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Journal of Clinical Oncology, Vol 23, No 24 (August 20), 2005: pp. 5774-5778 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.14.373 Phase II Trial of the Novel Retinoid, Bexarotene, and Gemcitabine Plus Carboplatin in Advanced Non-Small-Cell Lung CancerFrom the University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD Address reprint requests to Martin J. Edelman, MD, University of Maryland Greenebaum Cancer Center, 22 S Greene St, Baltimore, MD 21201-1595; e-mail: Medelman{at}umm.edu
PURPOSE: Platinum-based chemotherapy is the standard treatment for advanced non-small-cell lung cancer (NSCLC). Unfortunately, a plateau in efficacy with currently available agents has been reached. Previous studies of the retinoid, bexarotene, a retinoid X receptor-specific ligand, have indicated that it may improve outcome in advanced NSCLC. PATIENTS AND METHODS: Patients with previously untreated stage IIIB or stage IV disease, a performance status of 0 to 2, and adequate organ status were entered. Treatment consisted of up to six cycles of carboplatin (area under the curve = 5.0 on day 1) and gemcitabine (1,000 mg/m2 on days 1 and 8) administered every 21 days. Bexarotene 400 mg/m2 orally was to be administered continuously beginning on day 1 and until progression of disease. All patients received atorvastatin 10 mg orally beginning before bexarotene. The objective was to demonstrate a 1-year survival rate of more than 50%. RESULTS: Forty-eight patients were entered; all were assessable for survival, and 47 were assessable for toxicity and response. The therapeutic regimen was well tolerated except for hypertriglyceridemia. The median time to progression was 6.7 months, and overall median survival was 12.7 months. There was a 25% response rate and a 1-year survival rate of 53%. These results were compared with the outcome of 33 patients treated at our institution with two-drug, platinum-based chemotherapy on controlled trials with similar entry criteria in the previous 5 years. CONCLUSION: Bexarotene can be safely added to platinum-based chemotherapy provided that there is aggressive prophylaxis of hypertriglyceridemia. The median time to progression and overall survival are promising and warrant further evaluation of bexarotene in advanced NSCLC.
Of the 150,000 patients who will develop non-small-cell lung cancer (NSCLC) in the United States in the next year, at least 40% will present with metastatic disease, and the vast majority of the remainder will eventually develop metastases. Recent advances in chemotherapy have improved the outlook for patients with stage IV disease. Studies using best supportive care result in a 4- to 6-month median survival, with only 10% of patients alive at 1 year. By comparison, median survivals of approximately 6 to 8 months and a 1-year survival rate of 20% are achieved with earlier platinum-based (cisplatin or carboplatin) regimens (eg, single-agent platinum, cisplatin/etoposide, or cisplatin/vindesine). Most recent studies evaluating combinations of platinums with newer agents (carboplatin/paclitaxel, cisplatin/gemcitabine, and cisplatin/vinorelbine) have reported improved median survivals times of 8 to 10 months, with 1-year survival rates of 30% to 35%, and/or reduced toxicity relative to older combinations.1-3 Despite this improvement, it is clear that a plateau in efficacy has been reached. The addition of a third agent, either cytotoxic or biologic, has failed to improve the situation.4-6 Bexarotene (LGD1069, Targretin; Ligand, San Diego, CA) is a novel synthetic retinoid analog. Retinoids play critical roles in normal development and physiology by modulating cell growth, division, reproduction, differentiation, and immune function. They are capable of inhibiting cell growth, inducing differentiation, and inducing apoptosis (programmed cell death) in a variety of tumor cell lines.7
Bexarotene is a subtype-specific ligand, binding preferentially to members of the retinoid X receptor (RXR) subclass of receptors (RXR Bexarotene has been approved for the treatment of cutaneous T-cell lymphoma. In the course of its development, bexarotene was also evaluated in solid tumors. Phase I trials demonstrated good tolerability and evidence of disease stabilization in NSCLC.10 A phase I/II trial in NSCLC demonstrated excellent tolerability and promising survival using bexarotene in combination with cisplatin and vinorelbine.8 Another trial attempted to randomly assign patients to maintenance with varying bexarotene doses versus observation but failed to complete accrual. However, there was an interesting trend towards improved overall survival. Carboplatin/gemcitabine is an active, commonly used, and well-tolerated regimen that does not usually result in alopecia and does not have the neurotoxicity and pain associated with taxane-based regimens. Therefore, it is an excellent platform regimen for the addition of new agents in the treatment of NSCLC. It has demonstrated activity comparable to that of other currently used regimens in NSCLC.9 The goal of this trial was to assess the activity of carboplatin/gemcitabine combined with bexarotene for the treatment of advanced NSCLC.
Inclusion Criteria Patients with histologically documented, advanced (stage IIIB: pleural effusion or multiple lesions in a lobe containing a T3 or T4 primary tumor; or stage IV) NSCLC were eligible. An Eastern Cooperative Oncology Group performance status of 0 to 2 and acceptable renal (calculated creatinine clearance of > 50 mL/min), hepatic (serum bilirubin and transaminases < 2x the upper limit of normal), and hematologic function (absolute neutrophil count  1,800/µL, platelets 100,000/µL, and hemoglobin 10 g/dL) were required. Patients with a prior history of pancreatitis or uncontrolled hyperlipidemia (triglycerides > 200 mg/dL on therapy) were excluded. The study was approved by the institutional review board, and all patients gave written informed consent.
Treatment
Study Design and Treatment Evaluations Results from single institutions are frequently not replicated. Several factors may contribute to this problem, including selection bias, referral bias, random statistical noise, and so on. Recognizing this potential issue, we examined our prior experience with platinum-based, modern, two-drug chemotherapy in patients entered onto clinical trials in the previous 5 years. These patients met similar or more stringent entry criteria and were evaluated in a similar fashion at similar intervals. Thirty-three patients were identified meeting these criteria. Treatment regimens were carboplatin/paclitaxel (n = 12), carboplatin/gemcitabine (n = 8), carboplatin/docetaxel (n = 6), cisplatin/docetaxel (n = 4), and cisplatin/vinorelbine (n = 3). Time to progression and survival were compared using log-rank analysis.
Demographics Patients were enrolled onto this study between April 2002 and March 2004. The demographics of the patients entered onto this study are listed in Table 1. Eleven patients with stage IIIB disease were entered on the basis of pleural effusion, and one patient was entered on the basis of multiple lesions within a lobe. All patients were assessable for survival, and 47 patients were assessable for toxicity and response. One patient chose not to return after the first dose of treatment and received further carboplatin and gemcitabine without bexarotene at another facility. Except for a somewhat higher percentage of patients with stage IIIB disease, the study population was similar in most respects to patients entered onto recent national trials. Compared with previous patients entered onto studies at the University of Maryland, there were somewhat more patients with stage IIIB disease (pleural effusion) than patients with metastatic disease.
Toxicity Therapy was well tolerated overall. The degree of myelotoxicity observed was similar to the degree noted in prior studies of gemcitabine and carboplatin (Table 2). There were no formal guidelines in the protocol for transfusions. Fifteen patients received RBC transfusions, and 12 received platelet transfusions. Nonhematologic toxicities were also similar except for hypertriglyceridemia, which was attributable to bexarotene (Table 3). This resulted in frequent dosage adjustments and discontinuations of bexarotene. Consequently, the starting atorvastatin dose was increased to 40 mg. This resulted in improved tolerance to bexarotene in terms of hypertriglyceridemia. Data regarding the actual dose of bexarotene received were not rigorously captured. However, using chart records, we estimate that the first and second cycle median doses were 83% and 58%, respectively, before the amendment and 96% and 80%, respectively, after the amendment. Laboratory evidence of hypothyroidism developed in two patients, who responded well to hormone replacement.
Response and Survival There were 11 partial responders and one complete responder, for an overall response rate of 25% (95% CI, 14% to 40%). Twenty-eight patients had stable disease, seven patients had progressive disease, and one patient was not assessable for response. At this time, 47 of 48 patients have progressive disease. The median time to progression was 6.7 months, and the median overall survival was 12.7 months. At 1-year, 53% of the patients were alive. The median time to progression in our study was significantly superior to that of the historical control group (time to progression, 6.7 v 3.9 months, respectively; P = .003; Fig 1). Patients with stage IIIB disease (n = 12) had a median event-free survival time of 7.3 months, which was superior to the overall group. However, even with the removal of all stage IIIB patients, the median event-free survival time of 6.5 months was still significant (P = .02) when compared with all historical controls (ie, stage IIIB and IV). The median overall survival time of 12.7 months was numerically superior to historical controls (9.3 months); however, this improvement did not achieve statistical significance (P = .26). Stage IIIB patients treated with bexarotene had a median overall survival time of 10.8 months.
This study provides additional evidence that bexarotene may improve outcome in advanced NSCLC. The results demonstrating improved progression-free survival and a trend towards better overall survival are similar to the results of four other studies using bexarotene as a single agent, combined with chemotherapy, or sequentially with chemotherapy. The initial clinical trial of bexarotene noted major responses in cutaneous T-cell lymphoma and led to bexarotene's further development and eventual registration for that indication.10 Interestingly, eight of 20 patients with previously treated NSCLC were able to receive at least 3 months of therapy, and one patient was stable for 9 months. This duration of treatment was suggestive of drug activity in this heavily pretreated population. A remarkably similar result was noted in a phase I trial led by Rizvi et al.12 This study noted disease stabilization of greater than 3 months in five of 16 patients with advanced, previously treated NSCLC. Two NSCLC-specific trials have been fully reported. The first was a phase I and II trial combining bexarotene with cisplatin/vinorelbine. Bexarotene was escalated from 150 to 600 mg/m2. The 400 mg/m2 dose was established as the maximum-tolerated dose with this combination. This study noted a response rate (25%) similar to that observed with cisplatin/vinorelbine alone. However, there was a trend towards improved survival with higher bexarotene dose, and the median survival time of the 28 patients treated on the phase II dose of 400 mg/m2 was 14 months. A phase II trial that used bexarotene as maintenance therapy after patients achieved response or stable disease has been reported.13 This study randomly assigned patients between placebo and two different dose of bexarotene (300 or 600 mg/m2). This trial did not meet its enrollment objectives; however, analysis of the 54 randomly assigned patients indicated there was a numerically (although not statistically significant) improved time to progression for the patients receiving bexarotene compared with placebo. A third phase I and II study combining bexarotene with carboplatin/paclitaxel has also been reported in abstract form. No data regarding progression-free or overall survival have been reported.14 It is interesting to speculate that any improvement may reflect not only the activity of bexarotene but also the activity of atorvastatin. Atorvastatin, a statin lipid-lowering agent, functions as an inhibitor of 3-hydroxy-3-methylglutaryl coenzymeA reductase and may have significant antitumor properties.15 There is some in vitro evidence that statin agents may potentiate the effects of anticancer agents.16 Furthermore, recent epidemiologic studies demonstrate that patients receiving similar agents have a lower risk of colorectal cancer.17 Future trials may need to address the relative contributions of atorvastatin and bexarotene to improved outcomes in lung cancer. Although promising, these results must be viewed with caution because of the phase II nature of the study and the lack of a prospective control group. Recently completed randomized trials will determine the validity of this approach.
Although all authors have completed the disclosure declaration, the following author or their immediate family members has 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)
Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Bonomi P, Kim K, Fairclough D, et al: Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: Results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 18:623-631, 2000 2. Wozniak AJ, Crowley JJ, Balcerzak S, et al: Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small cell lung cancer: A cooperative group study. J Clin Oncol 10:1066-1073, 1992[Abstract]
3. Sandler A, Nemunatis J, Denham C, et al: Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced and metastatic non-small cell lung cancer. J Clin Oncol 18:122-130, 2000 4. Debaldo C, Syz N, Michiels S, et al: Adding a second or third drug to a chemotherapy regimen in patients with advanced non-small cell lung carcinoma: A meta-analysis of the literature. Proc Am Soc Clin Oncol 22:623, 2003 (abstr 2507)
5. Herbst RS, Giaccone G, Schiller JH: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 2. J Clin Oncol 22:785-794, 2004 6. Lynch TJ, Raju R, Lind M, et al: Randomized phase III trial of chemotherapy and antisense, oligonucleotide LY9000003 (ISIS 3521) in patients with advanced NSCLC: Initial report. Proc Am Soc Clin Oncol 22:623, 2003 (abstr 2504) 7. Sporn M, Roberts A: Role of retinoids in differentiation and carcinogenesis. J Natl Cancer Inst 73:1381-1387, 1984
8. 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
9. Rudd RM, Gower NH, Spiro SG, et al: Gemcitabine plus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non-small-cell lung cancer: A phase III randomized study of the London Lung Cancer Group. J Clin Oncol 23:142-153, 2005
10. Miller VA, Benedetti FM, Rigas J, et al: Initial clinical trial of a selective retinoid X receptor ligand, LGD 1069. J Clin Oncol 15:790-795, 1997 11. Green S, Weiss GR: Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 10:239-253, 1992[CrossRef][Medline]
12. 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 13. 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 advance non-small cell lung cancer. Clin Lung Cancer 2:210-215, 2001[Medline] 14. Rizvi NA, Miller W, Frank H, et al: Phase I/II safety evaluation of bexarotene in combination with carboplatin and paclitaxel in patients with chemotherapy-naive advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 21:334a, 2002 (abstr 1334)
15. Chan KW, Oza AM, Siu LL: The statins as anticancer agents. Clin Cancer Res 9:10-19, 2003
16. Holstein SA, Hohl RJ: Synergistic interaction of lovastatin and paclitaxel in human cancer cells. Mol Cancer Ther 1:141-149, 2001 17. Poynter JN, Rennert G, Bonner JD, et al: HMG CoA reductase inhibitors and the risk of colorectal cancer. J Clin Oncol 22:1s, 2004 (abstr 1, suppl) Submitted February 1, 2005; accepted April 25, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
, RXRß, and RXR
). Bexarotene differs from all-trans-retinoic acid, which is a naturally occurring, endogenous hormone that binds with high affinity only to the retinoic acid receptor (RAR) subtypes. Bexarotene also differs from alitretinoin (9-cis-retinoic acid, Panretin; Ligand), which is a naturally occurring, endogenous pan-agonist (ie, binding and activating all known retinoid receptors, including RAR and RXR families).
grade 1. 
