HLA-B*57:01 Associated with Pazopanib Hepatotoxicity

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.

Experimental Design: The discovery analysis tested association between four-digit HLA alleles and alanine aminotransferase (ALT) elevation in pazopanib-treated patients with cancer from eight clinical trials (N = 1,188). We conducted confirmatory analysis using an independent dataset of pazopanib-treated patients from 23 additional trials (N = 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 = 5.0 x 10^–5 for maximum on-treatment ALT (MaxALT); P = 4.8 x 10^–4 for time to ALT > 3x upper limit of normal (ULN) event; P = 4.1 x 10^–5 for time to ALT > 5x ULN event] that is significant after adjustment for number of HLA alleles tested. We confirmed these associations with time to ALT elevation event (P = 8.1 x 10^–4 for ALT > 3x ULN, P = 9.8 x 10^–3 for ALT > 5x ULN) in an independent dataset. In the combined data, HLA-B*57:01 carriage was associated with ALT elevation (P = 4.3 x 10^–5 for MaxALT, P = 5.1 x 10^–6 for time to ALT > 3xULN event, P = 5.8 x 10^–6 for time to ALT > 5x ULN event). In HLA-B*57:01 carriers and noncarriers, frequency of ALT > 3x ULN was 31% and 19%, respectively, and frequency of ALT > 5x 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-mediated mechanism for pazopanib-associated hepatotoxicity in some patients. Clin Cancer Res; 22(6); 1371–7. ©2015 AACR.

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