Cited by 349Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchGastric Cancer Management and Outcomes

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Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors

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Yap, Timothy A., Vidal, Laura, Adam, Jan, Stephens, Peter, Spicer, James, Shaw, Heather, Ang, Jooern, Temple, Graham, Bell, Susan, Shahidi, Mehdi, Uttenreuther-Fischer, Martina, Stopfer, Peter, Futreal, Andrew, Calvert, Hilary, de Bono, Johann S., Plummer, Ruth·2010·Journal of Clinical Oncology

DOI 10.1200/jco.2009.26.7278

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Abstract

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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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.
ORCID: Yap, Timothy A.
Vidal, Laura
Spicer, James
Shaw, Heather
Stopfer, Peter
Plummer, Ruth
Venue: Journal of Clinical Oncology
Publisher: American Society of Clinical Oncology (ASCO)
Published: 2010-09-01
Volume: 28
Issue: 25
Pages: 3965-3972
ISSN: 0732-183X (ISSN-L)
1527-7755
DOI: 10.1200/jco.2009.26.7278
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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Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors

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