Cancer Therapy: Clinical HLA-B 57:01 Confers Susceptibility to Pazopanib- Associated Liver Injury in Patients with Cancer

Purpose: Pazopanib is an effective treatment for advanced renal cell carcinoma and soft-tissue sarcoma. Transaminase elevations have been commonly observed in pazopanib-treated patients. We conducted pharmacogenetic analyses to explore mechanistic insight into pazopanib-induced liver injury. ExperimentalDesign: Thediscovery analysis tested association between four-digit HLA alleles and alanine aminotransferase (ALT) elevation in pazopanib-treated patients with cancer from eight clinical trials (N 1⁄4 1,188). We conducted confirmatory analysis using an independent dataset of pazopanib-treated patients from 23 additional trials (N 1⁄4 1,002). Genome-wide association study (GWAS) for transaminase elevations was also conducted. Results: The discovery study identified an association between HLA-B 57:01 carriage and ALT elevation [P 1⁄4 5.0 10 5 for maximum on-treatment ALT (MaxALT); P 1⁄4 4.8 10 4 for time toALT>3 upper limit of normal (ULN) event;P1⁄44.1 10 5 for time to ALT > 5 ULN event] that is significant after adjustment for number ofHLA alleles tested.We confirmed these associations with time to ALT elevation event (P 1⁄4 8.1 10 4 for ALT > 3 ULN, P 1⁄4 9.8 10 3 for ALT > 5 ULN) in an independent dataset. In the combined data, HLA-B 57:01 carriage was associated with ALT elevation (P 1⁄4 4.3 10 5 for MaxALT, P 1⁄4 5.1 10 6 for time to ALT > 3 ULN event, P 1⁄4 5.8 10 6 for time to ALT > 5 ULN event). In HLA-B 57:01 carriers and noncarriers, frequency of ALT > 3 ULN was 31% and 19%, respectively, and frequency of ALT > 5 ULN was 18% and 10%, respectively. GWAS revealed a possible borderline association, which requires further evaluation. Conclusions: These data indicate that HLA-B 57:01 carriage confers higher risk of ALT elevation in patients receiving pazopanib and provide novel insight implicating an immune-mediatedmechanism for pazopanib-associated hepatotoxicity in some patients. Clin Cancer Res; 22(6); 1371–7. 2015 AACR.