A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours
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To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment). An additional 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics analysis in skin biopsies did not show significant changes in EGFR-associated biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed. No partial or complete responses were observed, stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD.
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As monotherapy, afatinib and dacomitinib fail to overcome T790M-mediated resistance in patients because effective preclinical concentrations cannot be reached due to wild-type EGFR toxicity.
“However, as monotherapy, they have failed to overcome T790M-mediated resistance in patients (28, 29), because concentrations at which these irreversible TKIs overcome T790M activity pre-clinically are not achievable in humans due to dose-limiting toxicity related to non-selective inhibition of wild-type EGFR (30).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [30]
Afatinib is reported to be ineffective against lung cancer harboring EGFR T790M positive mutations because concentrations needed are not achievable in humans due to dose limiting toxicities, indicating a narrow therapeutic window.
“Afatinib is reported to be ineffective against lung cancer harboring EGFR T790M positive mutations, because concentrations at which afatinib inhibits lung cancer cells harboring EGFR T790M are not achievable in humans due to dose limiting toxicities such as skin rash and diarrhea, indicating a narrow therapeutic window of afatinib for EGFR T790M [40].”
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- Authors
- Eskens, F. A. L. M., Mom, C. H., Planting, A. S. T., Gietema, J. A., Amelsberg, A., Huisman, H., van Doorn, L., Burger, H., Stopfer, P., Verweij, J., & de Vries, E. G. E.
- Affiliations
- Erasmus MC (NL)
- University Medical Center Groningen (NL)
- Boehringer Ingelheim (United States) (US)
- Boehringer Ingelheim (Netherlands) (NL)
- Boehringer Ingelheim (Germany) (DE)
- Corresponding author
- Eskens, F A L M
- Venue
- British Journal of Cancer
- Published
- 2007-11-20
- Volume
- 98
- Issue
- 1
- Pages
- 80-85
- ISSN
- 0007-0920 (ISSN-L)
- 1532-1827
- PMC
- PMC2359721
- OpenAlex
- W2153156618
- Cited by
- 234
- References
- 16
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 7 · 2020: 12 · 2019: 5 · 2018: 9 · 2017: 11 · 2016: 16 · 2015: 21 · 2014: 23 · 2013: 28 · 2012: 21
- FWCI
- 7.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- www.springer.com/tdm (unspecified)
- Locations
- British Journal of Cancer (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-sa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- 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
- afatinib, eribulin, EGFR tyrosine kinase inhibitors, HER2 tyrosine kinase inhibitor, dose escalation, advanced solid tumors, dose-limiting toxicity, rash, diarrhea, pharmacokinetics, pharmacodynamics, keratinocyte proliferation, recommended dose, tolerability
- MeSH terms
- Afatinib, Adolescent, Adult, Aged, Aged, 80 and over, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Neoplasms, Quinazolines, Skin, Time Factors, Tissue Distribution, Keratinocytes, Treatment Outcome, Erb-b2 Receptor Tyrosine Kinases, Maximum Tolerated Dose, ErbB Receptors
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