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.

PURPOSE To investigate safety, tolerability, dose-related pharmacologic properties, and pharmacodynamics of ZD1839 (gefinitib, Iressa; AstraZeneca Pharmacueticals, Wilmington, DE), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with solid tumor types known to express or highly express EGFR. METHODS This was an open-label, phase I, dose escalation safety/tolerability trial of oral ZD1839 (150 to 1,000 mg/d), administered once daily for 28-continuous-day cycles until disease progression or undue toxicity. RESULTS Of 71 (69 assessable for safety; 58 for efficacy) patients at seven dose levels, most had non-small-cell lung (n = 39) or head and neck (n = 18) cancer, and 68 of 71 patients received prior cancer therapy (two or more regimens in 54 patients [78%]). Diarrhea and rash, the primary dose-limiting toxicities (DLTs), occurred at 800 mg. Frequent treatment-related grade 1/2 adverse events were diarrhea (55%), asthenia (44%), and acne-like follicular rash (46%). At doses >or= 800 mg, 45% of patients required dose reductions. No increased or cumulative toxicity was observed over 250 patient-months of exposure. Pharmacokinetic analysis showed that steady-state occurred by day 7, interpatient exposure was more variable than intrapatient exposure, and variability of exposure did not change with dose. One patient experienced a partial response, but antitumor activity manifested mainly as prolonged stable disease (45% of patients >or= 3 months, 22% >or= 6 months, and 7.2% >or= 1 year). No relationship between dose, response, or duration on study was observed. CONCLUSION Rash and diarrhea, generally mild and tolerable at doses <or= 600 mg/d, were DLTs at 800 mg/d (maximum-tolerated dose). Antitumor activity was observed at all doses. Pharmacokinetic analyses confirmed suitability of once-daily oral dosing.

[1]  R. Day,et al.  Levels of TGF-α and EGFR Protein in Head and Neck Squamous Cell Carcinoma and Patient Survival , 1998 .

[2]  G. Tortora,et al.  Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[3]  A. Klippel,et al.  Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt , 1997, Molecular and cellular biology.

[4]  K. Pavelić,et al.  Evidence for a role of EGF receptor in the progression of human lung carcinoma. , 1993, Anticancer research.

[5]  J. Baselga,et al.  Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  K. O'Byrne,et al.  A biological staging model for operable non-small cell lung cancer , 2001, Thorax.

[7]  J. Woodburn,et al.  The epidermal growth factor receptor and its inhibition in cancer therapy. , 1999, Pharmacology & therapeutics.

[8]  C. Angeletti,et al.  Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small-cell lung cancer: amphiregulin and microvessel count are independent prognostic indicators of survival. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[9]  N. Normanno,et al.  Epidermal growth factor-related peptides and their receptors in human malignancies. , 1995, Critical reviews in oncology/hematology.

[10]  J. Baselga.  Therapeutic monoclonal antibodies in oncology: an update: Monoclonal antibodies directed at growth factor receptors , 2000 .

[11]  D. Tulsky,et al.  The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. , 1993, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  Z. Chen,et al.  Correlation of cisplatin sensitivity with differential alteration of EGFR expression in head and neck cancer cells. , 2000, Anticancer research.

[13]  A. Wakeling,et al.  Growth factors and their receptors: new targets for prostate cancer therapy. , 2001, Urology.

[14]  D. Tulsky,et al.  Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. , 1995, Lung cancer.

[15]  C. Morris,et al.  Pharmacokinetics and Tolerability of the Orally Active Selective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 in Healthy Volunteers , 2001, Clinical pharmacokinetics.

[16]  E K Rowinsky,et al.  Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  S. Fox,et al.  The Epidermal Growth Factor Receptor in Breast Cancer , 1997, Journal of Mammary Gland Biology and Neoplasia.

[18]  S. Aaronson,et al.  Growth factors and cancer. , 1991, Science.

[19]  R. Hellman,et al.  A phase I dose escalation study of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor CP-358,774 in patients (pts) with advanced solid tumors , 2000 .

[20]  M. Fukuoka.  Final results from a phase II trial of ZD1839 ("Iressa") for patients with advanced non-small-cell lung cancer (IDEAL 1) , 2002 .

[21]  K. Kikuchi,et al.  Epidermal growth factor receptor expression correlates with poor prognosis in non-small cell lung cancer patients with p53 overexpression. , 2000, Oncology reports.

[22]  D. Harpole,et al.  Molecular biologic substaging of stage I lung cancer according to gender and histology. , 2000, The Annals of thoracic surgery.

[23]  K. Gibson,et al.  ZD1839, AN EPIDERMAL GROWTH FACTOR TYROSINE KINASE INHIBITOR SELECTED FOR CLINICAL DEVELOPMENT , 1997 .

[24]  M. Kris,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. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  N R Hunter,et al.  Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  G. Gibson,et al.  The relationship of quantitative epidermal growth factor receptor expression in non-small cell lung cancer to long term survival. , 1993, British Journal of Cancer.

[27]  Edward S. Kim,et al.  IMC-C225, an anti-epidermal growth factor receptor monoclonal antibody, for treatment of head and neck cancer , 2001, Seminars in oncology.

[28]  E. Dmitrovsky,et al.  Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. , 1993, Cancer research.

[29]  R Simon,et al.  Clinical trial designs for cytostatic agents: are new approaches needed? , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  M. Volm,et al.  Prognostic value of ERBB-1, VEGF, cyclin A, FOS, JUN and MYC in patients with squamous cell lung carcinomas. , 1998, British Journal of Cancer.

[31]  M. Kris,et al.  Objective regressions in non-small cell lung cancer patients treated in Phase I trials of oral ZD1839 (IressaTM), a selective tyrosine kinase inhibitor that blocks the epidermal growth factor receptor (EGFR) , 2000 .

[32]  H. Poulsen,et al.  Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. , 1997, Annals of oncology : official journal of the European Society for Medical Oncology.

[33]  R. Bjerkvig,et al.  Epidermal growth factor and laminin receptors contribute to migratory and invasive properties of gliomas. , 1997, Invasion & metastasis.

[34]  S. Bates,et al.  Reduced growth rate accompanied by aberrant epidermal growth factor signaling in drug resistant human breast cancer cells. , 2000, Biochimica et biophysica acta.

[35]  M. Kris,et al.  Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[36]  E. Vokes,et al.  The performance status scale for head and neck cancer patients and the functional assessment of cancer therapy‐head and neck scale: A study of utility and validity , 1996, Cancer.

[37]  H. Quon,et al.  Potential molecular prognostic markers in head and neck squamous cell carcinomas , 2001, Head and Neck.

[38]  D S Tulsky,et al.  Reliability and validity of the Functional Assessment of Cancer Therapy-Breast quality-of-life instrument. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.