Bexarotene and erlotinib for aerodigestive tract cancer.

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.

[1]  Renato Martins,et al.  Erlotinib in previously treated non-small-cell lung cancer. , 2005, The New England journal of medicine.

[2]  E. Dmitrovsky,et al.  A proof-of-principle trial of bexarotene in patients (pts) with resectable non-small cell lung cancer (NSCLC) , 2005 .

[3]  F. Khuri,et al.  A randomized phase III trial comparing bexarotene/carboplatin/paclitaxel versus carboplatin/paclitaxel in chemotherapy-naive patients with advanced or metastatic non-small cell lung cancer (NSCLC) , 2005 .

[4]  R. Ramlau,et al.  A randomized phase III trial comparing bexarotene/cisplatin/vinorelbine versus cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small cell lung cancer (NSCLC) , 2005 .

[5]  F. Hirsch,et al.  Systemic therapy of advanced bronchioloalveolar cell carcinoma: challenges and opportunities. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  E. Dmitrovsky,et al.  Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition Represses Cyclin D1 in Aerodigestive Tract Cancers , 2004, Clinical Cancer Research.

[7]  J. Rigas,et al.  Determinants of tumor response and survival with erlotinib in patients with non--small-cell lung cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  W. Lamph,et al.  A retinoid X receptor (RXR)-selective agonist bexarotene produces synergistic growth inhibitory activity with gefitinib in non-small-cell lung cancer (NSCLC) cell lines. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  F. Hirsch,et al.  Bronchioloalveolar Carcinoma , 2004, Clinical Cancer Research.

[10]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[11]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[12]  M. Sporn,et al.  Specific Chemopreventive Agents Trigger Proteasomal Degradation of G1 Cyclins: Implications for Combination Therapy , 2004, Clinical Cancer Research.

[13]  David Cella,et al.  Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. , 2003, JAMA.

[14]  E. Dmitrovsky,et al.  Retinoids in cancer therapy and chemoprevention: promise meets resistance , 2003, Oncogene.

[15]  Bernd Groner,et al.  Sequence-specific Peptide Aptamers, Interacting with the Intracellular Domain of the Epidermal Growth Factor Receptor, Interfere with Stat3 Activation and Inhibit the Growth of Tumor Cells* , 2003, Journal of Biological Chemistry.

[16]  J. Turkson,et al.  Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells , 2003, Oncogene.

[17]  E. Dmitrovsky,et al.  Retinoid Targets in Cancer Therapy and Chemoprevention , 2003, Cancer biology & therapy.

[18]  David M. Thomas,et al.  Role of the Retinoblastoma Protein in Differentiation and Senescence , 2003, Cancer biology & therapy.

[19]  J. Grandis,et al.  STAT3 activation abrogates growth factor dependence and contributes to head and neck squamous cell carcinoma tumor growth in vivo. , 2002, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[20]  M. Masuda,et al.  Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. , 2002, Cancer research.

[21]  R. Eckert,et al.  Retinoids Suppress Epidermal Growth Factor-associated Cell Proliferation by Inhibiting Epidermal Growth Factor Receptor-dependent ERK1/2 Activation* , 2002, The Journal of Biological Chemistry.

[22]  K. Makino,et al.  Nuclear localization of EGF receptor and its potential new role as a transcription factor , 2001, Nature Cell Biology.

[23]  R. Figlin,et al.  Multi-institutional phase I/II trial of oral bexarotene in combination with cisplatin and vinorelbine in previously untreated patients with advanced non-small-cell lung cancer. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  N. Rizvi,et al.  Placebo-controlled trial of bexarotene, a retinoid x receptor agonist, as maintenance therapy for patients treated with chemotherapy for advanced non-small-cell lung cancer. , 2001, Clinical lung cancer.

[25]  J. Marshall,et al.  A Phase I study of LGD1069 in adults with advanced cancer. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  E. Dmitrovsky,et al.  Cyclin D1 proteolysis: a retinoid chemoprevention signal in normal, immortalized, and transformed human bronchial epithelial cells. , 1999, Journal of the National Cancer Institute.

[27]  E. Dmitrovsky,et al.  Posttranslational regulation of cyclin D1 by retinoic acid: a chemoprevention mechanism. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Kris,et al.  Initial clinical trial of a selective retinoid X receptor ligand, LGD1069. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  D. Nathans,et al.  In vitro activation of Stat3 by epidermal growth factor receptor kinase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[30]  E. Dmitrovsky,et al.  Inhibited transformation of immortalized human bronchial epithelial cells by retinoic acid is linked to cyclin E down-regulation. , 1996, Oncogene.

[31]  E. Dmitrovsky,et al.  The epidermal growth factor receptor and its ligands as therapeutic targets in human tumors. , 1996, Cytokine & growth factor reviews.

[32]  J. Grandis,et al.  Retinoic acid normalizes the increased gene transcription rate of TGF–α and EGFR in head and neck cancer cell lines , 1996, Nature Medicine.

[33]  W. Greco,et al.  The search for synergy: a critical review from a response surface perspective. , 1995, Pharmacological reviews.

[34]  C. Harris,et al.  Transformation of human bronchial epithelial cells by infection with SV40 or adenovirus-12 SV40 hybrid virus, or transfection via strontium phosphate coprecipitation with a plasmid containing SV40 early region genes. , 1988, Cancer research.

[35]  A. Jemal,et al.  Cancer Statistics, 2004 , 2004, CA: a cancer journal for clinicians.

[36]  E. Dmitrovsky,et al.  Lung cancer prevention: the guidelines. , 2003, Chest.

[37]  E. Dmitrovsky,et al.  Evidence for the epidermal growth factor receptor as a target for lung cancer prevention. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[38]  R. Perez-soler.  A phase II trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor OSI-774, following platinum-based chemotherapy, in patients (pts) with advanced-EGFR-expressing, non-small cell lung cancer (NSCLC) , 2001 .

[39]  T. Chou,et al.  Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. , 1984, Advances in enzyme regulation.