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Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas.

Publication ,  Journal Article
Burris, HA; Hurwitz, HI; Dees, EC; Dowlati, A; Blackwell, KL; O'Neil, B; Marcom, PK; Ellis, MJ; Overmoyer, B; Jones, SF; Harris, JL; Smith, DA ...
Published in: J Clin Oncol
August 10, 2005

PURPOSE: This study (EGF10004) assessed the safety/tolerability, pharmacokinetics, and clinical activity of daily oral dosing with lapatinib (GW572016) in patients with ErbB1-expressing and/or ErbB2-overexpressing advanced-stage refractory solid tumors. PATIENTS AND METHODS: Heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers were randomly assigned to one of five dose cohorts of lapatinib administered once daily. Pharmacokinetic samples were obtained on days 1 and 20. Clinical response was assessed every 8 weeks. RESULTS: Sixty-seven patients with metastatic solid tumors were treated with lapatinib. The most frequently reported drug-related adverse events were diarrhea (42%) and rash (31%). No grade 4 drug-related adverse events were reported. Five grade 3 drug-related toxicities (gastrointestinal events and rash) were experienced by four patients. Drug-related interstitial pneumonitis or cardiac dysfunction associated with other ErbB-targeted therapies was not reported. Four patients with trastuzumab-resistant metastatic breast cancer-two of whom were classified as having inflammatory breast cancer-had partial responses (PRs). Twenty-four patients with various other carcinomas experienced stable disease, of whom 10 received lapatinib for > or = 6 months. The relationships between lapatinib dose or serum concentration and clinical response could not be adequately characterized due to the limited response data. The incidence of diarrhea increased with increasing dose, whereas the incidence of rash was not related to dose. CONCLUSION: Lapatinib was well tolerated at doses ranging from 500 to 1,600 mg once daily. Clinical activity was observed in heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers, including four PRs in patients with trastuzumab-resistant breast cancers and prolonged stable disease in 10 patients.

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Published In

J Clin Oncol

DOI

ISSN

0732-183X

Publication Date

August 10, 2005

Volume

23

Issue

23

Start / End Page

5305 / 5313

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Safety
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Quinazolines
  • Oncology & Carcinogenesis
  • Neoplasms
  • Neoplasm Recurrence, Local
  • Neoplasm Metastasis
  • Middle Aged
 

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Burris, H. A., Hurwitz, H. I., Dees, E. C., Dowlati, A., Blackwell, K. L., O’Neil, B., … Spector, N. L. (2005). Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol, 23(23), 5305–5313. https://doi.org/10.1200/JCO.2005.16.584
Burris, Howard A., Herbert I. Hurwitz, E Claire Dees, Afshin Dowlati, Kimberly L. Blackwell, Bert O’Neil, Paul K. Marcom, et al. “Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas.J Clin Oncol 23, no. 23 (August 10, 2005): 5305–13. https://doi.org/10.1200/JCO.2005.16.584.
Burris HA, Hurwitz HI, Dees EC, Dowlati A, Blackwell KL, O’Neil B, Marcom PK, Ellis MJ, Overmoyer B, Jones SF, Harris JL, Smith DA, Koch KM, Stead A, Mangum S, Spector NL. Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol. 2005 Aug 10;23(23):5305–5313.

Published In

J Clin Oncol

DOI

ISSN

0732-183X

Publication Date

August 10, 2005

Volume

23

Issue

23

Start / End Page

5305 / 5313

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Safety
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Quinazolines
  • Oncology & Carcinogenesis
  • Neoplasms
  • Neoplasm Recurrence, Local
  • Neoplasm Metastasis
  • Middle Aged