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Cited by 829HER2/EGFR in Cancer ResearchLung Cancer Treatments and MutationsColorectal Cancer Treatments and Studies

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

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Baselga, J., Rischin, D., Ranson, M., Calvert, H., Raymond, E., Kieback, D.G., Kaye, S.B., Gianni, L. +7 more·2002·Journal of Clinical Oncology
DOI 10.1200/jco.2002.03.100
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Abstract

PURPOSE: To establish the safety and tolerability of ZD1839 (Iressa), a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and to explore its pharmacokinetic and pharmacodynamic effects in patients with selected solid tumor types. PATIENTS AND METHODS: This was a phase I dose-escalating trial of oral ZD1839 150 mg/d to a maximum of 1,000 mg/d given once daily for at least 28 days. Patients with either advanced non–small-cell lung, ovarian, head and neck, prostate, or colorectal cancer were recruited. RESULTS: Eighty-eight patients received ZD1839 (150 to 1,000 mg/d). At 1,000 mg/d, five of 12 patients experienced dose-limiting toxicity (grade 3 diarrhea [four patients] and grade 3 somnolence [one patient]). The most frequent drug-related adverse events (AEs) were acne-like rash (64%) and diarrhea (47%), which were generally mild (grade 1/2) and reversible on cessation of treatment. No change in ZD1839 safety profile was observed with prolonged administration. Pharmacokinetic analysis showed steady-state exposure to ZD1839 in 98% of patients by day 7. Nineteen patients had stable disease and received ZD1839 for ≥ 3 months; seven of these patients remained on study drug for ≥ 6 months. Serial skin biopsies taken before treatment and at approximately day 28 revealed changes indicative of inhibition of the EGFR signaling pathway. CONCLUSION: ZD1839 was generally well tolerated, with manageable and reversible AEs at doses up to 600 mg/d and dose-limiting toxicity observed at 1,000 mg/d. ZD1839 treatment resulted in clinically meaningful disease stabilization across a range of tumor types and doses. Pharmacodynamic changes in skin confirmed inhibition of EGFR signaling, which was predicted from the mode of action of ZD1839.

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  • Cells bearing Y764_V765insHH, M766_A767insAI, A767_V769dupASV, D770_N771insNPG, D770_N771insSVD, and H773_V774insH are not inhibited by clinically achievable doses of gefitinib, erlotinib, or afatinib.

    “We characterized Y764_V765insHH, M766_A767insAI, A767_V769dupASV, D770_N771insNPG, D770_N771insSVD and H773_V774insH using in vitro models and found that cells bearing these mutant EGFR proteins are not inhibited by clinically-achievable doses of gefitinib, erlotinib 12,35,52–54 or the irreversible EGFR inhibitor afatinib 35,55.”

    From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [53]

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Authors
Baselga, J., Rischin, D., Ranson, M., Calvert, H., Raymond, E., Kieback, D. G., Kaye, S. B., Gianni, L., Harris, A., Bjork, T., Averbuch, S. D., Feyereislova, A., Swaisland, H., Rojo, F., & Albanell, J.
Affiliations
  • Maastricht University Medical Centre (NL)
  • From Vall d’Hebron University Hospital, Barcelona, Spain; Peter MacCallum Institute, Melbourne, Australia; Christie Hospital National Health Service Trust, Manchester, Northern Centre for Cancer Treatment, Newcastle-upon-Tyne, The Royal Marsden Hospital, Sutton, Churchill Hospital, Oxford, and AstraZeneca, Alderley Park, United Kingdom; Institut Gustave Roussy, Villejuif, France; Maastricht University Medical Center, Maastricht, the Netherlands; Istituto Nazionale Tumori, Milan, Italy;...
ORCID
Venue
Journal of Clinical Oncology
Publisher
American Society of Clinical Oncology (ASCO)
Published
2002-11-01
Volume
20
Issue
21
Pages
4292-4302
ISSN
  • 0732-183X (ISSN-L)
  • 1527-7755
DOI
10.1200/jco.2002.03.100
OpenAlex
W2126314379
Cited by
829
References
33
Citations by year
2026: 6 · 2025: 4 · 2024: 5 · 2023: 15 · 2022: 9 · 2021: 10 · 2020: 12 · 2019: 10 · 2018: 12 · 2017: 10 · 2016: 17 · 2015: 27 · 2014: 22 · 2013: 29 · 2012: 30
FWCI
43.01
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion)
  • Newcastle University ePrints (Newcastle Univesity)
Topics
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Keywords
gefitinib, EGFR tyrosine kinase inhibitors, epidermal growth factor receptor, solid tumors, non-small cell lung cancer, ovarian cancer, head and neck cancer, prostate cancer, colorectal cancer, dose-limiting toxicity, diarrhea, acne-like rash, pharmacokinetics, pharmacodynamics, skin biopsy, EGFR signaling inhibition, stable disease
MeSH terms
Gefitinib, Administration, Oral, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Biopsy, Carcinoma, Non-Small-Cell Lung, Diarrhea, Dose-Response Relationship, Drug, Female, Head and Neck Neoplasms, Humans, Lung Neoplasms, Male, Middle Aged, Ovarian Neoplasms, Prostatic Neoplasms, Quinazolines, Skin, Colorectal Neoplasms, Treatment Outcome, Disease Progression

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