Initial testing (stage 1) of lapatinib by the pediatric preclinical testing program.

Journal Article (Journal Article)

BACKGROUND: Lapatinib is a small molecule reversible tyrosine kinase inhibitor of EGFR and ErbB2 that shows in vitro and in vivo activity against a range of EGFR and ErbB2-dependent adult cancer cell lines and that has clinical efficacy against ErbB2-overexpressing breast cancer. METHODS: Lapatinib was tested against the cell lines of the PPTP in vitro panel at concentrations ranging from 1.0 nM to 10.0 microM. Lapatinib was tested against the xenografts of the PPTP in vivo panels using a twice-daily oral administration schedule for 6 weeks (5 days on, 2 days off) at a dose of 160 mg/kg (320 mg/kg/day). Lapatinib pharmacokinetic parameters were determined in scid(-/-) mice. RESULTS: The median IC(50) value for lapatinib against the entire PPTP cell line panel was 6.84 microM (range, 2.08 to >10.0 microM). Lapatinib was well tolerated in vivo, with toxicity in only 1.5% of the treated animals. Lapatinib induced significant differences in EFS distribution compared to controls in 1 of 41 xenografts tested. No objective responses were observed in any of the solid tumor panels or in the ALL panel. Lapatinib systemic exposure was consistent with previously observed values. CONCLUSIONS: Lapatinib has little activity against the xenografts of the PPTP's in vivo panel, and its in vitro activity occurs at concentrations above those associated with specific EGFR/ErbB2 inhibition. These results likely reflect lack of ErbB2 overexpression in the models studied and suggest that adult and pediatric cancers may fundamentally differ in the applicability of EGFR family members as therapeutic targets.

Full Text

Duke Authors

Cited Authors

  • Gorlick, R; Kolb, EA; Houghton, PJ; Morton, CL; Phelps, D; Schaiquevich, P; Stewart, C; Keir, ST; Lock, R; Carol, H; Reynolds, CP; Maris, JM; Wu, J; Smith, MA

Published Date

  • October 2009

Published In

Volume / Issue

  • 53 / 4

Start / End Page

  • 594 - 598

PubMed ID

  • 19554571

Pubmed Central ID

  • PMC2731000

Electronic International Standard Serial Number (EISSN)

  • 1545-5017

Digital Object Identifier (DOI)

  • 10.1002/pbc.21989


  • eng

Conference Location

  • United States