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.
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.
The discovery study identified an association between HLA-B*57:01 carriage and ALT elevation (P=5. 0×10-5 for maximum on-treatment ALT [MaxALT]; P=4. 8×10-4 for time to ALT>3×upper limit of normal [ULN] event; P=4. 1×10-5 for time to ALT>5×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. 1×10-4 for ALT>3×ULN, P=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=4. 3×10-5 for MaxALT, P=5. 1×10-6 for time to ALT>3×ULN event, P=5. 8×10-6 for time to ALT>5×ULN event). In HLA-B*57:01 carriers and non-carriers, 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.
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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2015 Nov 06 [Epub ahead of print]
Chun-Fang Xu, Toby Johnson, Xiaojing Wang, Christopher Carpenter, Alan Graves, Liling Warren, Zhengyu Xue, Karen S King, Dana J Fraser, Sandy Stinnett, Linda P Briley, Ionel Mitrica, Colin F Spraggs, Matthew R Nelson, Hiroomi Tada, Andreas du Bois, Thomas Powles, Neil Kaplowitz, Lini N Pandite
Genetics Division, GlaxoSmithKline Medicines Research Centre, Research and Development, GlaxoSmithKline. , Research and Development, ConvaTec (previously employed by GSK; work performed on this publication done while employed by GSK). , R&D, GlaxoSmithKline. , Oncology R&D, GlaxoSmithKline. , Statistical Genetics, Omicsoft (previously employed by GSK; work performed on this publication done while employed by GSK). , Genetics Division, GlaxoSmithKline Research and Development. , PAREXEL International (previously employed by GSK; work performed on this publication done while employed by GSK). , Translational Sciences, Parexel (previously employed by GSK; work performed on this publication done while employed by GSK). , R&D, GlaxoSmithKline. , PAREXEL International (previously employed by GSK; work performed on this publication done while employed by GSK). , Research and Development, GlaxoSmithKline. , Genetics, GlaxoSmithKline Research and Development. , Research and Development, GlaxoSmithKline. , Immuno-Oncology Development, Incyte (previously employed by GSK; work performed on this publication done while employed by GSK). , Department of Gynecology & Gynecologic Oncology, Dr. Horst Schmidt Klinik (HSK). , Experimental Cancer Medicine Centre, Queen Mary University of London. , Keck School of Medicine, University of Southern California. , Clinical Development, Adaptimmune (previously employed by GSK; work performed on this publication done while employed by GSK).