PGx7521: Evaluation of validated HLA markers with DILI in lapatinib clinical trial EGF106903

Trial description: Lapatinib is a potent, selective, and reversible oral dual tyrosine kinase inhibitor of both epidermal growth factor receptors ErbB1 (epidermal growth factor receptor [EGFR]) and ErbB2 (human epidermal growth factor receptor [HER2]). Lapatinib is currently being evaluated in multiple solid tumor types that express or overexpress EGFR and/or HER2, with ongoing Phase II/III studies in metastatic breast cancer (MBC). Study EGF106903 [study protocol, BIG 1-06 / EGF106903] is a randomised, multi-centre, open-label, phase III study comparing the efficacy of neo-adjuvant lapatinib plus paclitaxel, versus trastuzumab plus paclitaxel, versus concomitant lapatinib and trastuzumab plus paclitaxel given as neo-adjuvant treatment in HER2/ErbB2 over-expressing and/or amplified primary breast cancer. Patients were randomised to receive either: lapatinib 1500 mg daily, trastuzumab 4 mg/kg intravenous (iv) load followed by 2 mg/kg iv weekly, or lapatinib 1000 mg daily with trastuzumab 4 mg/kg iv load followed by 2 mg/kg iv weekly for a total of 6 weeks. After this biological window, patients on monotherapy arms were continued on the same targeted therapy plus weekly paclitaxel 80 mg/m2 for a further 12 weeks, up to definitive surgery. In the combination arm, patients received lapatinib 750 mg daily in combination with trastuzumab 2 mg/kg iv plus weekly paclitaxel 80mg/m2 iv for a further 12 weeks, up to definitive surgery. After surgery, patients received three courses of adjuvant chemotherapy (fluorouracil, epirubicin or cyclophosphamide [FEC]) followed by the same targeted therapy as in the biological window of the neo-adjuvant setting for a further 34 weeks (in the combination arm, lapatinib dose was 1000 mg daily in combination with trastuzumab). The planned total duration of the anti-HER2 therapy was one year. Previous PGx analyses identified, confirmed, and validated the association of HLA-DRB1*07:01 with lapatinib-induced liver injury using clinical data from multiple studies of lapatinib, as monotherapy and in combination with other anti-cancer agents in patients with metastatic and adjuvant breast cancer. Patients who carry the HLA-DRB1*07:01 allele have increased risk of lapatinib-induced liver injury. In a large, randomized clinical trial of lapatinib monotherapy (EGF105485, n=1,194), the overall risk of severe liver injury (i.e.,alanine aminotransferase (ALT) >5 times the upper limit of normal, NCI CTCAE grade 3) was 2%, the risk in HLA-DRB1*07:01 allele carriers was 8% and the risk in HLA non-carriers was 0.5%. Carriage of the HLA-DRB1*07:01 allele is common (15 to 25%) in Caucasian, Asian, African and Hispanic populations but lower (approximately 1%) in Japanese populations. The primary objective of this pharmacogenetic study therefore is to compare the frequency of liver injury (using ALT elevation) between patients who carry HLA-DRB1*07:01 allele and non-carriers during study drug treatment, and to determine the predictive characteristics of HLA-DRB1*07:01 allele carriage in patients from this study. Furthermore, in addition to HLA-DRB1*07:01, the UGT1A1*28 and UGT1A1*6 genotypes will be used to characterize possible Hy’s Law cases on study for Gilbert’s syndrome status.