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Objective: To identify the issues of using overall survival (OS) as a primary endpoint in the presence of crossover and the statistical analyses available to adjust for confounded OS due to crossover in oncology clinical trials., Methods: An indirect comparison was conducted between pazopanib and sunitinib in advanced renal cell carcinoma. Statistical adjustment methods were used to estimate the true comparative effectiveness of these treatments. Recently, a head-to-head trial comparing pazopanib and sunitinib was completed. This provided the opportunity to compare the OS treatment effect estimated for pazopanib versus sunitinib using indirect comparison and statistical adjustment techniques with that observed in the head-to-head trial., Results: Using a rank-preserving structural failure time model to adjust for crossover in the pazopanib registration trial, the indirect comparison of pazopanib versus sunitinib resulted in an OS hazard ratio (HR) of 0.97, while an unadjusted analysis resulted in an OS HR of 1.96. The head-to-head trial reported a final OS HR of 0.92 for pazopanib versus sunitinib., Conclusion: This case study supports the need to adjust for confounded OS due to crossover, which enables trials to meet ethical standards and provides decision makers with a more accurate estimate of treatment benefit., (© 2016 S. Karger AG, Basel.)

Aim: Pazopanib, an oral antiangiogenic agent, is associated with improved outcomes in patients with metastatic renal cell carcinoma. In this retrospective analysis, we explore hypertension, an on-target adverse event, as a predictive marker., Methods: Data from the pazopanib arm of the phase III COMPARZ trial (NCT00720941) comprised the test set. Pooled data from phase II (NCT00244764) and III (NCT00334282) pazopanib trials comprised the validation set. Data from the sunitinib arm of COMPARZ were analysed separately. Measures of efficacy were response rate, progression-free survival (PFS), and overall survival (OS). Mean arterial blood pressure (MAP) was the primary metric, and systolic hypertension (S-HTN) and diastolic hypertension (D-HTN) were secondary metrics; 4- and 12-week landmark analyses were performed., Results: Analyses revealed no significant associations at the landmarks between response and MAP. We observed a trend towards improved PFS with S-HTN at week 4 (hazard ratio [HR] = 0.79, P = 0.060) and week 12 (HR = 0.75, P = 0.073) among pazopanib-treated patients in COMPARZ. This trend was not confirmed at week 12 in the validation set or in sunitinib-treated patients. In the test set, there was a trend towards increased OS in patients with S-HTN by week 4 (HR = 0.76, P = 0.062) and with D-HTN by week 4 (HR = 0.71, P = 0.016) but not by week 12. No significant differences in OS were observed in sunitinib-treated patients for S-HTN or D-HTN., Conclusion: Neither hypertension nor any blood pressure elevation above baseline was associated with efficacy outcomes of pazopanib or sunitinib. Accordingly, management of tyrosine kinase inhibitor-induced hypertension is unlikely to compromise outcome., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Drug-induced liver chemistry abnormalities, primarily transaminase elevations, are commonly observed in pazopanib-treated patients. This meta-analysis characterises liver chemistry abnormalities associated with pazopanib. Data of pazopanib-treated patients from nine prospective trials were integrated (N=2080). Laboratory datasets were used to characterise the incidence, timing, recovery and patterns of liver events, and subsequent rechallenge with pazopanib. Severe cases of liver chemistry abnormalities were clinically reviewed. Multivariate analyses identified predisposing factors. Twenty percent of patients developed elevated alanine aminotransferase (ALT) >3×ULN. Incidence of peak ALT >3-5×ULN, >5-8×ULN, >8-20×ULN and >20×ULN was 8%, 5%, 5% and 1%, respectively. Median time to onset for all events was 42days; 91% of events were observed within 18weeks. Recovery rates based on peak ALT >3-5×ULN, >5-8×ULN, >8-20×ULN and >20×ULN were 91%, 90%, 90% and 64%, respectively. Median time from onset to recovery was 30days, but longer in patients without dose interruption. Based on clinical review, no deaths were associated with drug-induced liver injury. Overall, 38% of rechallenged patients had ALT elevation recurrence, with 9-day median time to recurrence. Multivariate analysis showed that older age was associated with development of ALT >8×ULN. There was no correlation between hypertension and transaminitis. Our data support the current guidelines on regular liver chemistry tests after initiation of pazopanib, especially during the first 9 or 10weeks, and also demonstrate the safety of rechallenge with pazopanib., (Copyright © 2015. Published by Elsevier Ltd.)

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.

Background: Pazopanib, an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR)/c-Kit, is approved in locally advanced/metastatic renal cell carcinoma (RCC)., Methods: Data from trials in advanced solid tumours and advanced/metastatic RCC were used to explore the relationships between plasma pazopanib concentrations and biomarker changes, safety, and efficacy. Initially, the relationships between pharmacokinetic parameters and increased blood pressure were investigated, followed by analysis of steady-state trough concentration (Cτ) and sVEGFR2, safety, progression-free survival (PFS), response rate, and tumour shrinkage. Efficacy/safety end points were compared at Cτ decile boundaries., Results: Strong correlation between increased blood pressure and Cτ was observed (r(2)=0.91), whereas weak correlation was observed between Cτ and decline from baseline in sVEGFR2 (r(2)=0.27). Cτ threshold of >20.5 μg ml(-1) was associated with improved efficacy (PFS, P<0.004; tumour shrinkage, P<0.001), but there was no appreciable benefit in absolute PFS or tumour shrinkage from Cτ >20.5 μg ml(-1). However, the association of Cτ with certain adverse events, particularly hand-foot syndrome, was continuous over the entire Cτ range., Conclusions: The threshold concentration for efficacy overlaps with concentrations at which toxicity occurs, although some toxicities increase over the entire Cτ range. Monitoring Cτ may optimise systemic exposure to improve clinical benefit and decrease the risk of certain adverse events.

Purpose: Inactivation of von Hippel-Lindau (VHL) gene in clear-cell renal cell carcinoma (RCC) leads to increased levels of hypoxia-inducible factors (HIF) and overexpression of HIF target genes, such as VEGF and others. VEGF-targeted agents are standard in advanced clear-cell RCC but biomarkers of activity are lacking., Experimental Design: We analyzed tumor tissue samples from metastatic clear-cell RCC patients who received pazopanib as part of clinical trial VEG102616. We evaluated several components of the VHL/HIF pathway: VHL gene inactivation (mutation and/or methylation), HIF-1α and HIF-2α immunohistochemistry staining, and HIF-1α transcriptional signature. We evaluated the association of these biomarkers with best overall response rate (ORR) and progression-free survival (PFS) to pazopanib, a standard first-line VEGF-targeted agent., Results: The VEG102616 trial enrolled 225 patients, from whom 78 samples were available for tumor DNA extraction. Of these, 70 patients had VHL mutation or methylation. VHL gene status did not correlate with ORR or PFS. Similarly, HIF-1α (65 samples) and HIF-2α (66 samples) protein levels (high vs. low) did not correlate with ORR or PFS to pazopanib. The HIF-1α transcriptional signature (46 samples) was enriched in tumors expressing high HIF-1α levels. However, the HIF-1α gene expression signature was not associated with clinical outcome to pazopanib., Conclusions: In patients with advanced clear-cell RCC, several potential biomarkers along the VHL/HIF-1α/HIF-2α axis were not found to be predictive for pazopanib activity. Additional efforts must continue to identify biomarkers associated with clinical outcome to VEGF-targeted agents in metastatic RCC., (©2013 AACR.)

Background: Pazopanib has activity in relapsed non-adipocytic soft-tissue sarcomas (STS). A series of serum cytokines and angiogenic factors (CAFs) at baseline and changes in soluble vascular endothelial growth factor receptor-2 (sVEGFR2) or placental-derived growth factor (PlGF) levels during treatment were explored for their association with outcome., Methods: Twenty-three baseline CAFs, and sVEGFR2 and PlGF changes were measured in 85 and 32 patients, respectively. Associations between baseline CAF levels and efficacy parameters, plus between-week 12 sVEGFR2 and PlGF levels and pazopanib-specific toxicities were investigated., Results: At baseline, low interleukin (IL)-12 p40 subunit and MPC3 levels were associated with better progression-free survival (PFS) at 12 weeks (PFS(12wks)), low basic nerve growth factor and hepatocyte growth factor with a better PFS, and low inter-cellular adhesion molecule-1 and IL-2 receptor alpha with prolonged overall survival (OS; all P<0.05). Pazopanib decreased sVEGFR2 and increased PlGF levels. Low sVEGFR2 and high PlGF levels at week 12 were associated with higher-grade hypertension, with TSH elevations and with poorer PFS(12wks), and OS (both P<0.05)., Conclusion: Several baseline CAFs were related to outcome parameters. Low sVEGFR2 and high PlGF at week 12 associate with several pazopanib-specific toxicities and poorer efficacy. If confirmed, these factors may be used as early markers for response to and toxicity from pazopanib, enabling further individualisation of STS treatment.

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 Gilbert's 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 x upper limit of the normal range (ULN), respectively. Of the 38 patients with hyperbilirubinemia (> or = 1.5 x 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 Gilbert's syndrome, thus supporting continuation of pazopanib monotherapy in this setting.

PURPOSE Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Results Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. CONCLUSION Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.

Purpose: Inactivation of the von Hippel-Lindau gene in clear-cell renal cell carcinomas (RCC) leads to overexpression of hypoxia inducible factor, a transcription factor regulating vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) gene expression. Pazopanib, an angiogenesis inhibitor targeting VEGF receptor, PDGF receptor, and c-KIT, was evaluated in patients with RCC., Patients and Methods: This phase II study was designed as a randomized discontinuation study but was revised to an open-label study on the recommendation of the data monitoring committee (based on week 12 response rate [RR] of 38% in the first 60 patients). The primary end point was changed from progressive disease rate at 16 weeks postrandomization to RR. Pazopanib 800 mg was administered orally once daily. Pazopanib 800 mg was administered orally once daily., Results: The study enrolled 225 patients with metastatic RCC; 155 patients (69%) were treatment naïve, and 70 patients (31%) had received one prior cytokine- or bevacizumab-containing regimen. Overall RR was 35%; median duration of response was 68 weeks. Median progression-free survival (PFS) was 52 weeks. Eastern Cooperative Oncology Group performance status of 0 and time from diagnosis to treatment of more than 1 year were correlated with prolonged PFS. Pazopanib was generally well tolerated. The most common adverse events were diarrhea, fatigue, and hair depigmentation. The most common laboratory abnormalities were elevated AST and ALT., Conclusion: Pazopanib demonstrated durable activity in patients with advanced RCC and was generally well tolerated in this population. These findings support the further development of pazopanib in advanced RCC.

PURPOSE Given the importance of angiogenesis in soft tissue sarcoma (STS), pazopanib, an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptor and platelet-derived growth factor receptor, was explored in patients with advanced STS. PATIENTS AND METHODS Patients with intermediate- or high-grade advanced STS who were ineligible for chemotherapy or who had received no more than two prior cytotoxic agents for advanced disease, who had documented progression, who had adequate performance status, and who had good organ function were eligible. Pazopanib 800 mg was given daily. The primary end point was progression-free rate at 12 weeks (PFR(12 weeks)). Secondary end points were response, safety, and overall survival. Four different strata were studied: adipocytic STS, leiomyosarcomas, synovial sarcomas, and other STS types. A Simon two-stage design was applied (P1 = 40%; P0 = 20%; alpha = beta = .1) for each stratum. Results One hundred forty-two patients were enrolled. The adipocytic STS stratum was closed after the first stage, given insufficient activity (PFR(12 weeks), five [26%] of19). PFR(12 weeks) was 18 (44%) of 41 patients in the leiomyosarcoma cohort, 18 (49%) of 37 in the synovial sarcomas, and 16 (39%) of 41 in the other STS types. Compared with historical controls who were treated with second-line chemotherapy, progression-free and overall survivals were prolonged in the three cohorts in which the primary end point was reached. The most frequent drug-related toxicities were hypertension, fatigue, hypopigmentation, and nausea. Other toxicities included liver enzyme elevations, myelosuppression, and proteinuria, all of which were mostly grades 1 to 2. The most frequent grades 3 to 4 toxicities were hyperbilirubinemia (6.3%), hypertension (7.7%), and fatigue (7.7%). CONCLUSION Pazopanib is well tolerated in patients with relapsed, advanced STS and demonstrates interesting activity that warrants additional study in patients with leiomyosarcomas, synovial sarcomas, and other STS types.

Purpose: The safety, pharmacokinetics, and clinical activity of pazopanib (GW786034), an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, were evaluated in patients with advanced-stage refractory solid tumors., Experimental Design: Patients were enrolled into sequential dose-escalating cohorts (50 mg three times weekly to 2,000 mg once daily and 300-400 mg twice daily). Escalation or deescalation was based on toxicities observed in the preceding dose cohort. Pharmacokinetic and biomarker samples were obtained. Clinical response was assessed every 9 weeks., Results: Sixty-three patients were treated (dose escalation, n = 43; dose expansion, n = 20). Hypertension, diarrhea, hair depigmentation, and nausea were the most frequent drug-related adverse events, the majority of which were of grade 1/2. Hypertension was the most frequent grade 3 adverse event. Four patients experienced dose-limiting toxicities at 50 mg, 800 mg, and 2,000 mg once daily. A plateau in steady-state exposure was observed at doses of >or=800 mg once daily. The mean elimination half-life at this dose was 31.1 hours. A mean target trough concentration (C(24)) >or=15 microg/mL (34 micromol/L) was achieved at 800 mg once daily. Three patients had partial responses (two confirmed, one unconfirmed), and stable disease of >or=6 months was observed in 14 patients; clinical benefit was generally observed in patients who received doses of >or=800 mg once daily or 300 mg twice daily., Conclusion: Pazopanib was generally well tolerated and showed antitumor activity across various tumor types. A monotherapy dose of 800 mg once daily was selected for phase II studies.