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Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors
Open accessAbstract
PURPOSE: Preclinical data have demonstrated that BIBW 2992 is a potent irreversible inhibitor of ErbB1 (EGFR/HER1) and mutated ErbB1 receptors including the T790M variant, as well as ErbB2 (HER2). A phase I study of continuous once-daily oral BIBW 2992 was conducted to determine safety, maximum-tolerated dose, pharmacokinetics (PK), food effect, and preliminary antitumor efficacy. PATIENTS AND METHODS: Patients with advanced solid tumors were treated. PK evaluation was performed after the first dose and at steady-state. RESULTS: Fifty-three patients received BIBW 2992 at 10 to 50 mg/d. BIBW 2992 was generally well-tolerated. The most common adverse effects included diarrhea, nausea, vomiting, rash, and fatigue. Dose-limiting toxicities included grade 3 rash (n = 2) and reversible dyspnea secondary to pneumonitis (n = 1). The recommended phase II dose was 50 mg/d. PK was dose proportional with a terminal elimination half-life ranging between 21.3 and 27.7 hours on day 1 and between 22.3 and 67.0 hours on day 27; BIBW 2992 exposure decreased after food intake. Three patients with non-small-cell lung carcinoma (NSCLC; two with in-frame exon 19 mutation deletions) experienced confirmed partial responses (PR) sustained for 24, 18, and 34 months, respectively. Two other patients (esophageal carcinoma and NSCLC) had nonconfirmed PRs. A patient with a PR at 10 mg/d progressed and developed symptomatic brain metastases, which subsequently regressed with an increased dose of 40 mg/d of BIBW 2992. A further seven patients had disease stabilization lasting > or = 6 months. CONCLUSION: Continuous, daily, oral BIBW 2992 is safe and has durable antitumor activity. It is currently being evaluated in phase III trials.
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“Administration after a high-fat meal results in an approximately 40% reduction in the area under the time–concentration curve from time 0 to infinity (414 ng · h/ml fed; 676 ng · h/ml fasted)”
From Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings (2020) · cites this paper as [55]
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“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 [55]
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Metadata
- Authors
- Yap, T. A., Vidal, L., Adam, J., Stephens, P., Spicer, J., Shaw, H., Ang, J., Temple, G., Bell, S., Shahidi, M., Uttenreuther-Fischer, M., Stopfer, P., Futreal, A., Calvert, H., de Bono, J. S., & Plummer, R.
- Affiliations
- Royal Marsden NHS Foundation Trust (GB)
- National Health Service (GB)
- From the Drug Development Unit, the Royal Marsden National Health Service Foundation Trust, and The Institute of Cancer Research, Sutton, Surrey; Northern Institute for Cancer Research, Newcastle upon Tyne; Boehringer Ingelheim, Bracknell; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; and Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.
- Venue
- Journal of Clinical Oncology
- Published
- 2010-09-01
- Volume
- 28
- Issue
- 25
- Pages
- 3965-3972
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2114095518
- Cited by
- 349
- References
- 34
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 7 · 2023: 14 · 2022: 4 · 2021: 12 · 2020: 8 · 2019: 12 · 2018: 18 · 2017: 18 · 2016: 33 · 2015: 40 · 2014: 47 · 2013: 42 · 2012: 48
- FWCI
- 33.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- AstraZeneca
- American Society of Clinical Oncology
- Royal Marsden NHS Foundation Trust
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- Cancer Research UK
- National Institute for Health and Care Research
- Newcastle University
- Genentech
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Oncology › Gastric Cancer Management and Outcomes
- Keywords
- afatinib, irreversible kinase inhibitors, EGFR, HER2, EGF receptor, T790M mutation, advanced solid tumors, non-small cell lung cancer, pharmacokinetics, food effect, safety, maximum tolerated dose, anticancer activity, brain metastases, esophageal cancer
- MeSH terms
- Afatinib, Adult, Aged, Drug Administration Schedule, Female, Humans, Male, Middle Aged, Neoplasms, Quinazolines, Erb-b2 Receptor Tyrosine Kinases, Protein Kinase Inhibitors, ErbB Receptors
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