Lapatinib (L) plus capecitabine (C) in HER2+ advanced breast cancer (ABC): Genomic and updated efficacy data

Abstract

1035 Background: EGF100151 demonstrated L+C improved TTP relative to C alone in women with HER2 positive, trastuzumab- exposed ABC (Geyer, NEJM;355(26):2006). We report updated efficacy data and results of correlative studies to determine if gene expression levels in the 5-FU and HER pathways are associated with clinical benefit in L+C. Methods: Tumor blocks are available on 217/399 patients, and so far sufficient mRNA has been extracted from 64/217 blocks using qRT-PCR. Tumors were evaluated for expression of HER1–4, TS, TP, PTEN, c-MYC. In addition to univariate and multivariate analyses, a SpotFire™ DecisionTree analysis was performed to determine the genes most significantly associated with RR; these genes were further analyzed for association with TTP. Results: Updated efficacy results through April 3, 2006 demonstrate: TTP L+C (27 wks)vs C (19 wks) HR 0.57 [0.43,0.77] p=0.00013; ORR L+C (24%)vs C (14%), Odds Ratio 1.9[1, 1.34] p=0.017; OS L+C vs C HR 0.78 [0.55,1.12] p=0.177; progression in CNS L+C (2%)vs C (11%) p=0.0445. Preliminary analysis of the first 64 samples indicates that elevated baseline mRNA expression of HER2 is associated with a higher RR and longer TTP (p<0.0001) with L+C. The opposite was seen in the C arm, where elevated HER2 mRNA expression seemed to predict for a poorer outcome. Analyses of ErbB3,4, PTEN and MYC as well as TS did not correlate with RR. Conclusion: The updated efficacy results confirm the prior demonstrated benefit of L+Cvs C and provide the first evidence for a systemic anti-HER2 therapy to have an effect on the development of CNS metastases. This preliminary analysis suggests a correlation between elevated HER2 mRNA levels and RR/TTP. Further investigation, including full genome microarray analysis of samples is ongoing. [Table: see text]