemic therapy. Bexarotene has demonstrated promising results in patients with NSCLC in early phase I and II trials. The rationale for rexinoid multitargeted therapy will be presented, along with the clinical profile of bexarotene, the agent in this class that is furthest along in clinical development for the treatment of NSCLC.


   RETINOIDS
Top
 Learning Objectives
 Abstract
 Introduction
 Retinoids
Rexinoids in the Treatment...
 Summary and Conclusions
 References
 
Retinoids, including vitamin A (retinol) and its analogues, are critical for a variety of biologic functions. Retinol is metabolized in retinal pigment epithelial cells to 11-cis-retinal and is required for normal ocular function [13]; retinol and retroretinoids have also been implicated in maintaining and regulating immune function [14, 15]. Retinol is also essential for epithelial differentiation [16] and the control of embryonic development [17].

The vast majority of retinoid-driven biologic effects are mediated by retinoic acids (RAs), the active metabolites of retinol. All-trans-retinoic acid (ATRA) and 9-cis-RA both play an important role in the regulation of gene transcription that ultimately results in the regulation of cell division, growth, differentiation, and proliferation [18, 19]. RAs exert their biologic activity by binding to nuclear receptors that regulate transcriptional activity of a variety of target genes, which are implicated in the inhibition of cell growth, the induction of cell differentiation, and the induction of apoptosis in a variety of tumor cell lines [20, 21]. These nuclear receptors are members of the steroid/thyroid receptor superfamily and are involved in selective transcriptional regulation of specific genes [22].

Retinoid Mechanism of Action
There are two known families of retinoid nuclear receptors [22]. The first to be characterized was the RAR family [23]; more recently, the RXR family was characterized [24]. Each receptor family has three subtypes ({alpha}, ß, and {gamma}), and each subtype has multiple isoforms. Each isoform controls both distinctive and common target genes, and thus is part of the vast array of biologic effects initiated on retinoid receptor activation. The RAR family is endogenously activated by ATRA and 9-cis-RA, whereas the RXR family is activated by 9-cis-RA only [18]. Neither RAR nor RXR binds 13-cis-RA directly; however, 13-cis-RA is readily converted to ATRA [25]. Therefore, 13-cis-RA exerts its activity primarily via RARs.

Ligand binding to retinoid receptors results in the formation of retinoid receptor homodimers and heterodimers that directly bind to distinct RA response elements in gene promoter regions [26]. Because RARs must dimerize with an RXR to bind to a response element, agonists to RXR may be more effective in altering gene expression than agonists to RARs. In addition, RAR-ß is frequently methylated and silenced in several cancers, including lung cancer [27, 28]. Therefore, the multitargeted approach of RXR agonists may have greater promise in the treatment of lung cancer than RAR agonists. The RXRs also play a critical role in binding a variety of other nuclear receptors, including the thyroid receptor, vitamin D3 receptor, and peroxisome proliferator-activated receptor [29]. Functional heterodimerization with an RXR is also required for binding these nuclear receptors to their hormone response elements. In the ligand-free state, retinoid receptors are bound to co-repressors that repress gene transcription (Fig. 1Go) [30]. Binding of the ligand causes the dissociation of the co-repressors and the binding of coactivators that are required for gene transcription. The various ligand, retinoid receptor dimer, repressor, and coactivator complexes that are formed determine which genes are activated and which are repressed, resulting in diverse gene expression and pleiotropic effects [29, 31].



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  		Figure 1. Schematic representation of the formation of the retinoid receptor transcription complex. Binding of the retinoid to its receptor releases a co-repressor and causes dimerization of two nuclear receptors. Addition of coactivators completes the transcription complex, which binds to the appropriate response element to initiate transcription. NR = nuclear receptor; RARE = retinoic acid response element. Data from [30].

 
Role of Retinoids in the Treatment of Cancer
Retinoids have long been used for the treatment of psoriasis and acne [32, 33]. In addition, preclinical, clinical, and epidemiologic data suggest that retinoids may play a role in cancer prevention [34, 35] and treatment [36]. A long-term follow-up of a randomized study has confirmed that treatment with ATRA and chemotherapy is superior to chemotherapy alone in patients with acute promyelocytic leukemia (APL) [37]. Indeed, the use of ATRA in the treatment of patients with APL has rendered APL the most curable subtype of acute myeloid leukemia in adults [38]. The use of ATRA has also been investigated in solid tumors. However, in a phase I trial, Lee et al. [39] reported that patients with advanced solid tumors who were treated with ATRA experienced cheilitis, skin reactions, headache, and nausea and vomiting. Skin reactions were considered dose limiting. Further, patients experienced transient elevations of liver enzymes and triglycerides. Given this toxicity profile, the role of ATRA in the treatment of solid tumors needs to be carefully investigated.

Several synthetic retinoids are currently under investigation in the treatment of malignancies (Table 2Go). Two recently developed synthetic retinoids, TAC-101 (Taiho Pharmaceutical Co., Ltd.; Tokyo, Japan; http://www.taiho.co.jp) and tazarotene (AVAGETM; Allergan Inc.; Irvine, CA; http://www.allergan.com) have just entered phase I clinical trials in solid tumors. Both have selective binding affinity for the RAR family of receptors. In a dose-escalation study in patients with advanced solid tumors, TAC-101 was associated with myalgia, arthralgia, and hypertriglyceridemia; however, no dose-limiting toxicities were reported during the first 28 days of treatment with up to 28 mg/m2 [40]. Seven of 21 patients experienced venous thromboembolic events during TAC-101 treatment. One patient with NSCLC had a complete response. Because of the toxicity associated with this agent, it was recommended that alternative dosing schedules be investigated.


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  		Table 2. Synthetic retinoids and rexinoids in clinical development
 
In a separate dose-escalation study in 17 patients, tazarotene (starting dose 2.8 mg/day) was associated with dry skin, cheilitis, headache, and hypertriglyceridemia [41]. In addition, grade 1 or 2 anemia and thrombocytopenia were reported in heavily pretreated patients on tazarotene treatment. At 42 mg/day, one patient had grade 3 hypertriglyceridemia, which persisted after decreasing the dose to 21 mg/day, and a second patient had grade 2 hypertriglyceridemia at 21 mg/day. There were no reported antitumor responses. Because these data are preliminary, it is too early to determine whether these synthetic retinoids will gain regulatory approval for the treatment of advanced solid tumors.

The use of 13-cis-RA in the treatment of malignancies has been more fully characterized. In an early phase I study, patients treated with 13-cis-RA at doses >60 mg/m2 experienced intense headaches, urethritis, and dermatitis [42]. Nonetheless, the potential role of 13-cis-RA in the treatment of malignancies has continued to be investigated, primarily in combination with other agents. In a phase I/II study in patients with advanced or recurrent squamous cell carcinoma of the head and neck, the combination of 13-cis-RA, ifosfamide, and cisplatin was generally well tolerated and resulted in an objective response rate of 72% [43]. In phase II studies, the combination of 13-cis-RA, interferon alfa, and cisplatin has demonstrated activity in extensive locally advanced squamous skin cancer [44] and recurrent cervical cancer [45]. Likewise, the combination of 13-cis-RA, interferon alfa, and paclitaxel has demonstrated activity in advanced prostate [46] and breast cancers [47] and in advanced renal cell carcinoma [48]. Recently, however, Vaishampayan et al. [49] reported that this combination had only minimal activity in advanced renal cell carcinoma. Further, the addition of 13-cis-RA to vinblastine and interferon gamma did not appear to increase the efficacy of this combination in renal cell carcinoma, a highly chemoresistant tumor [50]. Clearly, 13-cis-RA has potential for the treatment of advanced cancers. However, additional studies are required to fully characterize the role of this synthetic retinoid in treating malignancies.

All of the previously discussed synthetic retinoids that exert their activity by binding to RARs are associated with toxicities that are typically linked to traditional retinoid therapy, including dry skin, cheilitis, headache, mucosal dryness, hypercalcemia, and hypertriglyceridemia. Synthetic retinoids that bind to RXRs (rexinoids) appear to offer an improved safety profile compared with that of retinoids that bind to RARs. Because of the central role of RXRs in nuclear receptor signaling, the multitargeted potential for rexinoids that bind to RXRs may offer promise in the treatment of cancer.


   REXINOIDS IN THE TREATMENT OF LUNG CANCER
Top
 Learning Objectives
 Abstract
 Introduction
 Retinoids
 Rexinoids in the Treatment...
Summary and Conclusions
 References
 
Rationale for Rexinoid Therapy in Lung Cancer
Several lines of evidence suggest that rexinoid therapy may be beneficial in the treatment of patients with lung cancer. A proportion of NSCLC biopsy specimens demonstrates decreased expression of RAR-ß, RAR-{gamma}, and RXR-ß [51–53]. Patients whose tumors exhibited low levels of RXR-ß expression had significantly lower overall survival compared with patients who had higher expression levels of this receptor [53]. Houle et al. [54] suggested that RAR-ß acts as a tumor suppressor gene in epidermoid lung tumorigenesis. Interestingly, overall survival was significantly reduced in patients with stage I NSCLC who had strong expression of RAR-ß [55]. These findings may indicate a disruption in the delicate balance between RAR and RXR signaling in tumors. Further investigations are required to determine what roles, if any, are played by specific subtypes and isoforms of retinoid receptors as prognostic indicators in NSCLC. Nevertheless, retinoid receptors appear to have a part in lung cancer tumorigenesis, and rexinoids may be potent treatment options in the management of this disease.

In addition to the altered expression of retinoid receptors in NSCLC, the effect of retinoids on the cell cycle kinetics suggests that retinoids may be useful agents in the treatment of NSCLC. Overexpression of cyclin D1, a tumor-suppressor gene that regulates the cell cycle, has been reported in NSCLC [56, 57]. It has been suggested that cyclin D1 may be a prognostic tool in early-stage NSCLC [58]. Recently, RA has been shown to promote the degradation of cyclin D1 by ubiquitination and proteolysis, resulting in inhibition of cell growth [59, 60]. Synthetic retinoids that also lead to cyclin D1 degradation may inhibit cell growth in tumor cells overexpressing cyclin D1.

Upregulation of transforming growth factor-{alpha} (TGF-{alpha}) and EGFR is an early event in several carcinomas. Rubin Grandis et al. [61] reported that RA normalized the increased expression of TGF-{alpha} and EGFR in head and neck cancer cell lines. Likewise, the overexpression of EGFR normally observed in carcinogen-transformed human bronchial epithelial cells BEAS-2BNNK was repressed in the presence of ATRA [62]. Further, Song et al. [63] reported that the RXR-specific retinoid bexarotene decreased the proliferation of a head and neck cancer cell line by interfering with the TGF-{alpha} and EGFR autocrine signaling pathway. Because overexpression of EGFR has been reported in nearly 50% of NSCLC [64], retinoids may be important regulators of tumor growth in NSCLC tumors overexpressing EGFR.

Clinical Development of Rexinoids in Lung Cancer
Bexarotene is a novel oral synthetic rexinoid that specifically binds to RXRs and does not have significant RAR binding and transactivation of RAR-responsive genes, except at higher dose levels [65]. Activation of RXR and its heterodimer partners modulates a number of gene-expression pathways, which can ultimately modulate converging signaling pathways responsible for cell differentiation and apoptosis. This multitargeted approach of mediating cell differentiation, apoptosis, and proliferation suggests that bexarotene may be a particularly active agent in the treatment of malignancies, especially in combination with chemotherapeutic agents (Fig. 2Go). Bexarotene is currently approved for the treatment of cutaneous manifestation of T-cell lymphoma in patients who are refractory to at least one prior systemic therapy [66]. Because of the central role of RXR in the regulation of retinoid receptor signaling, and the evidence suggesting that rexinoids may play an important role in the treatment of lung cancer, the antitumor activity and tolerability of bexarotene have been the subjects of considerable clinical interest (Table 3Go).



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  		Figure 2. Mechanism of action of bexarotene in combination with chemotherapy. NR = nuclear receptor.

 

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  		Table 3. Summary of clinical trials investigating bexarotene in the treatment of NSCLC
 
Phase I Studies of Bexarotene Treatment Alone
The safety and tolerability of bexarotene in patients with advanced cancer was studied in two phase I studies. In one trial by Miller et al. [67], a total of 52 patients, including 20 with NSCLC, were treated at 14 dose levels of oral bexarotene ranging from 5 to 500 mg/m2/day. Bexarotene at these dose levels was generally well tolerated, and no grade 4 toxicities were observed. Only seven (14%) patients experienced grade 3 toxicities, including skin reaction (n = 3), neutropenia (n = 1), hypercalcemia (n = 1), hypertriglyceridemia (n = 1), and elevated aspartate transaminase (AST) (n = 1). Because grade 3 neutropenia and elevated AST occurred in patients treated at the 400-mg/m2/day dose level (the maximum tolerated dose in this study), the recommended dose for subsequent studies in cutaneous T-cell lymphoma was 300 mg/m2/day. Dose- and time-dependent hyperlipidemia, including mild hypercholesterolemia and hypertriglyceridemia, was observed in the majority of patients. However, only one patient experienced a grade 3 elevation in serum triglycerides. The characteristic dry skin or mucous membrane dryness observed with retinoid treatment occurred in 41% of patients, which compares favorably with the 90% of patients who experience skin reactions, in some cases severe and dose limiting, when treated with the non-RXR-selective retinoids ATRA [39] and 13-cis-RA [42]. Two of nine patients with cutaneous manifestation of cutaneous T-cell lymphoma experienced a tumor response, and 8 of 20 patients with NSCLC completed ≥3 months of therapy. In addition, one NSCLC patient had stable disease for 9 months [67].

In a second phase I study in patients with advanced cancer, 60 patients were treated with bexarotene at 16 dose levels ranging from 5 to 1,000 mg/m2/day [68]. Sixteen patients had lung cancer, and all but one patient had solid tumors. No dose-limiting toxicities were reported at dose levels <500 mg/m2/day. Grade 3 toxicities were reported in six (10%) patients: leukopenia (n = 2), skin toxicity (n = 1), diarrhea (n = 1), elevated bilirubin (n = 1), and elevated transaminase (n = 1). Grade 4 elevated bilirubin was reported in one patient. Dose- and time-dependent hypertriglyceridemia was observed in the majority of patients and typically occurred within 1 week of starting treatment. However, no clinical sequelae were observed from the hyperlipidemia, which was reversible on discontinuation of the study drug. Further, the characteristic headache, mucocutaneous toxicity, skin toxicity, and hypercalcemia observed with retinoid treatment were mild to moderate in all but one patient (grade 3 skin toxicity). Based on the toxicity profile, the recommended dose of bexarotene for phase II studies was 500 mg/m2/day.

A long-term, follow-up survival analysis of the 36 patients with NSCLC from these two phase I trials was subsequently conducted [69]. Despite the lack of major objective tumor response in these patients, disease stabilization was noted in 14 (39%) patients. The Kaplan-Meier estimate of median survival was 11.1 months, with estimated 1-year and 2-year survival rates of 42% and 15%, respectively. Given that the median duration of survival in previously untreated patients with advanced NSCLC who receive current two-drug combinations is approximately 8 months, these data in previously treated patients suggest that bexarotene may play a role in extending the survival of patients with NSCLC.

Phase I/II Studies of Bexarotene in Combination with Other Agents
The tolerability and antitumor activity of bexarotene in combination with other agents has also been investigated. Based on preclinical evidence of synergy with bexarotene and cisplatin, a phase I/II study was conducted to investigate oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with stage IIIB (with pleural effusion) or stage IV NSCLC [70]. During the phase I dose-escalation portion of the study, 21 patients were treated with oral bexarotene ranging from 150 to 600 mg/m2/day in combination with vinorelbine and cisplatin. Bexarotene was initiated 1 week before the start of chemotherapy and was administered daily except on the day after each dose of cisplatin. The optimal dose of bexarotene in combination with cisplatin and vinorelbine was determined to be 400 mg/m2/day. In the phase II portion of the study, 28 patients were treated with 400 mg/m2/day, including all six patients from the phase I portion of the trial who were treated at this dose level. Of the 28 patients, seven (25%) experienced a partial response. One patient obtained a near complete resolution of radiographic lesions. Stable disease was achieved in 14 (50%) patients after two cycles. The median survival of these patients was 14 months. The Kaplan-Meier survival estimate for these patients is illustrated in Figure 3Go [70]. The 1-, 2-, and projected 3-year survival rates were 61%, 32%, and 30%, respectively. However, it should be noted that similar promising results with ISI 3521 in the phase II setting failed to translate into significant improvements in survival in the phase III setting [6]. Grade 3/4 nonhematologic toxicities included hyperlipidemia (31%), nausea (21%), vomiting (21%), dyspnea (9%), and asthenia (9%). Six patients experienced grade 3 pneumonia. Grade 3/4 hematologic toxicities included leukopenia (56%) and anemia (9%).



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  		Figure 3. An estimate of overall survival in patients with NSCLC treated with bexarotene in combination with cisplatin and vinorelbine. Reprinted with permission from the American Society of Clinical Oncology. 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 2001;19:2626–2637[Abstract/Free Full Text].

 
The safety of bexarotene in combination with carboplatin and paclitaxel has also been investigated in previously untreated patients with advanced (stage IIIB with malignant effusion or stage IV) NSCLC [71]. Patients received oral bexarotene 400 mg/m2 once daily plus paclitaxel 200 mg/m2 and carboplatin area under the concentration time curve (AUC) equal to 6 by i.v. infusion on day 1 every 3 weeks. Because hypertriglyceridemia was expected, patients also received antilipid therapy before or on the same day that bexarotene treatment began. In a preliminary analysis of 19 patients, grade 3 or 4 neutropenia was reported in 44% and 38% of patients, respectively. Grade 3 anemia and grade 4 thrombocytopenia were both reported in 6% of patients. Although 50% of patients experienced bexarotene dose reduction because of strict dose reduction guidelines, only one patient had grade 3 hypertriglyceridemia. An objective response rate of 40% was observed in 15 evaluable patients, including one complete response and five partial responses. An additional 24 patients have been treated in this multicenter study, and the data are currently being analyzed. Stable disease was reported in an additional 17 (52%) patients.

Phase II/III Maintenance Therapy Study
Bexarotene was also studied as maintenance therapy in patients with advanced NSCLC who had responded to first-line chemotherapy [72]. A total of 52 patients who had demonstrated stable or responsive disease after prior chemotherapy were eligible for the trial. Fifty-two percent had achieved an objective response and 48% had achieved stable disease in response to prior chemotherapy. The majority (69%) of these patients had received prior paclitaxel/carboplatin chemotherapy. Patients were randomized to bexarotene 300 mg/m2/day, bexarotene 600 mg/m2/day, or placebo.

The median TTP increased from 8 weeks for patients treated with placebo to 11.7 weeks for patients treated with bexarotene 300 mg/m2/day. This increase in TTP appeared to be dose dependent, with the TTP in patients treated with 600 mg/m2/day increased to 18.3 weeks. However, this trial was prematurely terminated because of slow accrual and, therefore, was insufficiently powered to detect statistical differences among the treatment groups. Nevertheless, these results are suggestive of a benefit for bexarotene over placebo in maintenance therapy. Dose-dependent hyperlipidemia was the only grade 3/4 toxicity associated with bexarotene therapy reported in more than three patients, with the exception of decreased absolute lymphocyte count. However, grade 3/4 absolute lymphocyte counts were as common in the placebo group as in the bexarotene-treated groups. Thyroid-stimulating hormone (TSH) levels <75% of normal were noted in 58% of patients receiving bexarotene. Dose-dependent dry skin, headache, and asthenia were the most common bexarotene-related toxicities. However, these were mild to moderate and were manageable.

Current Phase III Trials
Enrollment in two phase III trials has recently been completed to investigate the efficacy and safety of bexarotene in combination with chemotherapy in previously untreated patients with stage IIIB (with malignant pleural effusion) or stage IV NSCLC. In the first randomized, open-label, parallel-group controlled trial in patients with advanced NSCLC, the regimen is paclitaxel 200 mg/m2 via a 3-hour i.v. infusion on day 1 every 3 weeks followed by carboplatin AUC equal to 6 by i.v. infusion every 3 weeks, with or without oral bexarotene 400 mg/m2 once daily starting on day 1. All patients treated with bexarotene also receive antilipid therapy concomitantly or on the same day of bexarotene therapy. In the second trial, chemotherapy-naïve patients with advanced NSCLC receive cisplatin 100 mg/m2 by i.v. infusion on day 1 of a 4-week cycle and weekly vinorelbine 25 mg/m2 by i.v. infusion, with or without oral bexarotene 400 mg/m2/day. Similar to the other phase III trial, patients receiving bexarotene are initiating antilipid therapy before or on the study drug start date. Both studies are ongoing as the primary efficacy parameter is survival.

Management of Treatment-Related Adverse Events
The use of retinoids that bind to the RARs is associated with significant and often dose-limiting skin toxicity (dry, peeling, or flaking skin), mucocutaneous toxicity (eye dryness, conjunctivitis), hypercalcemia, and headache [39, 42]. These toxicities have dramatically slowed the clinical application of this class of agents [73]. In contrast, rexinoids are not associated with hypercalcemia and are associated with only mild to moderate skin toxicity.

Another adverse event associated with both retinoid and rexinoid therapy is hyperlipidemia with elevations in both triglycerides and cholesterol. However, these two classes of agents appear to affect lipoprotein homeostasis in different ways. In an analysis of patients treated with ATRA, 9-cis-RA, and bexarotene in phase I or II clinical studies, triglyceride levels were elevated in patients who received higher doses of 9-cis-RA [74, 75]. Significant elevations in cholesterol levels were observed in patients treated with bexarotene and with 9-cis-RA at doses >60 mg/m2/day. Cholesterol elevations in these patients were associated with significantly higher calculated levels of low-density lipoprotein cholesterol. Overall, significantly lower high-density lipoprotein cholesterol and apolipoprotein A1 levels were only observed in patients treated with 9-cis-RA at doses >60 mg/m2/day and not in the bexarotene-treated patients. Only patients treated with doses of 9-cis-RA >60 mg/m2/day experienced a significant decrease in high-density lipoprotein and apolipoprotein A1. In contrast, patients treated with bexarotene experienced increases in total cholesterol and low-density lipoprotein cholesterol without significant changes in high-density lipoprotein cholesterol and apolipoprotein A1. These data suggest that treatment with the selective RXR ligand bexarotene causes alterations primarily in cholesterol metabolism, whereas treatment with the pan retinoid receptor ligand 9-cis-RA causes elevations in plasma cholesterol and triglyceride levels that are associated with significant decreases in high-density lipoproteins. These findings suggest that changes in triglyceride metabolism and less favorable alterations in cholesterol metabolism are mediated by the RARs.

Since hyperlipidemia and hypothyroidism are anticipated adverse events, they can be managed proactively with proper planning, oral medications, and careful patient monitoring. There is now considerable experience in the management of hyperlipidemia in patients treated with bexarotene, and general guidelines have been developed (Table 4Go). Bexarotene should be used with caution in patients predisposed to pancreatitis and liver dysfunction. Baseline fasting triglyceride and cholesterol levels should be optimized before starting bexarotene therapy. Atorvastatin or fenofibrate are the most extensively used antilipid agents; gemfibrozil is not recommended because of its interaction with bexarotene [76]. Lipid levels and liver function should be monitored regularly.


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  		Table 4. Management of hypertriglyceridemia in patients treated with bexarotene
 
Bexarotene therapy has also been associated with central hypothyroidism characterized by a reduction in thyroxine (total T4) and TSH levels [77]. Total T4 levels should be obtained at baseline, and patients should be started on levothyroxine therapy starting at 0.05 to 0.075 mg/day. Total T4 and TSH levels should be determined every 3–4 weeks until the discontinuation of bexarotene therapy because biochemical hypothyroidism does not always manifest clinically. Levothyroxine therapy should be provided during treatment with bexarotene to maintain total T4 levels within normal limits. The levels of TSH will remain suppressed despite the administration of levothyroxine. Hypothyroidism associated with bexarotene therapy is reversible, and normal thyroid function will return quickly after the discontinuation of bexarotene therapy.


   SUMMARY AND CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Retinoids
 Rexinoids in the Treatment...
 Summary and Conclusions
References
 
Results from early clinical trials investigating bexarotene in the treatment of patients with advanced NSCLC suggest that bexarotene, an RXR-specific retinoid, shows promise in the treatment of this disease. Bexarotene is well tolerated and is associated with minimal hematologic adverse events. Although bexarotene is associated with hypertriglyceridemia and hypothyroidism, these nonhematologic toxicities are predictable and manageable. Furthermore, bexarotene is associated with much fewer skin reactions than are reported in the literature for other retinoid therapies. Early results have demonstrated a survival benefit in patients treated with this multitargeted agent. Given the poor prognosis for patients with advanced NSCLC, the benefits of bexarotene therapy should be considered when weighing the risks of therapy. Current phase III trials will elucidate the role of bexarotene in the treatment of patients with this disease.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Retinoids
 Rexinoids in the Treatment...
 Summary and Conclusions
 References
 

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