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Pharmacodynamic Studies of the Epidermal Growth Factor Receptor Inhibitor ZD1839 in Skin From Cancer Patients: Histopathologic and Molecular Consequences of Receptor Inhibition

From the Oncology Service, Vall d’Hebron University Hospital; Dermatology Service, Hospital Clinic; Transfusio i Banc de Teixits, Vall d’Hebron Vall d’Hebron University Hospital, Barcelona, Spain; AstraZeneca Pharmaceuticals, Wilmington, DE; Oncology Service, M.D. Anderson Cancer Center, Houston, TX; Oncology Service, Harper Hospital, Detroit, MI; AstraZeneca Pharmaceuticals, Alderley Park; Department of Pharmacology, Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, United Kingdom; and Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Melbourne, Australia.

Address reprint requests to Jose Baselga, MD, Oncology Service, Vall d’Hebron University Hospital, Paseo Vall d’Hebron 119-129, Barcelona 08035, Spain; email: baselga{at}hg.vhebron.es

PURPOSE: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca Pharmaceuticals, Alderley Park, United Kingdom) is under development as an anticancer agent. We studied the pharmacodynamic effects of ZD1839 on EGFR in the skin, an EGFR-dependent tissue, in cancer patients participating in ZD1839 phase I clinical trials.

PATIENTS AND METHODS: We studied 104 pre– and/or on–ZD1839 therapy ( at day 28 of therapy) skin biopsies from 65 patients receiving escalating doses of daily oral ZD1839. We measured ZD1839 effects on EGFR activation by immunohistochemistry using an antibody specific for the activated (phosphorylated) EGFR. Effects on receptor signaling (activated mitogen-activated protein kinase [MAPK]), proliferation, p27^KIP1, and maturation were also assessed.

RESULTS: Histopathologically, the stratum corneum of the epidermis was thinner during therapy (P < .001). In hair follicles, prominent keratin plugs and microorganisms were found in dilated infundibula. ZD1839 suppressed EGFR phosphorylation in all EGFR-expressing cells (P < .001). In addition, ZD1839 inhibited MAPK activation (P < .001) and reduced keratinocyte proliferation index (P < .001). Concomitantly, ZD1839 increased the expression of p27^KIP1 (P < .001) and maturation markers (P < .001) and increased apoptosis (P < .001). These effects were observed at all dose levels, before reaching dose-limiting toxicities.

CONCLUSION: ZD1839 inhibits EGFR activation and affects downstream receptor-dependent processes in vivo. These effects were profound at doses well below the one producing unacceptable toxicity, a finding that strongly supports pharmacodynamic assessments to select optimal doses instead of a maximum-tolerated dose for definitive efficacy and safety trials.

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				J. W. Mandell Phosphorylation State-Specific Antibodies: Applications in Investigative and Diagnostic Pathology Am. J. Pathol., November 1, 2003; 163(5): 1687 - 1698. [Abstract] [Full Text] [PDF]

				M. G. Kris, R. B. Natale, R. S. Herbst, T. J. Lynch Jr, D. Prager, C. P. Belani, J. H. Schiller, K. Kelly, H. Spiridonidis, A. Sandler, 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 JAMA, October 22, 2003; 290(16): 2149 - 2158. [Abstract] [Full Text] [PDF]

				F. C. Holsinger, D. D. Doan, S. A. Jasser, E. A. Swan, J. S. Greenberg, B. A. Schiff, B. N. Bekele, M. N. Younes, C. D. Bucana, I. J. Fidler, et al. Epidermal Growth Factor Receptor Blockade Potentiates Apoptosis Mediated by Paclitaxel and Leads to Prolonged Survival in a Murine Model of Oral Cancer Clin. Cancer Res., August 1, 2003; 9(8): 3183 - 3189. [Abstract] [Full Text] [PDF]

				F. Cappuzzo, V. Gregorc, E. Rossi, A. Cancellieri, E. Magrini, C. T. Paties, G. Ceresoli, L. Lombardo, S. Bartolini, C. Calandri, et al. Gefitinib in Pretreated Non-Small-Cell Lung Cancer (NSCLC): Analysis of Efficacy and Correlation With HER2 and Epidermal Growth Factor Receptor Expression in Locally Advanced or Metastatic NSCLC J. Clin. Oncol., July 15, 2003; 21(14): 2658 - 2663. [Abstract] [Full Text] [PDF]

				J. Mendelsohn and J. Baselga Status of Epidermal Growth Factor Receptor Antagonists in the Biology and Treatment of Cancer J. Clin. Oncol., July 15, 2003; 21(14): 2787 - 2799. [Abstract] [Full Text] [PDF]

				J. Baselga Skin as a Surrogate Tissue for Pharmacodynamic End Points: Is It Deep Enough? Clin. Cancer Res., July 1, 2003; 9(7): 2389 - 2390. [Full Text] [PDF]

				M. Daneshmand, D. A. E. Parolin, H. W. Hirte, P. Major, G. Goss, D. Stewart, G. Batist, W. H. Miller Jr., S. Matthews, L. Seymour, et al. A Pharmacodynamic Study of the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 in Metastatic Colorectal Cancer Patients Clin. Cancer Res., July 1, 2003; 9(7): 2457 - 2464. [Abstract] [Full Text] [PDF]

				S. N. Malik, L. L. Siu, E. K. Rowinsky, L. deGraffenried, L. A. Hammond, J. Rizzo, S. Bacus, M. G. Brattain, J. I. Kreisberg, and M. Hidalgo Pharmacodynamic Evaluation of the Epidermal Growth Factor Receptor Inhibitor OSI-774 in Human Epidermis of Cancer Patients Clin. Cancer Res., July 1, 2003; 9(7): 2478 - 2486. [Abstract] [Full Text] [PDF]

				V. Grunwald and M. Hidalgo Developing Inhibitors of the Epidermal Growth Factor Receptor for Cancer Treatment J Natl Cancer Inst, June 18, 2003; 95(12): 851 - 867. [Abstract] [Full Text] [PDF]

				S. Garattini New approaches to cancer therapy Ann. Onc., June 1, 2003; 14(6): 813 - 816. [Full Text] [PDF]

				P. M. LoRusso, R. S. Herbst, D. Rischin, M. Ranson, H. Calvert, E. Raymond, D. Kieback, S. Kaye, L. Gianni, A. Harris, et al. Improvements in Quality of Life and Disease-related Symptoms in Phase I Trials of the Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 in Non-Small Cell Lung Cancer and Other Solid Tumors Clin. Cancer Res., June 1, 2003; 9(6): 2040 - 2048. [Abstract] [Full Text] [PDF]

				M. L. Janmaat, F. A. E. Kruyt, J. A. Rodriguez, and G. Giaccone Response to Epidermal Growth Factor Receptor Inhibitors in Non-Small Cell Lung Cancer Cells: Limited Antiproliferative Effects and Absence of Apoptosis Associated with Persistent Activity of Extracellular Signal-regulated Kinase or Akt Kinase Pathways Clin. Cancer Res., June 1, 2003; 9(6): 2316 - 2326. [Abstract] [Full Text] [PDF]

				E. K. Rowinsky Challenges of Developing Therapeutics That Target Signal Transduction in Patients With Gynecologic and Other Malignancies J. Clin. Oncol., May 15, 2003; 21(90100): 175s - 186. [Abstract] [Full Text] [PDF]

				C. L. Arteaga and J. Baselga Clinical Trial Design and End Points for Epidermal Growth Factor Receptor-targeted Therapies: Implications for Drug Development and Practice Clin. Cancer Res., May 1, 2003; 9(5): 1579 - 1589. [Full Text] [PDF]

				J. Anido, P. Matar, J. Albanell, M. Guzman, F. Rojo, J. Arribas, S. Averbuch, and J. Baselga ZD1839, a Specific Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor, Induces the Formation of Inactive EGFR/HER2 and EGFR/HER3 Heterodimers and Prevents Heregulin Signaling in HER2-overexpressing Breast Cancer Cells Clin. Cancer Res., April 1, 2003; 9(4): 1274 - 1283. [Abstract] [Full Text] [PDF]

				J. M. Knowlden, I. R. Hutcheson, H. E. Jones, T. Madden, J. M. W. Gee, M. E. Harper, D. Barrow, A. E. Wakeling, and R. I. Nicholson Elevated Levels of Epidermal Growth Factor Receptor/c-erbB2 Heterodimers Mediate an Autocrine Growth Regulatory Pathway in Tamoxifen-Resistant MCF-7 Cells Endocrinology, March 1, 2003; 144(3): 1032 - 1044. [Abstract] [Full Text] [PDF]

				K. A. Knuti, R. H. Wharton, K. L. Wharton, B. A. Chabner, T. J. Lynch Jr., and R. T. Penson Living as a Cancer Surpriser: A Doctor Tells His Story Oncologist, February 1, 2003; 8(1): 108 - 122. [Abstract] [Full Text] [PDF]

				D. B. Mendel, A. D. Laird, X. Xin, S. G. Louie, J. G. Christensen, G. Li, R. E. Schreck, T. J. Abrams, T. J. Ngai, L. B. Lee, et al. In Vivo Antitumor Activity of SU11248, a Novel Tyrosine Kinase Inhibitor Targeting Vascular Endothelial Growth Factor and Platelet-derived Growth Factor Receptors: Determination of a Pharmacokinetic/Pharmacodynamic Relationship Clin. Cancer Res., January 1, 2003; 9(1): 327 - 337. [Abstract] [Full Text] [PDF]

				J. Baselga, D. Rischin, M. Ranson, H. Calvert, E. Raymond, D.G. Kieback, S.B. Kaye, L. Gianni, A. Harris, T. Bjork, et al. Phase I Safety, Pharmacokinetic, and Pharmacodynamic Trial of ZD1839, a Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Five Selected Solid Tumor Types J. Clin. Oncol., November 1, 2002; 20(21): 4292 - 4302. [Abstract] [Full Text] [PDF]

				R. S. Herbst, A.-M. Maddox, M. L. Rothenberg, E. J. Small, E. H. Rubin, J. Baselga, F. Rojo, W. K. Hong, H. Swaisland, S. D. Averbuch, et al. Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 Is Generally Well-Tolerated and Has Activity in Non-Small-Cell Lung Cancer and Other Solid Tumors: Results of a Phase I Trial J. Clin. Oncol., September 15, 2002; 20(18): 3815 - 3825. [Abstract] [Full Text] [PDF]

				J. Mendelsohn Targeting the Epidermal Growth Factor Receptor for Cancer Therapy J. Clin. Oncol., September 15, 2002; 20(90001): 1s - 13. [Full Text] [PDF]

				C. L. Arteaga Epidermal Growth Factor Receptor Dependence in Human Tumors: More Than Just Expression? Oncologist, August 15, 2002; 7(90004): 31 - 39. [Abstract] [Full Text] [PDF]

				J. Baselga Targeting the Epidermal Growth Factor Receptor With Tyrosine Kinase Inhibitors: Small Molecules, Big Hopes J. Clin. Oncol., May 1, 2002; 20(9): 2217 - 2219. [Full Text] [PDF]

				M. Ranson, L. A. Hammond, D. Ferry, M. Kris, A. Tullo, P. I. Murray, V. Miller, S. Averbuch, J. Ochs, C. Morris, et al. ZD1839, a Selective Oral Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor, Is Well Tolerated and Active in Patients With Solid, Malignant Tumors: Results of a Phase I Trial J. Clin. Oncol., May 1, 2002; 20(9): 2240 - 2250. [Abstract] [Full Text] [PDF]