7093 Background: We previously reported the overexpression of the epidermal growth factor receptor (EGFR) and cyclin D1 as early events in lung carcinogenesis. All-trans-retinoic acid (RA) suppressed EGFR expression through a transcriptional mechanism and cyclin D1 through proteasome-dependent proteolysis. Non-classical retinoids such as the rexinoid, bexarotene (B), repress both cyclin D1 and EGFR expression but signal independent of RAR-beta, which is often deregulated in lung carcinogenesis. Combining an EGFR tyrosine kinase inhibitor, erlotinib (E), with B induced at least additive suppression of growth and cyclin D1 expression in RA-resistant human bronchial epithelial cells which had silenced RAR beta and in some lung cancer cell lines. Methods: A phase I trial of E and B was conducted in patients (pts) with advanced aerodigestive tract cancers. Primary objective - maximum tolerated dose. Secondary objectives - toxicities, efficacy, and surrogate markers of response (cyclin D1) in buccal swabs from pts at the highest dose. 3 dose levels - 1: B 300 mg/m2, E 100 mg; 2: B 300 mg/m2, E 150 mg; 3: B 400 mg/m2, E 150 mg. At least 3 pts were enrolled at each level. All pts received atorvastatin for elevated triglycerides. Results: Twenty-four pts were enrolled including 46% women and 79% with NSCLC. The median age was 61 years, 62% had first-line and 21% second line chemotherapy, one third had KPS of 70, and 67% were former smokers. Toxicities were mild with frequent hypertriglyceridemia and skin rash. No cases of pancreatitis were observed. Two DLTs were observed: CPK elevation and systemic pain. Four objective partial responses were seen in pts with NSCLC, eight pts (5 NSCLC, 3 head/neck) had stable disease. Median time to progression was 2.23 months, median overall survival was 14.1 months, and one-year survival was 59%. EGFR sequencing revealed no activating mutations in exons 18, 19, and 21 for two responding cases. Cyclin D1 protein expression was repressed in buccal swabs from 5/6 pts. Conclusions: The recommended phase II doses are erlotinib 150 mg and bexarotene 400 mg/m2 daily. This regimen is well tolerated and shows preliminary evidence of activity for the treatment of advanced aerodigestive tract cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ligand Genentech, Ligand Genentech, Ligand