A phase II clinical and PET study of erlotinib and bexarotene for heavily pretreated advanced non-small cell lung cancer (NSCLC)

Abstract

19079 Background: We previously reported a phase I trial of the EGFR tyrosine kinase inhibitor, erlotinib (E), and the nonclassical retinoid, bexarotene (B), in patients (pts) with advanced aerodigestive tract cancers showing minimal toxicities and preliminary evidence of clinical activity. Combining E with B also induced at least additive suppression of growth and cyclin D1 expression in human bronchial epithelial cells and in some lung cancer cell lines. Methods: A phase II trial of E and B was conducted in pts with stage IV NSCLC, mostly as third line or higher. Primary objective - radiographic response rate. Secondary objectives - survival, time to progression, toxicities, and correlation of early metabolic response by PET at 8–12 days and 2 months. Doses: E 150 mg, B 400 mg/m2 daily orally. Results: Forty pts were enrolled including 52% women and 60% with adenocarcinoma. Median age was 66 years, median number of prior therapies was 2 (range 0–5), 12% were current smokers, 17% were never smokers. Nine pts had prior anti-EGFR therapy. Six pts withdrew consent, mostly within the first month for difficulty swallowing pills. Toxicities were mild with frequent hypertriglyceridemia and skin rash. Treatment was discontinued for grade 3 pulmonary hemorrhage (1), rash/mouth sores (1), cough (1), hypereosinophilic syndrome (1), and abdominal pain (1). There were 2 objective partial responses, 7 pts had stable disease including one pt with prior gefitinib (35 wks). Median time to progression was 7 wks, median overall survival was 21 wks (intent-to-treat). Analysis of metabolic activity on early PET imaging at 10 days and the radiographic findings at 2 months will be presented. A proof-of-principle pilot study will assess if this combined regimen is better than the single agents in repressing EGFR and/or cyclin D1. Conclusions: The regimen of E and B is well tolerated and shows evidence of activity in heavily pretreated patients with NSCLC. Taken together, these findings implicate clinical benefit of dual targeting of EGFR and cyclin D1 in NSCLC. A randomized trial comparing E+B to E is needed to confirm the enhanced activity of the combination. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech, OSI Eisai, Genentech, Ligand