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

Purpose: Bexarotene (Targretin; Ligand Pharmaceuticals, Inc, San Diego, CA) is a retinoid-X-receptor (RXR)-selective retinoid with preclinical antitum or activity in squamous cell cancers. In this phase I/II trial, we combined bexarotene with cisplatin and vinorelbine in the treatment of patients wit h non-small-cell rung cancer (NSCLC). Patients and Methods: Forty-three patients who had stage IIIB NSCLC with pl eural effusion or stage IV NSCLC and hold received no prior therapy receive d bexarotene in combination with cisplatin (100 mg/m(2)) and vinorelbine (a lternating doses of 30 mg/m(2) and 15 mg/m(2)). In the phase I portion, the daily dose of bexarotene was escalated in cohorts of three patients from 1 50 mg/m(2) to 600 mg/m(2), beginning 1 week before the start of the cisplat in-vinorelbine regimen, Once the maximum-tolerated dose (MTD) of bexarotene wars 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 paints. 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 treat\ment. The median survival time in the phase II portion was 14 months; nine (32%) of t he 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 mo st common grade 3 and 4 adverse events were hyperlipemia, leukopenia, nause a, vomiting, pneumonia, dyspnea, anemia, and asthenia. Grade 3 and 4 labora tory abnormalities with incidences greater than 5% were decreased hemoglobi n levels and WBC, absolute neutrophil, and absolute lymphocyte counts and i ncreased prothrombin time and creatinine and amylase levels. Of the two cas es of pancreatitis, one required hospitalization and both were associated w ith increased triglyceride levels. There was one death secondary to renal i nsufficiency unrelated to bexarotene treatment, Conclusion: In patients with advanced NSCLC, bexarotene with cisplatin and vinorelbine yielded acceptable phase II response rates (25%) and was associ ated with better-than-expected survival (14-month median survival time; 61% I-year, 32% 2-year, and 30% projected 3-year survival rates). The regimen should be studied in larger clinical trials.