Pazopanib-Induced Liver Toxicity in Patients With Metastatic Renal Cell Carcinoma: Effect of UGT1A1 Polymorphism on Pazopanib Dose Reduction, Safety, and Patient Outcomes

Abstract

Treatment of patients with metastatic renal cell carcinoma with pazopanib has been associated with an increased probability of developing liver toxicity in the presence of polymorphisms in the gene UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1), leading to treatment interruptions and permanent discontinuation. We have demonstrated that UGT1A1-guided dosing can manage pazopanib-induced liver toxicity and also that UGT1A1 polymorphisms are associated with improved outcomes, despite pazopanib interruption and substantial dose reductions. Background: Pazopanib can induce liver toxicity in patients with metastatic renal cell carcinoma (mRCC). We assessed the effect of a TA repeat polymorphism in the UGT1A1 (uridine diphosphate glucuronosyltransferase 1A1) gene encoding uridine diphosphate glucuronosyltransferase 1A1 on liver toxicity, dose reductions, and patient outcomes. Patients and Methods: Patients with mRCC treated with first-line pazopanib developing liver toxicity underwent genotyping for the UGT1A1 polymorphism. Liver toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.0. Progression-free survival and overall survival were assessed using the Kaplan-Meier and log-rank methods. Results: Of 261 patients, 34 (13%) had developed liver toxicity after a median of 29 days (range, 5-155 days). Grade 4, 3, and 2 alanine aminotransferase or bilirubin had increased in 2 (6%), 17 (50%), and 8 (24%) patients, respectively. The UGT1A1 assessment demonstrated that 18 patients (53%) had TA6/TA7, 7 (21%) had TA7/TA7, and 9 (26%) had wild-type TA6/TA6. The UGT1A1 polymorphism was associated with improved median progression-free survival (TA6/TA6, 5.5 months; TA6/TA7, 34.2 months; TA7/TA7, 22.3 months; unknown UGT1A1 status, 9.2 months; UGT1A1 polymorphisms combined vs. unknown status, P ¼ .021). UGT1A1 polymorphism was associated with improved median overall survival (TA6/TA6, 8.1 months, TA6/TA7 or TA7/TA7 not reached, unknown UGT1A1 status, 16.6 months; UGT1A1 polymorphisms combined vs. unknown status, P ¼ .033). Patients with UGT1A1 polymorphism safely resumed pazopanib at ultra-low doses determined by the degree of liver toxicity and UGT1A1 polymorphism. Conclusions: UGT1A1 polymorphisms were associated with improved outcomes, despite pazopanib interruption and dose reductions. UGT1A1 assessment could improve the management of pazopanibinduced liver toxicity in patients with mRCC.

Severe tyrosine-kinase inhibitor induced liver injury in metastatic renal cell carcinoma patients: two case reports assessed for causality using the updated RUCAM and review of the literature

“…Preceding pharmacogenetic studies have reported association between Gilbert syndrome uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) variants and hyperbilirubinemia in patiens treated with pazopanib and sunitinib [ 38 , 39 ]. The UGT1A1 enzyme is inhibited by pazopanib, and patients carrying the UGT1A1∗28 allele have been identified to be at risk of hyperbilirubinemia [ 40 ]. Xu et al reported on a potential association between the presence of a mutation of the hemochromatosis gene (HFE) on chromosome 6 and human leukocyte antigen B∗57:01 (HLA-B∗57:01) carrier status, and ALT elevation in pazopanib-treated patients [ 41 ].…”

Influence of UGT1A1 *6/*28 Polymorphisms on Irinotecan-Related Toxicity and Survival in Pediatric Patients with Relapsed/Refractory Solid Tumors Treated with the VIT Regimen

“…39 Similarly, the findings by Henriksen et al revealed that UGT1A1*28 improved the PFS and OS in metastatic renal cell carcinoma. 40 In contrast, the study by Yamaguchi et al confirmed that UGT1A1*6 and *28 were shown to be related to a shorter OS in advanced gastric cancer when irinotecan monotherapy was used as a third-line treatment. 41 In the present study, the K-M survival analysis revealed that patients with mutant UGT1A1*6 (P = 0.146) or *28 (P = 0.195) genotypes had a non-significant inferior OS compared to those with the wild genotype.…”

Modern developments in germline pharmacogenomics for oncology prescribing

“…69 A recent retrospective analysis of pazopanib-treated patients who had metastatic RCC and treatment-related hepatotoxicity demonstrated that UGT1A1 poor metabolizers required frequent dosing interruptions. 70 Those authors proposed that UGT1A1 assessment to guide dosing could improve the management of pazopanib-induced liver toxicity. The FDA cautions that UGT1A1 poor metabolizers may be at risk for hyperbilirubinemia but does not suggest a dose modification in the label.…”

“…Genome‐wide association studies (GWAS), including a large analysis conducted in patients with RCC (n = 1099), have also demonstrated a significant relationship between elevated bilirubin levels and UGT1A1 variants in patients treated with pazopanib ( P = 2.9 × 10 −17 ) 69 . A recent retrospective analysis of pazopanib‐treated patients who had metastatic RCC and treatment‐related hepatotoxicity demonstrated that UGT1A1 poor metabolizers required frequent dosing interruptions 70 . Those authors proposed that UGT1A1 assessment to guide dosing could improve the management of pazopanib‐induced liver toxicity.…”

“…Parallel to these developments, there has been immense progress in identifying and describing germline pharmacogenomic variants that predispose patients to variable drug responses and treatment‐related toxicities (Table 1). 14‐76 These data are coupled with recent advances in the technology and systems for incorporating germline PGx testing into routine medical care. In recognition of this progress, international bodies, such as the Clinical Pharmacogenomic International Consortium (CPIC), 77 the Dutch Pharmacogenomics Working Group, 78 and the Canadian Pharmacogenomics Network for Drug Safety (CPNDS), 79 have published guidelines regarding the role of testing and dosing recommendations of pharmacogenes and their effects on numerous medications, including anticancer therapies.…”