Zhengyu Xue

Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism

Background:Pazopanib has shown clinical activity against multiple tumour types and is generally well tolerated. However, isolated elevations in transaminases and bilirubin have been observed. This study examined polymorphisms in molecules involved in pharmacokinetic and pharmacodynamic pathways of pazopanib and their association with hepatic dysfunction.Methods:Twenty-eight polymorphisms in 11 genes were evaluated in pazopanib-treated renal cell carcinoma patients. An exploratory analysis was conducted in 116 patients from a phase II study; a replication study was conducted in 130 patients from a phase III study.Results:No polymorphisms were associated with alanine aminotransferase elevation. The Gilberts uridine-diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) TA-repeat polymorphism was significantly associated with pazopanib-induced hyperbilirubinemia in the phase II study. This association was replicated in the phase III study (P<0.01). Patients with TA6/TA6, TA6/TA7, and TA7/TA7 genotypes experienced median bilirubin increases of 0.31, 0.37, and 0.71 × upper limit of the normal range (ULN), respectively. Of the 38 patients with hyperbilirubinemia (⩾1.5 × ULN), 32 (84%) were either TA7 homozygotes (n=18) or TA7 heterozygotes (n=14). For TA7 homozygotes, the odds ratio (95% CI) for developing hyperbilirubinemia was 13.1 (5.3–32.2) compared with other genotypes.Conclusions:The UGT1A1 polymorphism is frequently associated with pazopanib-induced hyperbilirubinemia. These data suggest that some instances of isolated hyperbilirubinemia in pazopanib-treated patients are benign manifestations of Gilberts syndrome, thus supporting continuation of pazopanib monotherapy in this setting.

Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma

BACKGROUND & AIMS Pazopanib has demonstrated clinical benefit in patients with advanced renal cell carcinoma (RCC) and is generally well tolerated. However, transaminase elevations have commonly been observed. This 2-stage study sought to identify genetic determinants of alanine transaminase (ALT) elevations in pazopanib-treated white patients with RCC. METHODS Data from two separate clinical studies were used to examine the association of genetic polymorphisms with maximum on-treatment ALT levels. RESULTS Of 6852 polymorphisms in 282 candidate genes examined in an exploratory dataset of 115 patients, 92 polymorphisms in 40 genes were significantly associated with ALT elevation (p<0.01). Two markers (rs2858996 and rs707889) in the HFE gene, which are not yet known to be associated with hemochromatosis, showed evidence for replication. Because of multiple comparisons, there was a 12% likelihood the replication occurred by chance. These two markers demonstrated strong linkage disequilibrium (r(2)=0.99). In the combined dataset, median (25-75th percentile) maximum ALT values were 1.2 (0.7-1.9), 1.1 (0.8-2.5), and 5.4 (1.9-7.6)×ULN for rs2858996 GG (n=148), GT (n=82), and TT (n=1 2) genotypes, respectively. All 12 TT patients had a maximum ALT>ULN, and 8 (67%) had ALT≥3×ULN. The odds ratio (95% CI) for ALT≥3×ULN for TT genotype was 39.7 (2.2-703.7) compared with other genotypes. As a predictor of ALT≥3×ULN, the TT genotype had a negative predictive value of 0.83 and positive predictive value of 0.67. No TT patients developed liver failure. CONCLUSIONS The rs2858996/rs707889 polymorphisms in the HFE gene may be associated with reversible ALT elevation in pazo-panib-treated patients with RCC.

IL8 polymorphisms and overall survival in pazopanib- or sunitinib-treated patients with renal cell carcinoma

Background:We evaluated germline single nucleotide polymorphisms (SNPs) for association with overall survival (OS) in pazopanib- or sunitinib-treated patients with advanced renal cell carcinoma (aRCC).Methods:The discovery analysis tested 27 SNPs within 13 genes from a phase III pazopanib trial (N=241, study 1). Suggestive associations were then pursued in two independent datasets: a phase III trial (COMPARZ) comparing pazopanib vs sunitinib (N=729, study 2) and an observational study of sunitinib-treated patients (N=89, study 3).Results:In study 1, four SNPs showed nominally significant association (P≤0.05) with OS; two of these SNPs (rs1126647, rs4073) in IL8 were associated (P≤0.05) with OS in study 2. Because rs1126647 and rs4073 were highly correlated, only rs1126647 was evaluated in study 3, which also showed association (P≤0.05). In the combined data, rs1126647 was associated with OS after conservative multiple-test adjustment (P=8.8 × 10−5; variant vs reference allele hazard ratio 1.32, 95% confidence interval: 1.15–1.52), without evidence for heterogeneity of effects between studies or between pazopanib- and sunitinib-treated patients.Conclusions:Variant alleles of IL8 polymorphisms are associated with poorer survival outcomes in pazopanib- or sunitinib-treated patients with aRCC. These findings provide insight in aRCC prognosis and may advance our thinking in development of new therapies.

Hyperbilirubinemia in pazopanib- or sunitinib-treated patients in COMPARZ is associated with UGT1A1 polymorphisms

Pazopanib and sunitinib are angiogenesis inhibitors approved for treatment of advanced renal cell carcinoma. Treatmentassociated elevations in alanine aminotransferase (ALT) and bilirubin have been reported for both therapies [1]. UGT1A1 polymorphisms are known to cause reduced expression/ activity of UGT1A1 and predispose individuals to Gilbert’s syndrome, a benign form of episodic jaundice [2, 3]. Our analyses of previous pazopanib clinical trials found that UGT1A1 *28 was associated with on-treatment hyperbilirubinemia [4]. This study extended our previous analysis of UGT1A1*28 to additional alleles (*36, *37, and *6) and investigated their association with on-therapy serum total bilirubin in COMPARZ (NCT00720941 and NCT01147822), a phase III, randomized, clinical trial comparing pazopanib versus sunitinib for the treatment of advanced renal cell carcinoma [1]. Of 1110 randomized participants, on-therapy hyperbilirubinemia [total bilirubin ≥1.5 × upper limit of the normal range (ULN)] was observed in 16% (89/557) of pazopanib-arm patients and 9% (49/553) of sunitinib-arm patients. In the pharmacogenetic population (patients who received at least one dose of study treatment, consented, and were successfully genotyped, n = 719), the incidence of hyperbilirubinemia was 17% (62 of 369) for pazopanib and 10% (34 of 350) for sunitinib. The incidence of hyperbilirubinemia varies by UGT1A1 genotypes for both therapies (Figure 1). Logistic regression adjusted for ancestry principal components was used to compare hyperbilirubinemia cases (pazopanib n = 62; sunitinib n = 34) against controls (pazopanib n = 211; sunitinib n = 212). Controls were defined as patients with all on-therapy bilirubin ≤1 × ULN and treatment exposure equal to or greater than median exposure until bilirubin elevation in cases (defined in the supplementary materials, available at Annals of Oncology online). Patients with predicted reduced UGT1A1 function (homozygous or inferred compound heterozygous for *28, *37, and *6) had higher baseline bilirubin and were more likely to experience hyperbilirubinemia when receiving either pazopanib (P = 7.7 × 10) or sunitinib (P = 1.7 × 10), with odds ratios (95% confidence interval) 9.97 (4.13–24.03) and 5.83 (2.04–16.68), respectively. After adjusting for baseline bilirubin, patients with predicted, reduced UGT1A1 function remained more likely to experience hyperbilirubinemia when receiving pazopanib (P = 0.012) or sunitinib (P = 0.024), with odds ratios (95% confidence interval) 3.65 (1.31–10.16) and 4.51 (1.26–16.11), respectively. UGT1A1 genotypes were not significantly associated with ALT ≥3 × ULN in pazopanib-treated patients. A borderline significant association (P = 0.030) was seen between UGT1A1 genotypes with reduced function (predicted) and decreased incidence of ALT ≥3 × ULN in sunitinib-treated patients; additional studies are required to confirm this observation. Pazopanib is a potent inhibitor of UGT1A1 in vitro [4]. Our data suggest that hyperbilirubinemia in pazopanibtreated patients may be the result of inhibition of UGT1A1 combined with effects of genetic variants in the UGT1A1 gene. We expect this would result in higher levels of unconjugated hyperbilirubinemia, usually associated with a benign clinical course. Sunitinib, however, does not inhibit UGT1A1 [5]. To our knowledge, this is the first study reporting the association between UGT1A1 genotype and hyperbilirubinemia in patients receiving sunitinib. Our data suggest that some instances of hyperbilirubinemia in patients treated with pazopanib or sunitinib may be benign manifestations of Gilbert’s syndrome. Bilirubin fractionation or, if not available, UGT1A1 genotyping, would enable further characterization of liver safety risk and help in making treatment decisions.