gms | German Medical Science

Background: Bexarotene (Targretin) is a selective retinoid X receptor (RXR, rexinoid) agonist. Microarray gene expression studies indicate that bexarotene controls pathways in NSCLC cell lines related to cellular proliferation (CDC25B, ODC1), metastasis (TFPI2, ANGPTL4), and response to chemotherapy. Additionally, bexarotene has been shown to decrease expression of cyclin D1, EGFR, Her-2, and MDR-1. In a phase II study in patients with advanced NSCLC, an improvement in survival to 13.7 months was noted when bexarotene was added to cisplatin/vinorelbine chemotherapy. This prompted two large, phase III randomized, multicenter, multinational trials of bexarotene in combination with either cisplatin/vinorelbine (SPIRIT I) or carboplatin/paclitaxel (SPIRIT II), which have recently been completed.

Methods: 612 chemotherapy-naïve NSCLC patients with stage IIIb disease with pleural effusion or stage IV disease, performance status ECOG 0-1, were randomized to receive carboplatin/paclitaxel alone (Arm A) or bexarotene capsules (400 mg/m2/day) with carboplatin/paclitaxel (Arm B). In anticipation of increased triglycerides, patients were also started on a lipid-lowering agent. The study primary endpoint was overall survival, calculated using a stratified log-rank test, with a secondary endpoint of a Kaplan-Meier projected two-year survival.

Results: Patient characteristics were well balanced with a median age of 63 years (A + B), 87% stage IV patients (A + B) and adenocarcinoma in 50% v 55% (A vs. B). No significant difference in overall survival (median survival 9.2 mo vs. 8.5 mo, 2-yr survival 16.3% v 12.4%, A vs. B) and progression free survival (median PFS 4.9 mo vs. 4.1 mo, A vs. B) was detected. Hypertriglyceridemia and neutropenia were significantly increased in the bexarotene arm (Grade 3/4 hypertriglyceridemia 32% vs. 0%, Grade 3/4 neutropenia 28% vs.13%, p≤ 0.05). In a subset analysis, high triglyceride levels, in response to bexarotene were identified as a significant prognostic marker of improved survival (median survival 6.6 mo vs. 12.4 mo, Grade 0-2 triglycerides vs. Grade 3-4 triglycerides).

Conclusions: Addition of bexarotene to carboplatin/paclitaxel did not improve survival or progression free survival in NSCLC in this trial. However, when triglyceride levels were used as a surrogate marker for activity of bexarotene, Grade 3-4 hypertriglyceridemia correlated with improved survival. Further evaluation of genetic and biochemical markers might help to identify future bexarotene-responders.