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© 2001 American Society for Clinical Oncology 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 CancerFrom the Departments of Thoracic/Head and Neck Medical Oncology and Diagnostic Radiology, University of Texas M.D. Anderson Cancer Center, Houston, TX; Dartmouth-Hitchcock Medical Center, Lebanon, NH; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles; Ligand Pharmaceuticals, Inc, San Diego, CA; and Department of Medical Oncology, Ochsner Clinic, New Orleans, LA. Address reprint requests to Fadlo R. Khuri, MD, Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 80, Houston, TX 77030; email: fkhuri{at}mdanderson.org
PURPOSE: Bexarotene (Targretin; Ligand Pharmaceuticals, Inc, San Diego, CA) is a retinoid-X-receptor (RXR)-selective retinoid with preclinical antitumor activity in squamous cell cancers. In this phase I/II trial, we combined bexarotene with cisplatin and vinorelbine in the treatment of patients with non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-three patients who had stage IIIB NSCLC with pleural effusion or stage IV NSCLC and had received no prior therapy received bexarotene in combination with cisplatin (100 mg/m2) and vinorelbine (alternating doses of 30 mg/m2 and 15 mg/m2). In the phase I portion, the daily dose of bexarotene was escalated in cohorts of three patients from 150 mg/m2 to 600 mg/m2, beginning 1 week before the start of the cisplatin-vinorelbine regimen. Once the maximum-tolerated dose (MTD) of bexarotene was determined, the study entered the phase II portion. Response rate was the primary end point; median survival time and 1-year survival rate were secondary end points. RESULTS: In the phase I portion, the daily MTD of bexarotene was determined to be 400 mg/m2. Eight of 43 patients exhibited major responses. Seven (25%) of the 28 patients in the phase II portion responded to treatment. The median survival time in the phase II portion was 14 months; nine (32%) of the 28 patients were still alive at a minimum follow-up of 2 years. One-year and projected 3-year survival rates were 61% and 30%, respectively. The most common grade 3 and 4 adverse events were hyperlipemia, leukopenia, nausea, vomiting, pneumonia, dyspnea, anemia, and asthenia. Grade 3 and 4 laboratory abnormalities with incidences greater than 5% were decreased hemoglobin levels and WBC, absolute neutrophil, and absolute lymphocyte counts and increased prothrombin time and creatinine and amylase levels. Of the two cases of pancreatitis, one required hospitalization and both were associated with increased triglyceride levels. There was one death secondary to renal insufficiency unrelated to bexarotene treatment. CONCLUSION: In patients with advanced NSCLC, bexarotene with cisplatin and vinorelbine yielded acceptable phase II response rates (25%) and was associated with better-than-expected survival (14-month median survival time; 61% 1-year, 32% 2-year, and 30% projected 3-year survival rates). The regimen should be studied in larger clinical trials.
LUNG CANCER is the leading cause of cancer-related death both in the United States and worldwide.1-3 It was predicted that 164,100 new cases of lung cancer and 156,900 deaths from lung cancer would occur in the United States in 2000.1 Because of the dismal prognosis associated with this disease, much debate has centered around the treatment of advanced disease, with the result that many patients received only supportive care.4,5 Although a sense of therapeutic nihilism has often pervaded the treatment of stage IV NSCLC, several randomized trials of combination chemotherapy versus best supportive care have indicated that chemotherapy in patients with stage IV disease has modest advantages in terms of survival and quality of life.4-6 Retinoids play critical roles in normal development and physiology by modulating cell growth, division, reproduction, differentiation, and immune function.7 They are also capable of inhibiting cell growth, inducing differentiation, and triggering apoptosis in a variety of tumor cell lines.7-9 The effects of retinoids seem to be due to changes in gene expression mediated through specific intracellular receptors.10,11 Retinoids exert their action through two subfamilies of intracellular receptors: the retinoic acid receptors (RARs) and the retnoid-X-receptors (RXRs).12,13 The RARs and the RXRs each have three subtypes, and each receptor subtype is thought to control both unique and overlapping target genes.
Over the last several years, retinoids have been used to treat a wide variety of neoplastic diseases. Clinical responses have been observed with acute promyelocytic leukemia, a disease in which a specific chromosomal translocation involving the RAR- The antitumor effects of retinoids, as well as their potential chemopreventive activity, support the need to further identify the spectrum of responsive tumors, to define the molecular mechanisms associated with retinoid action, and to develop new subclass-specific retinoids with unique properties and improved therapeutic indices. Bexarotene is a novel synthetic retinoid analog. Its chemical structure is shown in Fig 1. Bexarotene is a subclass-specific ligand; it binds preferentially to RXRs.19 These receptors play a role in the regulation of cell growth and differentiation through regulating transcription. Findings of in vitro studies, experiments in animal models, and clinical trials suggest that the spectrum of activity of bexarotene differs significantly from non–RXR-specific retinoids, such as 13-cis-retinoic acid and all-trans-retinoic acid.19-23 The subclass specificity could provide therapeutic selectivity and/or reduced toxicities.19 Bexarotene inhibits the growth of tumor cell lines of both hematopoietic and squamous cell origins20,21 and induces apoptosis in a number of those cell lines. Growth of xenografts of primary human squamous cell tumors are inhibited, sometimes with tumor regression in advanced-stage models, by bexarotene in nude mice (data on file, Ligand Pharmaceuticals, Inc, San Diego, CA). Furthermore, preclinical studies of another RXR agonist, alitretinoin (9-cis-retinoic acid, Panretin; Ligand Pharmaceuticals, Inc), led to speculation that bexarotene could sensitize tumor tissue to cisplatin.22
When we began the current study, three phase I trials of bexarotene in solid tumors had been conducted (Khuri et al, manuscript submitted for publication).23,24 In one trial, Miller et al23 evaluated 52 patients with various solid tumors after bexarotene had been administered orally once daily for 1 to 41 weeks in doses that ranged from 5 to 500 mg/m2. The toxic effects they noted (eg, reversible, asymptomatic increases on liver biochemical tests) were substantially different from those noted in phase I trials of RAR-specific retinoids. They also noted leukopenia, hypertriglyceridemia, and hypercalcemia. They did not report clinically significant classic retinoid toxicities such as cheilitis, headache, conjunctivitis, and skin dryness. Furthermore, they treated nine patients with cutaneous T-cell lymphoma, and two of these patients experienced major antitumor responses. Eight of 20 patients with NSCLC had prolonged disease stabilization. The daily maximum-tolerated dose (MTD) was 300 mg/m2. Rizvi et al24 conducted a phase I study of bexarotene in adults with advanced cancer. These investigators treated a total of 60 patients with oral bexarotene; daily doses ranged from 5 to 1,000 mg/m2. Pharmacokinetic sampling was performed on days 1 and 15. No dose-limiting toxicities were observed up to the 500 mg/m2 dose level. However, dose-limiting toxicities observed at and above the 650 mg/m2 dose level included desquamation, hyperbilirubinemia, increased transaminase levels, leukopenia, diarrhea, and prolongation of prothrombin time. Day 1 bexarotene maximal concentration (Cmax) and areas under the curve increased dose proportionally up to 800 mg/m2. Although Rizvi et al24 failed to see any objective tumor responses, tumor progression may have been substantially arrested or delayed in five of 16 cases of NSCLC and one of five cases of head and neck cancer. Khuri et al (manuscript submitted for publication) conducted a phase I tumor-specific evaluation of bexarotene in 26 extensively pretreated patients with recurrent head and neck squamous cell carcinoma (HNSCC). Daily doses were increased from 10 mg/m2 to 600 mg/m2. The median Zubrod performance status score was 1, and 19 patients had been previously treated with chemotherapy (median number of regimens, two; range, zero to five). No objective responses were seen, and the median time to progression (TTP) was 4 weeks (range, 2 to 14 weeks). However, the median survival time was 6.5 months from trial registration. The major toxicity was dose-related hypertriglyceridemia, which resulted in two cases of acute pancreatitis (at 600 mg/m2/d [300 mg/m2 twice a day]), including an episode of fatal hemorrhagic pancreatitis in a patient who continued to consume alcohol while taking the study drug. This patient’s triglyceride level increased from 235 mg/dL at baseline to 3,690 mg/dL on day 14. Thus, a better-than-expected median survival time in HNSCC patients and some evidence of delayed TTP in both NSCLC and HNSCC patients were among the reasons for our combining bexarotene with active chemotherapy in patients with advanced NSCLC. At the time this trial was launched in 1995, several new agents were under active investigation in patients with stage IV NSCLC. Of these, vinorelbine was among the first of the third-generation agents to demonstrate improved activity against NSCLC, both as a single agent and in combination with a platinum compound. LeChevalier et al25 and Wozniak et al26 conducted randomized trials in which the combination of cisplatin and vinorelbine was compared with either cisplatin and vindesine or cisplatin alone. Both studies found that the combination had statistically significant survival advantages. The median survival time in the LeChevalier study was 9.3 months, and the 1-year survival rate was 40%.25 In the study by Wozniak et al,26 the median survival time was 8 months and the 1-year survival rate was 36%. Both groups reported adverse events for the combination of cisplatin and vinorelbine, including grade 3 or 4 myelosuppression in approximately 80% of patients, sometimes with granulocytopenia-related fever or sepsis and anemia. Nonhematologic adverse events included grade 2, 3, or 4 nausea or vomiting in up to 58% of patients in the two studies, grade 3 or 4 malaise or weakness in approximately 15% of the patients in the study by Wozniak et al,26 and grade 3 or 4 renal toxicity in approximately 5% of patients in the two studies.
Patients were accrued at four institutions (the University of Texas M.D. Anderson Cancer Center, Dartmouth-Hitchcock Medical Center, the Ochsner Clinic, and the Jonsson Comprehensive Cancer Center, University of California Los Angeles) and were treated between December 12, 1995, and January 28, 1999. All patients signed an institutional review board–approved informed consent form. Patients were required to have pathologic (histologic or cytologic) confirmation of NSCLC, either stage IIIB with pleural effusion or stage IV; a life expectancy of at least 12 weeks; and a Karnofsky performance status score  70. Furthermore, they were required to have acceptable organ function, defined as follows: adequate hepatic function with bilirubin levels less than 1.5 times the upper limit of normal and ALT and AST levels  2.5 times the upper limit of normal; adequate renal function with serum creatinine levels 1.5 mg/dL or creatinine clearance 60 mL/min; and adequate hematologic function, normal coagulation parameters, and serum amylase levels 1.5 times the upper limit of normal. Furthermore, patients were required to have serum calcium concentrations 11.5 mg/dL and fasting serum triglyceride levels 1,000 mg/dL, or 500 mg/dL if clinical risk factors for pancreatitis (such as prior pancreatitis, uncontrolled hyperlipidemia, excessive alcohol consumption, uncontrolled diabetes mellitus, biliary tract disease, and treatment with medications known to increase triglyceride levels or to be associated with pancreatic toxicity) were present. At least one measurable or assessable indicator lesion that had not been irradiated was required for enrollment onto the study. Pleural effusion, bone metastasis, brain metastasis, increased serum enzyme levels, and radionuclide scans showing abnormalities were not considered acceptable as the only indicator lesions or the only signs of indicator lesions. The patients were required to be free of concurrent medical illness. Women of childbearing potential were required to have negative serum pregnancy test results (beta–human chorionic gonadotropin) 7 days before initiation of treatment and were also required to have used an effective means of contraception or to have been sexually abstinent for at least 4 weeks before the pregnancy test, because of the extensive teratogenic effects of retinoids. Men were required to ensure that they did not fertilize their partners, and women of childbearing potential were required to prevent pregnancy while taking bexarotene. Patients who had previously been treated with chemotherapy were ineligible, as were individuals who had undergone irradiation of major bone marrow areas within 3 weeks of study entry. All brain metastases were required to be radiographically stable or improved after whole-brain irradiation, with evidence of neurologic improvement or normalization. Because of the toxicity of cisplatin, patients with preexisting hearing loss of greater than National Cancer Institute grade I toxicity were not eligible for the study. Systemic treatment with vitamin A or other investigational compounds within 30 days of study entry was also an exclusion criterion.
Treatment Plan
After the first three patients were entered onto the study, the protocol was amended: the dose of cisplatin was decreased from 120 to 100 mg/m2. After the amendment, dose escalation proceeded, beginning at the lowest dose level across the three dose level groups (200, 400, and 600 mg/m2/d), with cohorts of three or six patients for each dose level. If three patients were entered and maintained at a given dose level through at least day 29 and no dose-limiting toxicity was noted, the next patient was entered at the next higher dose level. If more than one patient in a cohort experienced a dose-limiting toxicity, the MTD was considered to be exceeded and the cohort treated at the previous dose level was expanded from three to six patients.
After determination of the MTD of bexarotene in combination with vinorelbine and cisplatin, additional patients were enrolled at the MTD, for a total of eight assessable patients. Antitumor response was categorized as complete remission (disappearance of all clinical evidence of tumor [as determined by physical examination, roentgenography, and/or computed tomography or MRI] for a minimum of 4 weeks, with no new lesions appearing during that time), partial remission ( Instructions for dose modification of study agents were included in the protocol and were dependent on the nature of the toxicity reported and on the grade level. As the study progressed, stricter guidelines for the control of hypertriglyceridemia secondary to bexarotene therapy were developed. These guidelines included the administration of oral antilipid drugs and, as necessary, the temporary or permanent suspension of bexarotene therapy.
Forty-three patients were treated on this phase I/II study. Twenty-one patients were treated in the phase I portion of the study: three patients at the bexarotene dose level of 150 mg/m2/d, three patients at 200 mg/m2/d, six at 400 mg/m2/d, and nine at 600 mg/m2/d. The MTD of bexarotene in combination with cisplatin and vinorelbine was determined to be 400 mg/m2/d. A total of 28 patients were treated at the MTD in the phase II portion, including all six patients treated at the bexarotene dose level of 400 mg/m2/d during the phase I portion. Baseline demographics are summarized in Table 2 (all patients) and Table 3 (patients in the 400 mg/m2/d dose level group). The median age of the patients entered in the phase II portion was 59 years. This group was predominantly white (93%), and men made up two-thirds of the group. This distribution was representative of the total study population. Six (14%) of the study’s 43 patients had stage IIIB disease and 37 patients (86%) had stage IV disease. Two (7%) of the 28 patients in the phase II portion had stage IIIB NSCLC with pleural effusion, and 26 (93%) had stage IV disease.
Response Rates and Survival Seven (25%) of the 28 patients in the phase II portion of the trial manifested a partial response; one of the seven had nearly complete resolution of all radiographically demonstrated lesions. The median duration of treatment for the 400 mg/m2 dose level cohort was 152 days (range, 13 to 259 days). One other patient, in the 600 mg/m2/d dose level group in the dose-escalation portion of the study, had a partial response. Fourteen patients (50%) achieved disease stabilization after two cycles, and seven patients (25%) had a partial response in the phase II portion. The median treatment duration for the 14 patients with stable disease was 158 days (range, 75 to 231 days). The median survival time among these patients was 593 days, or 20 months (range, 273 to 1,284+ days), with four patients still alive on April 30, 2000. As for the seven responders in the phase II portion, the median duration of therapy was 232 days (range, 85 to 259 days), the median survival time had not been reached (range, 384 to 1,054+ days), and, with a minimum follow-up of 2 years, five were still alive on April 30, 2000 ( Fig 2).
Nine (32%) of the 28 patients in the phase II portion remained alive, with a minimum follow-up of 2 years and a median follow-up of 30 months (range, 24 to 42 months). The median survival time, according to Kaplan-Meier analysis, for the entire phase I/II study was 351 days (range, 19 to 1,284+ days). However, at the MTD level, the median survival time was 410 days, or 14 months (range, 55 to 1,284+ days). Kaplan-Meier survival estimates by dose group are shown in Fig 3. The 1-year survival rate as determined by life-table analysis was 61%, and the projected 3-year survival rate was 30%.
Toxicities For nine patients, including four in the 400 mg/m2/d dose level group, adverse events were the primary reason for withdrawal from the study. These adverse events are presented by dose level in Table 4. For two other patients (both in the 400 mg/m2 dose level group), withdrawal of consent was the primary reason for leaving the study, but secondary reasons were adverse events (one patient) and progressive disease (one patient). The incidences of all grade 3 or 4 adverse events, regardless of relationship to bexarotene or combination chemotherapy, is listed in Table 5. The incidences of adverse events as categorized by the investigator’s assessment of relationship to treatment regimen as related to therapy, is listed in Table 6. Grade 3 and grade 4 laboratory abnormalities, as defined by the National Cancer Institute common toxicity criteria, version 2, are listed in Table 7.
There was one death secondary to renal insufficiency, that of a patient in the 150 mg/m2/d dose group in the phase I portion of the study; however, this event was considered to be related to progressive disease and not to drug therapy. At the 600 mg/m2/d dose level, there were two incidences of grade 3 or higher renal insufficiency within the first 4 weeks of treatment. Both of these patients came off the trial before being assessable for treatment efficacy. Pancreatitis was also a concern. One episode of pancreatitis was seen in the nine patients at the 600 mg/m2 dose level. Despite extensive hyperlipidemia ( grade 2) in 22 of the 28 patients treated at the MTD of 400 mg/m2, only one episode of pancreatitis was noted at this dose, and this episode in the phase I portion of the study was transient and resolved with reduction of the dose of bexarotene. The most common adverse events, regardless of relationship to treatment, across all patients in the study included asthenia (81% of patients), leukopenia (74%), nausea (70%), hyperlipemia (67%; primarily hypertriglyceridemia), vomiting (58%), headache (56%), exfoliative dermatitis (56%; primarily skin peeling), and anorexia (51%). Grade 3 (moderately severe) and 4 (severe) adverse events with incidences greater than 5% in either category, without regard to relationship to bexarotene therapy, were hyperlipemia (grade 3, 26%; grade 4, 5%), leukopenia (23%, 33%), nausea (19%, 2%), vomiting (19%, 2%), pneumonia (14%, 0%), dyspnea (9%, 0%), anemia (9%, 0%), and asthenia (7%, 2%). Grade 3 and 4 laboratory abnormalities with incidences of greater than 5% in either category were decreased hemoglobin levels (grade 3, 12%; grade 4, 0%), WBC counts (16%, 9%), absolute neutrophil counts (30%, 35%), and absolute lymphocyte counts (44%, 26%), increased prothrombin time (12%, 8%) and amylase levels (13%, 4%), and decreased creatinine clearance (7%, 0%). Toxicities in the phase II portion of the trial were not significantly out of proportion with what one would expect with treatment with the combination of cisplatin and vinorelbine. In addition to the standard toxicities including nausea, vomiting, neuropathy, and mild to moderate renal insufficiency, the major toxicity noted in the phase II portion was hypertriglyceridemia secondary to bexarotene therapy that required treatment with atorvastatin and sometimes brief treatment interruptions. Treatment with atorvastatin on this trial proved substantially more successful than treatment with gemfibrozil in previous trials (because of a bexarotene-gemfibrozil drug interaction leading to increased bexarotene concentrations),27 and most patients were able to avoid dose interruptions. Generally, irreversible organ damage is not seen with bexarotene therapy. Clinical hypothyroidism was reported for only one patient on this trial, in contrast to 29% of patients with cutaneous T-cell lymphoma (data on file, Ligand Pharmaceuticals, Inc). Three patients required hospitalization for serious adverse events including pancreatitis, renal insufficiency, and hypercalcemia. Hospitalization for granulocytopenia-related fever or sepsis was not required in any case, which may be a reflection of the attenuated dosing schedule for vinorelbine used in this study (in their studies, Wozniak et al26 and Le Chevalier et al25 administered 30 mg/m2 weekly).
This regimen of cisplatin, vinorelbine, and bexarotene had significant activity in the phase II portion of the trial: the response rate was 25%, the median survival time was 14 months, and nine of 28 patients were alive after more than 2 years of follow-up. This survival is among the best reported for phase II trials involving patients with NSCLC. Particularly encouraging is the fact that our phase II multi-institutional trial, as opposed to other phase II single-institutional trials, had long-term survivors of 1 year at three of the four sites that participated in this study. In the absence of a markedly higher response rate than has been seen in other phase II studies, however, the enhanced survival on this trial is striking and the reasons for this are unclear. Reports of most phase II and phase III trials of cytotoxic agents in stage IIIB/IV NSCLC include response rates, median survival times, and 1-year survival rates, but in the few reports that have included 2-year survival rates, such rates have been far less impressive than those in our current study. Most recently, Roszkowski et al28 conducted a randomized phase III trial of docetaxel versus best supportive care in the front-line treatment of NSCLC. The 2-year survival rate in the docetaxel treatment arm was 12%, whereas none of the patients receiving best supportive care survived after 20 months. In other phase III trials of novel agents, even in combination with cisplatin, 2-year survival rates have been no better than 15%.29-31 Although ours is clearly a phase II trial, with some degree of patient selection (median performance status was Zubrod 1 or Karnofsky 80), we believe that our 61% 1-year, 32% 2-year, and 30% projected 3-year survival rates are the best reported for either phase II or III studies. The growth inhibitory properties of bexarotene were reviewed in our introduction. For the complete data set, 12 (33%) of 36 patients with NSCLC were treated for at least 90 days on previous phase I trials of single-agent bexarotene therapy.23,24 These 12 patients received a median of 176 days of treatment (range, 103 to 399 days) (data on file, Ligand Pharmaceuticals, Inc). Given the 98% 6-month progression rate reported by Roszkowski et al28 for NSCLC patients receiving best supportive care, this retinoid, when administered alone, may have some significant growth inhibitory properties. Furthermore, as previously discussed, in the phase I trial of bexarotene in extensively pretreated patients with head and neck cancer, the median survival duration from time of study entry was 6.5 months (Khuri et al, manuscript submitted for publication). This is equivalent to what others have reported in two front-line phase III trials of cisplatin and fluorouracil in patients with HNSCC.31,32 However, no classic, objective responses were noted in the NSCLC patients treated in both phase I bexarotene trials (the median survival time for these 36 patients was 11.1 months) or in the 26 HNSCC patients on the phase I trial of bexarotene.23,24 The potential for bexarotene to have beneficial effects in NSCLC is further reinforced by the results of a recently reported phase II/III study involving 54 patients.33 The study was designed as a large, multicenter, randomized, double-blinded, placebo-controlled trial and was terminated prematurely because of slow accrual. Patients with stage IIIB NSCLC with pleural effusion, stage IV NSCLC, or recurrent NSCLC were eligible if they had stable or responsive disease after first-line, platinum-based combination chemotherapy. Patients were initially treated with placebo or oral bexarotene 300 or 600 mg/m2/d. TTP was the primary end point and survival was a secondary end point. Patients were randomized by center to placebo (16 patients, 31%), bexarotene 300 mg/m2/d (21 patients, 40%), or bexarotene 600 mg/m2/d (15 patients, 29%) after demonstrating stable or responsive disease following first-line chemotherapy. The median TTP from the beginning of administration of study drug was 56 days for placebo and 82 days for moderate-dose and 128 days for high-dose bexarotene (P = .56, log-rank rank). For prior-chemotherapy responders only, the median TTP from the beginning of study drug treatment was 56 days for placebo and 146 days for moderate-dose and 177 days for high-dose bexarotene. More chemotherapy responders were randomized to placebo (63%) than to bexarotene treatment (moderate-dose, 48%; high-dose, 47%), further supporting a bexarotene-related improvement in TTP. Because this study was stopped prematurely, it did not have the statistical power to detect differences among the treatment groups. This study does show that patients can tolerate bexarotene at initial doses up to 600 mg/m2/d after platinum-based chemotherapy, and bexarotene may have the potential to delay disease progression in advanced-NSCLC patients with previously stable or responsive disease after platinum-based chemotherapy. The mechanistic interaction between the retinoid and the combination of cisplatin and vinorelbine is unclear. One would have expected this combination to result in higher response rates in the phase II portion of our trial; however, the 25% phase II response rate is in line with rates reported recently for other phase II combinations.34 As for the possibility of stage migration, the vast majority of patients on this trial (37 of 43) had true stage IV NSCLC, and all six patients with stage IIIB disease had pathologically confirmed malignant pleural effusions, a finding that usually portends a prognosis identical to that of stage IV disease. Thus, we are left with a provocative interaction between bexarotene, cisplatin, and vinorelbine, with a survival on this study that is remarkable. The question of the potential significance of response rates in phase II NSCLC studies therefore remains unanswered. Schiller et al35 tested several combination chemotherapy regimens in patients with stage IIIB or IV NSCLC, including combinations of cisplatin and paclitaxel, cisplatin and gemcitabine, cisplatin and docetaxel, and carboplatin and paclitaxel, all in an Eastern Cooperative Oncology Group randomized phase III trial. Although response rates ranged from 15.3% to 21.3%, median survival times did not differ significantly (range, 7.4 to 8.3 months), nor did 1-year survival rates (range, 31% to 36%). This further reinforces the point that there is at present no standard front-line regimen for stage IV NSCLC. Shepherd et al36 and Fossella et al37 conducted randomized trials of docetaxel in the second-line treatment of NSCLC. Although overall response rates in these two trials were modest (6% and 9%, respectively),36,37 the percentage of patients receiving docetaxel whose disease had not progressed at the time of the first assessment ranged from 36% to 45%, indicating that disease stabilization may be an important parameter to follow. Both studies demonstrated a survival benefit for docetaxel at a dose of 75 mg/m2, particularly at 1 year (37% and 32%, respectively, v 12% for best supportive care and 19% for the arm in which patients received either vinorelbine or ifosfamide; P = .003 and P = .025, respectively). These results further indicate that in patients with advanced NSCLC, classic responses, as opposed to disease stabilization, may not be as critical for achievement of survival benefit as previously thought. In our study, 50% of patients achieved disease stabilization on the phase II portion, and the median survival time for those patients was 394 days, or 13 months (> 817 days for the seven responders). In fact, the single longest survivor, with a current follow-up of 31/2 years, never achieved a response with the combination of bexarotene, cisplatin, and vinorelbine or with subsequent second- and third-line treatments with docetaxel or gemcitabine. However, he has remained fully active, with a Karnofsky performance status score of 90. In conclusion, a standard third-generation NSCLC chemotherapy regimen of cisplatin and vinorelbine combined with oral bexarotene at a MTD of 400 mg/m2 had significant activity, with the retinoid at that dose level adding acceptable toxicities to those of the cytotoxic chemotherapeutic agents. Furthermore, the median survival time on the phase II portion of this study was a robust 14 months, with nine (32%) of 28 patients remaining alive at more than 2 years of follow-up and with a projected 3-year survival rate of 30%. We believe that this intriguing combination of potent cytotoxics with an agent that has a role in growth, differentiation, and induction of apoptosis bears further investigation. Although this was an open-label study of the activity of bexarotene added to a standard regimen for NSCLC, the results of this study cannot be ignored. Given the accumulating evidence of activity of bexarotene against NSCLC, further investigations of the combination of bexarotene with cisplatin and vinorelbine are warranted. A phase III trial is being initiated in which the bexarotene combination is being compared with the cytotoxic agents (cisplatin and vinorelbine) alone.
Supported in part by grants from Ligand Pharmaceuticals, Inc (F.R.K., J.R.R., R.A.F., and R.J.G.). F.R.K. is a recipient of an American Cancer Society Clinical Oncology Career Development Award (ACS CO CDA96-41). W.K.H. is an American Cancer Society Clinical Research Professor. We thank Richard C. Yocum for his valuable scientific input; Julia Starr for her editorial expertise; Patricia Coldiron for transcription of the manuscript; Dinah Jaunakais, Rita Geiser, and Carol Manifold for their careful data evaluation; and Maria Jung for research nursing support.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
gene has been identified.
