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

GORLICK R.; KOLB E.A; HOUGHTON P.J.; MORTON C. L; PHELPS D; SCHAIQUEVICH P; STEWART C.F; KEIR S.T; LOCK R; REYNOLDS C.P; MARIS J. M; WU J; SMITH M. A.

PEDIATRIC BLOOD & CANCER

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 2009 vol. 53 p. 594 - 598

1545-5009

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 mM. Lapatinib was tested against the xenografts of the PPTP invivo 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. Themedian IC50 value for lapatinib against the entire PPTP cell line panel was 6.84 mM (range, 2.08 to >10.0 mM). Lapatinib was well tolerated in vivo, with toxicity in only 1.5%of the  treated animals. Lapatinib induced significant differences in EFSdistribution 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 ofErbB2 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.