Bexarotene and erlotinib for aerodigestive tract cancer

Konstantin H. Dragnev, W. Jeffrey Petty, Sumit Shah, Adrian Biddle, Neil B. Desai, Vincent Memoli, James R. Rigas, Ethan Dmitrovsky

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8757-8764
Number of pages8
JournalJournal of Clinical Oncology
Volume23
Issue number34
DOIs
StatePublished - Dec 1 2005

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Epidermal Growth Factor Receptor
Cyclin D1
Neoplasms
Non-Small Cell Lung Carcinoma
Clinical Trials, Phase I
Survival
Maximum Tolerated Dose
Hypertriglyceridemia
Therapeutics
Creatine Kinase
Exanthema
Sequence Analysis
Carcinogenesis
Survival Rate
Erlotinib Hydrochloride
bexarotene
Pain
Lung
Mutation
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dragnev, K. H., Petty, W. J., Shah, S., Biddle, A., Desai, N. B., Memoli, V., ... Dmitrovsky, E. (2005). Bexarotene and erlotinib for aerodigestive tract cancer. Journal of Clinical Oncology, 23(34), 8757-8764. https://doi.org/10.1200/JCO.2005.01.9521

Bexarotene and erlotinib for aerodigestive tract cancer. / Dragnev, Konstantin H.; Petty, W. Jeffrey; Shah, Sumit; Biddle, Adrian; Desai, Neil B.; Memoli, Vincent; Rigas, James R.; Dmitrovsky, Ethan.

In: Journal of Clinical Oncology, Vol. 23, No. 34, 01.12.2005, p. 8757-8764.

Research output: Contribution to journalArticle

Dragnev, KH, Petty, WJ, Shah, S, Biddle, A, Desai, NB, Memoli, V, Rigas, JR & Dmitrovsky, E 2005, 'Bexarotene and erlotinib for aerodigestive tract cancer', Journal of Clinical Oncology, vol. 23, no. 34, pp. 8757-8764. https://doi.org/10.1200/JCO.2005.01.9521
Dragnev KH, Petty WJ, Shah S, Biddle A, Desai NB, Memoli V et al. Bexarotene and erlotinib for aerodigestive tract cancer. Journal of Clinical Oncology. 2005 Dec 1;23(34):8757-8764. https://doi.org/10.1200/JCO.2005.01.9521
Dragnev, Konstantin H. ; Petty, W. Jeffrey ; Shah, Sumit ; Biddle, Adrian ; Desai, Neil B. ; Memoli, Vincent ; Rigas, James R. ; Dmitrovsky, Ethan. / Bexarotene and erlotinib for aerodigestive tract cancer. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 34. pp. 8757-8764.
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abstract = "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.",
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AU - Memoli, Vincent

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