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Bexarotene and Erlotinib for Aerodigestive Tract Cancer

From the Hematology/Oncology Section, Department of Medicine, Norris Cotton Cancer Center; Departments of Pharmacology and Toxicology and Pathology, Dartmouth Medical School and Dartmouth College Hanover; and Dartmouth-Hitchcock Medical Center, Lebanon, NH

Address reprint requests to Ethan Dmitrovsky, MD, Department of Pharmacology and Toxicology, Remsen 7650, Dartmouth Medical School, Hanover, NH 03755; e-mail: ethan.dmitrovsky{at}dartmouth.edu

PURPOSE: The epidermal growth factor receptor (EGFR) and cyclin D1 are overexpressed in lung carcinogenesis. The rexinoid, bexarotene, represses cyclin D1 and EGFR expression in vitro. It was hypothesized that combining bexarotene with the EGFR inhibitor, erlotinib, would augment clinical activity.

PATIENTS AND METHODS: In vitro studies and a phase I clinical trial were performed. Twenty-four patients with advanced aerodigestive tract cancers were enrolled; 79% had non–small-cell lung cancer (NSCLC). The primary objective was to determine the maximum-tolerated dose. Clinical activity was a secondary objective.

RESULTS: Combining erlotinib with bexarotene enhanced growth suppression in vitro compared with each single-agent treatment. This cooperatively repressed cyclin D1 expression. Clinically, the most frequent toxicities were mild hypertriglyceridemia and skin rash. Two serious treatment-related adverse events occurred (creatine phosphokinase elevation attributed to antilipid therapy and a case of generalized pain). Five objective responses (four partial and one minor) were observed in NSCLC patients. Responses were observed in males and smokers. EGFR sequence analyses did not reveal activating mutations in tumors from assessable responding patients. Median time to progression was 2.0 months; overall survival time was 14.1 months; and 1-year survival rate was 73.8%.

CONCLUSION: The recommended phase II doses are erlotinib 150 mg/d and bexarotene 400 mg/m²/d orally. These agents can be administered in combination at the recommended single-agent doses without added toxicity. Overall survival and clinical features of responding patients differ from prior reports of single-agent erlotinib treatment. These findings are encouraging and warrant further investigation of this regimen.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004; and the 16th European Organisation for Research and Treatment of Cancer–National Cancer Institute–American Association for Cancer Research Symposium on Molecular Targets and Cancer Therapeutics, Geneva, Switzerland, September 28-October 1, 2004.

Supported by Community Clinical Oncology Program Grant No. CA37447-21 (K.H.D.), the National Institutes of Health and the National Cancer Institute Grant Nos. RO1-CA087546 (E.D.), R01-CA111422 (E.D.), and RO1-CA62275 (E.D.); a Samuel Waxman Foundation Cancer Research Award (E.D.); and the Oracle Giving Fund (E.D.). W.J.P. received grant support from the CHEST Foundation of the American College of Chest Physicians and the LUNGevity Foundation, the National Research Service Award No. T32-CA009658 from the National Institutes of Health, and an American Society of Clinical Oncology (ASCO) Young Investigator Award. K.H.D. was also supported by an ASCO Young Investigator Award. Additional funding was provided by Ligand and Genentech (K.H.D.).

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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