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Journal of Clinical Oncology, Vol 24, No 30 (October 20), 2006: pp. 4848-4854 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.7404 Phase II Trial of Bexarotene Capsules in Patients With Advanced Non–Small-Cell Lung Cancer After Failure of Two or More Previous Therapies
From the Washington University School of Medicine, St Louis, MO; Cancer Research and Biostatistics, Seattle, WA; The West Clinic, Memphis, TN; Kenmar Research Institute, Los Angeles; California Cancer Care, San Mateo; Ligand Pharmaceuticals Inc, San Diego, CA; Moffitt Cancer Center, Tampa, FL; and the Vanderbilt Ingram Cancer Center, Nashville, TN Address reprint requests to Ramaswamy Govindan, MD, Associate Professor of Medicine, Washington University School of Medicine, 4960 Children's Place, Suite 108, St Louis, MO 63110; e-mail: rgovinda{at}im.wustl.edu
PURPOSE: To evaluate the effect of bexarotene on survival in patients with relapsed non–small-cell lung cancer (NSCLC).
PATIENTS AND METHODS: Patients with stage IIIB NSCLC with pleural effusion or stage IV NSCLC, who had Eastern Cooperative Oncology Group performance status 0 to 2, and were previously treated with RESULTS: For the 146 assessable patients treated with bexarotene, median age was 66 years (range, 34 to 87 years), 51% were men, and the median number of prior regimens was three (range, one to seven). The overall median survival was 5 months (95% CI, 4 to 7 months) and the 1-year survival was 23% (95% CI, 16% to 31%). Survival was significantly longer in patients with bexarotene-induced hypertriglyceridemia and/or skin rash. In 26 patients who had both adverse effects, the median and 1-year survival rates were 12 months (95% CI, 8 to 15 months) and 48%, respectively. In 40 patients who had neither adverse effect, median and 1-year survival rates were 2 months (95% CI, 2 to 5 months) and 15%, respectively (P = .0002). Twenty patients (14%) discontinued therapy because of bexarotene-related toxicity. For the remaining patients, adverse reactions to bexarotene were generally mild to moderate. CONCLUSION: In the intent-to-treat population, bexarotene given as third or subsequent line of therapy for relapsed NSCLC did not achieve the intended median survival of 6 months. Survival may have been extended in patients who developed bexarotene-induced hypertriglyceremia and/or skin rash. It is important to confirm these observations in a randomized controlled trial.
Platinum-based doublet chemotherapy remains the standard of care for patients with unresectable non–small-cell lung cancer (NSCLC) who have good performance status.1-5 Several cytotoxic agents are effective as second-line therapy, but the benefit is modest with objective response rates of 5% to 10%, median survival of 5 to 7 months, and fewer than one third of the patients surviving beyond 1 year.6-8 Patients seldom benefit from third-line chemotherapy, with less than 5% of patients achieving an objective response and median survival around 4 months.9,10 There is a need for active agents with novel mechanisms of action and no overlapping toxicity with chemotherapy. By directly interacting with the aberrant molecules responsible for cancer pathogenesis or progression, targeted therapies have the potential to halt tumor growth and can be associated with less myelosuppression and toxicity than cytotoxic chemotherapy. For example, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) were shown to have activity with manageable toxicity in patients with advanced NSCLC. Erlotinib given orally at 150 mg daily significantly improved survival compared with best supportive care in patients with NSCLC who had received one or two prior therapies; median survival was 6.7 months with erlotinib versus 4.7 months without it.11 However, erlotinib did not improve survival when added to a platinum-based chemotherapy in chemotherapy-naive advanced-NSCLC patients.12 Gefinitib, another EGFR-TKI, failed to improve survival when compared with best supportive care in previously treated patients and when combined with first-line chemotherapy.13-15
Bexarotene (Targretin capsules, Ligand Pharmaceuticals Inc, San Diego, CA) is a synthetic selective retinoid X receptor (RXR) modulator that binds selectively to members of the RXR subclass of nuclear receptors (RXR The expression of RXRß receptors has been shown to be reduced in lung cancer biopsies when compared with normal lung tissue, while increased RXRß expression in lung cancer biopsy specimens has been shown to be associated with improved survival.22-25 Bexarotene binding to RXRß was shown to induce receptor heterodimerization, resulting in activation of proapoptotic genes such as TRAP-1 TNF-associated protein and inhibition of antiapoptotic genes such as BAG-1 and survivin.26-28 In vitro studies have also revealed that bexarotene induces concentration-dependent repression of cyclin D1, cyclin D3, EGFR, and phospho-EGFR in bronchial epithelial cells.29 These findings suggest a potential role for bexarotene in the treatment of NSCLC. In phase I dose-escalation studies, bexarotene was shown to have promising activity in patients with a variety of tumor types, including relapsed NSCLC.30,31 In a phase I/II study of 43 patients with chemotherapy-naive advanced NSCLC, the maximum-tolerated dose of bexarotene given in combination with cisplatin and vinorelbine was 400 mg/m2, and in 28 patients who were administered this dose, the objective response rate was 25% and the median survival rate was 13.7 months.32 In a phase II study of 48 patients with chemotherapy-naive advanced NSCLC, bexarotene plus carboplatin and gemcitabine achieved a response rate of 25% and a median survival of 12.7 months.33 A randomized open-label three-arm phase II study evaluated the effect of maintenance bexarotene given at 300 or 600 mg/m2 versus no therapy in patients with advanced NSCLC who had achieved stable disease or better response to first-line chemotherapy.34 The study was closed prematurely due to poor accrual but showed a trend toward increased time to progression in the two bexarotene arms compared with the no-maintenance arm. On the basis of these early studies, two randomized phase III studies of a platinum-containing chemotherapy doublet with or without concomitant bexarotene were conducted in patients with previously untreated advanced NSCLC.35,36 Both studies showed that survival was significantly increased in the subset of patients who developed bexarotene-induced grade 3 to 4 hypertriglyceridemia compared with patients who were randomly assigned to the chemotherapy-only arm. While these two phase III studies were ongoing, we launched this phase II trial to evaluate the safety and efficacy of bexarotene monotherapy in patients with relapsed NSCLC.
Eligibility Criteria The main inclusion criteria included pathologically confirmed NSCLC, stage IIIB with malignant pleural effusion or stage IV disease at diagnosis, Eastern Cooperative Oncology Group (ECOG) PS of 0 to 2, progressive disease after at least two systemic therapies for NSCLC, which must have included a taxane and a platinum, acceptable organ function, and normal fasting serum triglyceride levels. Patients were not eligible for this study if they had previously received bexarotene or had a known hypersensitivity to bexarotene, if they had one or more risk factors for pancreatitis, had uncontrolled brain metastases, or had received any anticancer therapy within 14 days or investigational therapy within 30 days before starting study medications.
Trial Design
Study Hypothesis, Sample Size Calculation, and Statistical Analysis Descriptive statistics were performed for reporting baseline characteristics. Survival and PFS distributions were estimated with the Kaplan-Meier method and the log-rank statistic was used to test for differences between subgroups. The survival curves were generated after confirmation of patient status in April 2006. An interim analysis of the study results was presented previously.37
Assessments
Patients Disposition and Baseline Characteristics Between December 2003 and April 2005, 153 patients treated at 32 study sites signed an informed consent and were registered on study. Seven registered patients were excluded from analyses; six because they did not receive bexarotene and one because he had not signed the Health Insurance Portability and Accountability Act (HIPAA) release form. Thus, 146 patients were assessable for safety and efficacy. At the time of analysis, three patients were still receiving bexarotene. For the remaining 143 patients, treatment was discontinued because of disease progression in 82 patients (57%), worsening overall health condition in 41 patients (29%), and bexarotene-related toxicity in 20 patients (14%). Treatment-associated toxicity leading to bexarotene discontinuation consisted of six cases of hypertriglyceridemia, five of nausea and/or vomiting, and two cases each of skin rash, low blood cell counts, confusion, and three other causes.
The demographics and baseline characteristics of the 146 patients are listed in Table 1. Overall, 23% of the patients had an ECOG PS of 2, 36% were
Exposure to Study Drug Mean treatment duration was 57 days (range, 1 to 522+ days). The mean daily bexarotene dose was 375 mg/m2 (range, 149 to 523 mg/m2). Bexarotene dose reduction below 400 mg/m2 was reported in 35 patients (24%), and temporary dose interruption was reported in 13 patients (9%), usually due to increased triglycerides. As required by the protocol, nearly all patients received levothyroxine (97%) and antilipid therapy (99%), which was atorvastatin for most patients (88%).
Intent-to-Treat Analysis
Subset Analysis Several posthoc analyses were undertaken to evaluate the role of bexarotene in patient subsets. A landmarked survival analysis was performed for the subset of patients who had received at least 2 weeks of therapy. For the 126 patients who met this criterion, the median survival was 6 months (95% CI, 5 to 8 months) and the 1-year survival was 27% (95% CI, 19% to 36%). Survival was evaluated in the subset of patients who experienced bexarotene-induced hypertriglyceridemia and skin reactions (Figs 1, 2, and 3). In the subset of 74 patients (51%) who experienced grade 1 to 4 hypertriglyceridemia within 2 weeks after the onset of bexarotene, the median and 1-year survival rates were 6 months (95% CI, 4 to 8 months) and 30%, respectively. These rates were significantly higher (P = .004) than the median and 1-year survival rates of 3 months (95% CI, 2 to 5 months) and 18%, respectively, that were achieved in 67 patients who maintained normal triglyceride concentrations. Forty-one patients (28%) developed bexarotene-induced cutaneous adverse events, such as rash, dry skin, pruritis, erythema, and flushing within 3 weeks after the onset of bexarotene. The median and 1-year survival rates of patients who experienced grade 1 to 4 skin reactions were 8 months (95% CI, 5 to 12 months) and 34%, respectively. These rates were significantly higher (P = .01) than the median and 1-year survival rates of 4 months (95% CI, 3 to 5 months) and 19%, respectively, experienced by 95 patients without skin reactions. Furthermore, the median and 1-year survival rates for the 26 patients (18%) who experienced increased triglycerides and skin rash were 12 months (95% CI, 8 to 15 months) and 48%, respectively, which was significantly higher (P = .0002) than the median and 1-year survival rates of 2 months (95% CI, 2 to 5 months) and 15%, respectively, for the 40 patients (27%) who experienced neither adverse event.
Safety Overall, adverse events were generally mild to moderate in severity (Table 3). Hypertriglyceridemia was the most frequently reported laboratory abnormality, with 60% of patients having hypertriglyceridemia of any grade and 23% having grade 3/4 hypertriglyceridemia. The most frequent clinical adverse effects were dyspnea and fatigue, both likely due to the lung cancer. There were no deaths related to bexarotene. Eight patients died while receiving study drug: six from disease progression, one from esophageal hemorrhage, and one from renal failure.
We conducted this phase II study of bexarotene in patients with relapsed NSCLC because earlier studies have shown encouraging activity in previously untreated patients, and because the mechanism of action and safety profile of bexarotene are distinctly different from conventional chemotherapy. Because a few reports have indicated that the EGFR-TKI had activity as second-line therapy for advanced NSCLC,11 we evaluated bexarotene in later-stage disease (ie, as the third or subsequent line of therapy). Furthermore, we required patients to have failed previous treatments with a taxane and a platinum, the most active cytotoxic agents for NSCLC. To our knowledge, this is the largest trial to date investigating an anticancer agent as the third or subsequent line of therapy. Patients enrolled onto the study had a later stage disease than in most studies, with 65% having received three or more prior therapies. For example, compared with the phase III trial of erlotinib,11 patients on this study were on average 4 years older (median age, 66 years v 62 years) and more heavily pretreated (median of three prior therapies versus one prior regimen). In the intent-to-treat population, bexarotene resulted in a median survival of 5 months and a 1-year survival of 23%, with some patients still alive after 18 months. As we did not collect detailed data on antineoplastic therapies given after discontinuation of bexarotene, we cannot exclude the effect of subsequent therapies on survival. A large number of heavily pretreated patients with rapidly progressive disease or worsening performance status discontinued bexarotene soon after enrollment; in some cases, after only 1 day of therapy. Thus, we performed a 2-week landmarked survival analysis to exclude the effect of these rapidly worsening patients. Excluding 40 patients (14%) who withdrew from study within 2 weeks after the onset of bexarotene, the median survival for the remaining 126 patients was 6 months. Thus, our goal to achieve a 50% increase in median survival from 4 months, the rate expected with conventional third-line chemotherapy, to 6 months was met in the subset of patients who took bexarotene for at least 2 weeks. In this heavily pretreated patient population, baseline serum albumin of less than 3 g/dL and ECOG PS of 2 were associated with significantly shorter survival, corroborating similar findings reported with first-line chemotherapy in patients with advanced NSCLC. Both lipid elevation and skin rash are well-documented pharmacologic effects of bexarotene.39,40 Grade 3 to 4 hypertriglyceridemia has been recently reported to be associated with significantly longer survival in the two phase III studies of bexarotene plus chemotherapy in chemotherapy-naive advanced NSCLC patients.35,36 The present study also showed that patients who experienced hypertriglyceridemia of any grade (60% of all patients) had significantly longer survival than patients whose triglycerides remained in the normal range. Of note, the single patient who achieved a partial response in this trial had experienced grade 3 hypertriglyceridemia. In addition, this study showed a significant association between bexarotene-induced skin reaction (37% of all patients) and longer survival. Furthermore, patients who experienced both hypertriglyceridemia and skin reactions had the longest survival. At present, it is unknown whether bexarotene-induced hypertriglyceridemia and skin reactions represent predictive factors of bexarotene activity in NSCLC or are merely correlated to another true predictive factor that has yet to be identified. Nevertheless, these observations suggest that it may be possible to use these early drug-related reactions as markers to identify a subset of patients who may benefit most from bexarotene. Few studies have evaluated the activity of single-agent bexarotene in solid tumors.30,31,41 Most other studies have evaluated bexarotene in combination with chemotherapy, which confounds the assessment of bexarotene's effect on objective tumor response. In this study, the largest to date to have investigated bexarotene monotherapy in a solid tumor, only one patient achieved an objective response and disease stabilization was observed in 23 patients (16%). These results, similar to those previously reported in a phase II study in women with relapsed breast cancer are consistent with the known mechanism of action of bexarotene, and retinoids in general, which results in a cytostatic rather than a cytotoxic effect.41 Based on the successful model achieved with combination chemotherapy, it is possible that two or more targeted therapies aimed at different gene pathways may be more effective when used in combination than if either agent is used alone. To test this hypothesis, a phase I study investigating bexarotene plus erlotinib was conducted in 24 patients with relapsed/refractory aerodigestive tract cancer and demonstrated that these agents can be combined at their conventional dose without added toxicity.42 Of the 19 patients with relapsed NSCLC enrolled onto that study, four achieved an objective response and seven had stable disease, with the 1-year survival rate reported to be 72%. These results suggest a potential synergy between bexarotene and erlotinib, confirming previously reported in vitro observations.22 A larger phase II study is currently underway to further evaluate the activity of this combination therapy in patients with relapsed NSCLC (K. Dragnev, personal communication). In this study, treatment with bexarotene capsules given to heavily pretreated patients with NSCLC was usually well tolerated. The most common adverse effect was hypertriglyceridemia, an asymptomatic laboratory abnormality, which was documented in 60% of patients despite prophylactic antilipemic therapy. As a result of careful patient monitoring and bexarotene dose adjustment, no clinical event associated with hypertriglyceridemia was reported, even in patients with grade 3 to 4 lipid abnormalities (23% of all patients). The two most frequent adverse effects, dyspnea reported in 50% of patients and fatigue in 31%, were most likely due to lung cancer. All other grade 3/4 adverse events were reported in fewer than 2% of patients. In conclusion, bexarotene may extend survival in a subset of heavily pretreated patients with relapsed NSCLC. A posthoc subset analysis showed that bexarotene-induced hypertriglyceridemia and skin rash were associated with improved survival. Further investigations are needed to ascertain whether hypertriglyceridemia is a reliable biomarker predictive of bexarotene benefit in NSCLC. Additional investigations aimed at identifying more proximal biochemical and genetic biomarkers predictive of bexarotene efficacy are currently ongoing and may lead to better patient selection criteria for future studies.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank the following investigators for enrolling patients on this study: B. Baltz, Little Rock, AR; A. Baron, Greenbrae, CA; J.T. Beck, Springdale, AR; Z. Bernstein, Buffalo, NY; M. Carlson, Lincoln, NE; P. Conkling, Norfolk, VA; B. Ekstrand, San Mateo, CA; G. Favis, Daytona Beach, FL; N. Gabrail, Canton, OH; G. Geils, Charleston, SC; R. Govindan, St Louis, MO; C. Graham, Charleston, SC; P. Joseph, Cranston, RI; S. Kahanic, Sioux City, IA; M. Keaton, Augusta, GA; P. Kennedy, Los Angeles, CA; B. Kim Savannah, GA; S. Lakhanpal, Birmingham, AL; R. Langdon, Omaha, NE; B. Luskey, Savannah, GA; R. Patel, Bakersfield, CA; S. Rifkin, Arlington, IL; R. Robles, Concord, CA; M. Rovito, Drexel Hill, PA; M. Saltzman, North Miami Beach, FL; A. Sandler, Nashville, TN; L. Schwartzberg, Memphis, TN; P. Siberstein, Omaha, NE; C. Spiridonidis, Columbus, OH; R. Steis, Atlanta, GA; and C. Williams, Tampa, FL.
Supported by Ligand Pharmaceuticals Inc, San Diego, CA. Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005, and in poster format at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Dragnev KH, Petty WJ, Shah S, et al: Bexarotene and erlotinib for aerodigestive tract cancer. J Clin Oncol 23:8757-8764, 2005 Submitted June 15, 2006; accepted August 9, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
two different regimens that must have included a platinum and a taxane, received oral bexarotene 400 mg/m2/d plus concomitant levothyroxine and a lipid-lowering agent. Primary efficacy end point was survival. 
, RXRß, and RXR
). These RXRs receptors can heterodimerize with several partner proteins, including retinoic acid receptors, peroxisome proliferator-activated receptors, vitamin D nuclear receptor, and thyroid hormone receptor, and can function as transcription factors that regulate a variety of gene networks, which play a critical role in cellular growth modulation, division, induction of differentiation, and activation of apoptosis.
