A proof-of-principle trial of bexarotene in patients (pts) with resectable non-small cell lung cancer (NSCLC)

Abstract

7136 Background: Bexarotene (Targretin) is a selective retinoid X receptor (RXR) agonist that appears to prolong survival in pts with NSCLC. To determine mechanisms of action, preclinical studies and a short-term, proof-of-principle clinical trial were performed. Methods: BEAS-2B immortalized human bronchial epithelial cells were treated with bexarotene and effects on EGFR and cell cycle regulatory proteins were determined by Western analyses. To evaluate bexarotene tissue pharmacokinetic (PK) and pharmacodynamic effects, 12 pts with pathologically confirmed stage I and II NSCLC were enrolled. Subjects were given 300 mg/m2/day of bexarotene orally for 7 to 9 days prior to surgical resection. Resected tumor tissue was evaluated for biomarker expression and tumor tissue bexarotene concentrations. Plasma bexarotene concentrations were measured at the time of resection. Biomarker changes were assessed immunohistochemically comparing pre- and post-treatment tissues by pathologists blinded to the tissue origin and PK measures. Results: In vitro studies revealed that bexarotene induced concentration-dependent repression of cyclin D1, cyclin D3, total EGFR, and phospho-EGFR. In the clinical trial, 6 pts had paired pre- and post-treatment tissues that were evaluable for changes in biomarker expression. Of these 6, 1 demonstrated repression of cyclin D1 as well as a reduction of proliferation rate measured by Ki-67. One case demonstrated repression of cyclin D3 without a substantial reduction in Ki-67. These 2 pts exhibited considerably higher tumor tissue bexarotene concentrations (range 107 - 159 ng/g) than did cases demonstrating no appreciable change in these biomarkers (range 3.7–74 ng/g). Conclusions: Bexarotene induces concentration-dependent repression of cyclin D1 and cyclin D3 in vitro. Repression of these proteins also occurs in certain clinical NSCLC cases treated with this agent. Our data are compatible with a non-linear relationship between tumor tissue bexarotene concentrations and the tumor biomaker pharmacodynamics. Support for this study was provided in part by Samuel Waxman Cancer Research Foundation, CA23108, and Ligand. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ligand Ligand Ligand Ligand Bristol-Myers Squibb, Ligand