Pediatric preclinical testing program (PPTP) evaluation of the EGFR and ErbB2 inhibitor lapatinib

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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. Lapatinib was studied by the PPTP to develop data concerning the relevance of EGFR family members as therapeutic targets for childhood cancers.
 Methods: The PPTP includes a molecularly characterized in vitro panel of cell lines (n=27) and in vivo panel of xenografts (n=61) representing most of the common types of childhood solid tumors and childhood ALL. Lapatinib in vitro testing used media containing 20% FCS and evaluated concentrations from 1.0 nM to 10 µM, with viable cell numbers for treated and control replicates evaluated at 96 hours using the DIMSCAN fluorescence-based method. Lapatinib was tested against the PPTP in vivo panels using a twice-daily oral administration schedule for six weeks (5-days on, 2-days off) at a dose of 160 mg/kg (320 mg/kg/day). Three measures of antitumor activity were used: 1) response criteria modeled after the clinical setting; 2) treated to control (T/C) tumor volume at day 21; and 3) a time to event (4-fold increase in tumor volume) measure based on the median EFS of treated and control lines (intermediate activity required EFS T/C > 2, and high activity additionally required a net reduction in median tumor volume at the end of the experiment).
 Results: EGFR and/or ErbB2 were expressed at detectable levels in most of the PPTP’s cell lines and xenografts at the RNA level based upon data from Affymetrix U133 Plus 2.0 arrays. The median IC50 value for lapatinib against the entire PPTP cell line panel was 6.84 µM. IC50 values ranged from a low of 2.08 µM (Ramos, NHL) to a maximum exceeding 10.0 µM in seven cell lines. 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 evaluable xenografts tested. No xenografts met the criteria for intermediate activity for the PPTP EFS activity measure (EFS T/C value > 2.0 and a significant difference in EFS distribution). No objective responses were observed in any of the solid tumor panels or in the ALL panel. The best response observed was a single example of PD2 (progressive disease with growth delay).
 Conclusions: The response of the PPTP cell lines to lapatinib corresponds to the pattern of response described previously for adult cancer cell lines that do not overexpress EGFR or ErbB2 and that have IC50 values exceeding 1 µM. Thus, the lapatinib in vitro activity against the PPTP cell lines likely represents “off-target” kinase inhibition effects. The lack of in vivo activity for lapatinib is consistent with previous reports that EGFR mutation and ErbB2 amplification are uncommon for childhood cancers. These results do not preclude a role for lapatinib in a biological subtype of a pediatric cancer that is not represented within the PPTP panel. However, when combined with preclinical and clinical experience to date for EGFR small molecule inhibitors, the results do suggest a limited role for EGFR family members as therapeutic targets for childhood cancers. (Supported by NCI NO1CM42216)