PGx275 lapatinib liver safety pharmacogenetics in EGF30008

Trial description: GlaxoSmithKline (GSK) is developing TYKERB/TYVERB® (lapatinib, GW571016), a small molecule ErbB1/ErbB2 tyrosine kinase inhibitor (TKI), for the treatment of a variety of cancers, including breast cancer. Lapatinib was approved by the Food and Drug Administration (FDA) in the US on March 13, 2007 in combination with capecitabine (Xeloda®) for the treatment of patients with advanced or metastatic breast cancer (MBC) whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab (Herceptin®) [TYKERB Package Insert, March 2007]. With consideration of the FDA draft guidance document on distinguishing signals of drug induced liver injury (DILI) (http://www.fda.gov/cder/guidance/7507dft.htm), GSK is conducting retrospective analyses of the laboratory and clinical data from studies of lapatinib monotherapy and lapatinib in combination with other anti-cancer agents in patients with various stages of breast cancer. The overall estimated incidence of possible Hy’s law cases (AST/ALT above 3xULN, TBL above 2xULN and ALP below 2xULN) on the GSK clinical program is 0.2%, or 0.1% based on cases with a possible association to lapatinib. Other TKIs have been associated with hepatobiliary events; however the mechanism is currently unknown. Possible mechanisms for lapatinib associated hepatobiliary events include entrohepatic recycling, inhibition of the biliary transporters SLCO1B1 (OATP1B1), ABCB1 (p-glycoprotein) and ABCG2 (BCRP) and a possible unspecified effect on the major bile acid export pumps ABCB11 (BSEP) and ABCB4 (MDR3). It is also possible that EGFR inhibition may impair liver regeneration. It has been reported that genetic variation may be an important factor in predicting susceptibility to drug induced hepatobiliary events. This pharmacogenetic (PGx) study has been undertaken to determine if the observed hepatic events seen with lapatinib are associated with genetic risk factors. All available lapatinib-treated consented DNA samples from EGF30008 will be included in the present PGx evaluation. The PGx analysis population will consist of the subjects enrolled in the clinical study EGF30008 who provided written informed consent for PGx research, provided a blood sample for genotyping and were successfully genotyped for at least one of the genetic markers under study, have valid phenotype data and pass subject quality control measures.The clinical study being examined was not prospectively designed to address PGx research hypotheses and, thus, did not benefit from prospective sample size calculations or randomization schemes for the genetic markers. The distribution of genotypes will vary considerably from one genetic marker to the next (i.e., the genotype data within each genetic marker will not be balanced), and statistical power of the analyses cannot be guaranteed.Three case-control cohorts determined by the primary study endpoints of maximum on-treatment ALT xULN, maximum on-treatment TBL xULN, and a combination of these two endpoints will be evaluated in the case-control analysis. Other case and control definitions may also be explored as appropriate. A restriction placed on the definition of a control subject requires all controls to have received lapatinib for a minimum of thirteen weeks. This is done to refine our subset of controls for analysis and corresponds with previous analyses of lapatinib breast cancer trials (including EGF30008) that shows that by thirteen weeks, approximately 50% of the ALT cases (>3x ULN) had presented.