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 of afatinib after a high-fat meal results in approximately 40% reduction in AUC from time 0 to infinity.
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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.
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- Solca F, Schweifer N, Baum A, et al: BIBW 2992, an irreversible dual EGFR/HER2 kinase inhib- itor that shows activity on L858R / T790M EGFR mutants. Proceedings of the AACR-NCI-EORTC In- ternational Conference on Molecular Targets and Cancer Therapeutics, Philadelphia, PA, November 14-18, 2005, 118 (abstr A242)
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Self-citation
- 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 › Pulmonary and Respiratory Medicine › 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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