Occurrence of hepatotoxicity with pazopanib and other anti-VEGF treatments for renal cell carcinoma: an observational study utilizing a distributed database network

Pazopanib is a tyrosine kinase inhibitor indicated for the treatment of advanced renal cell carcinoma (RCC) and advanced soft tissue sarcoma. Prior to US Food and Drug Administration (FDA) approval of pazopanib for RCC in 2009, hepatotoxicity was observed in clinical trials, including two fatalities [1]. This led to a black box warning in the product label regarding liver safety and monitoring [2].

Pazopanib works in part by targeting tyrosine kinase inhibitors (TKIs) of vascular endothelial growth factor (VEGF) receptors. Other related medications indicated for RCC include the TKIs sunitinib and sorafenib as well as bevacizumab, an anti-VEGF monoclonal antibody [3]. Elevations in liver chemistry (LC) tests including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and bilirubin have been found not only with pazopanib [1, 4, 5], but also in some studies with bevacizumab [6, 7], sunitinib [4, 8] and sorafenib [4, 9]. Similar to pazopanib, a boxed warning regarding hepatotoxicity exists for sunitinib [10]. As part of post-approval regulatory commitments for pazopanib, a post-marketing safety study was conducted in three electronic medical record (EMR) databases to examine the incidence of hepatotoxicity in RCC patients treated with pazopanib or comparator anti-VEGF drugs.

This population-based retrospective cohort study used a distributed data network that included data from three EMR databases: Altos, the US Department of Veterans Affairs Veterans Health Administration System (VA), and PHARMO Database Network. Altos contains EMR data for over 400,000 cancer patients seen in 150 outpatient oncology practices serving more than 1000 clinicians in the USA. Data obtained for each patient visit include diagnoses and treatment prescribed by or administered in the oncology clinic. Laboratory results are available through an automated link from the clinical laboratory. The VA is a national, integrated healthcare system with longitudinal clinical data for more than 12 million veterans during the most complete era of electronic data capture. Data on inpatient and outpatient encounters, procedures, all inpatient and outpatient medications, and all laboratory tests are available spanning 13 years. In addition, data on cause-specific mortality are available for all veterans. The Dutch-based PHARMO Institute has access to the PHARMO Database Network serving more than three million residents in The Netherlands. The database includes information on patient demographics, drug dispensing, hospital morbidity, clinical laboratory, pathology and general practitioner information.

Across the three databases, a common protocol was implemented by a coordinating center to ensure that patient selection and methodology were consistent within each database. New adult (18+ years) users of pazopanib, bevacizumab, sorafenib, or sunitinib with a diagnosis of RCC (ICD-9 codes 189.0 or 189.1) were identified from the earliest date of availability of pazopanib in the each health system (October 1, 2009, in the USA; February 1, 2011, in The Netherlands) through February 17, 2013 (6 weeks prior to the study end date of March 31, 2013). Because many patients beginning cancer treatment may be new to the oncology practice, no minimum duration of enrollment in the healthcare database was required prior to the drug start date. Included patients had at least one ALT and bilirubin measurement within 30 days before or on the drug start date to allow a comparison between drug initiation (baseline) and follow-up laboratory values. Patients prescribed more than one anti-VEGF agent concurrently were excluded, but patients could use more than one anti-VEGF agent during different time periods. Use of other antineoplastic treatments was permitted.

A total of 156 pazopanib initiators in the Altos database and 243 in the VA qualified for the analysis. Pazopanib prescription in the PHARMO Database Network lagged considerably behind the US-based data sources, due in part to later reimbursement, formulary approval and availability of the drug in The Netherlands (February 2011), with only three pazopanib initiators identified by the end of the study period. This database was therefore excluded from the present analyses. Pazopanib was used for a mean duration of 4.2 months in Altos and 10.3 months in the VA population. The mean age was 65.1 years for Altos and 68.1 for the VA cohort; 64.2 and 98.3 % of patients were male in Altos and the VA, respectively (Table 1). Pazopanib was prescribed as first-line therapy for 38.5 % of Altos patients and 71.6 % of patients in the VA.

Overall, the number of patients with ALT ≥3x ULN ranged from 3 to 23 across the anti-VEGF cohorts, corresponding to an incidence rate of 6.5–25.9 per 100 person-years (py); the highest rates were observed among pazopanib-treated patients from the VA (Table 2). Few cases (range 0–4) of ALT ≥8x ULN were seen across the anti-VEGF cohorts, resulting in an incidence rate of 0–8.2 per 100 py. Rates of bilirubin elevation ≥2x ULN ranged from 2.6 to 11.9 per 100 py (range 1–30 cases), with the highest rates found among the patients from the VA treated with sorafenib or sunitinib. The median time to onset of these liver events varied substantially across the anti-VEGF cohorts (Table 3).

There was no discernible pattern in the variation of incidences for the first-line setting (Table 4) compared to the second-line setting (Table 5), aside from a drop in the incidence rate for most measures of ALT or bilirubin elevation among the pazopanib-treated cohort in both the Altos and VA databases. The exception was a greater incidence rate (per 100 py) of bilirubin ≥2x ULN in the second-line setting compared to the first-line setting, respectively, for pazopanib users in Altos (9.3, 6.3) and the VA (8.1, 5.4).

No cases of Hy’s law identified by combination LC elevations were seen in patients treated with pazopanib or bevacizumab; three cases were observed in those treated with sorafenib (n = 1) and sunitinib (n = 2) at the VA. Among the VA population, one case of adjudicated DILI, as captured by ICD-9 codes, was found in a sunitinib-treated patient. No adjudicated case of DILI was seen among patients treated with pazopanib, bevacizumab or sorafenib.

Results from this study show that severe liver injury occurred infrequently during pazopanib exposure in a population-based, real-world setting. Further, no combinations of LC elevations meeting the laboratory definition of Hy’s law were observed in all pazopanib-exposed patients from either database, and no pazopanib-related adjudicated DILI outcomes were identified among more than 300 RCC patients accrued in the VA. Few liver toxicity events were identified among patients using the other anti-VEGF agents.

Liver toxicity among pazopanib users was less frequently reported in the present population-based study compared to a recent report of 1149 pazopanib-treated RCC patients from nine prospective clinical trials [1]. Among the trial participants, 23 % of patients developed elevated ALT >3x ULN compared to 4.6 % of patients in the Altos population and 11.4 % among VA patients for ALT ≥3x ULN. Further, the cumulative incidence of severe liver toxic was higher among clinical trial patients (ALT >8x ULN, 8.4 %) compared to the Altos (1.9 %) and VA (1.0 %) population (ALT ≥8x ULN). It is possible that transient or asymptomatic LC elevations were missed in the present study of real-world patients where liver monitoring may be less rigorous compared to a trial setting.

Several factors are potential limitations in this study. Small numbers of patients in several analytic groups, including line of therapy, led to some imprecise estimates. Advanced RCC could not be identified separately from total kidney cancers; metastases may be underreported, especially in the Altos database. Exposure time to oral medications, including pazopanib, imputed from dates for orders and refills may be imprecise, resulting in inaccurate computation of person-time used in the incidence rate calculations. It is also possible that some pazopanib users were not new users on the drug start date, if prior pazopanib prescriptions did not appear in the database, leading to an underestimate for the rate of LC elevations during treatment. In the Altos population, serious liver events resulting in hospitalization and LC elevations measured outside the oncology practice EMR could not be captured, unless the information was manually entered into the EMR database, thus potentially underestimating the rate of severe LC elevations. The VA database included hospital data and can therefore allow for fuller capture of patient experiences, although patients who received medical care outside of the VA system may also have had missing LC test results. It is possible the ICD-9 codes used for screening potential cases of DILI in the VA population may be inaccurate.

This population-based study has a number of strengths. Patients come from real-world oncology settings, allowing for more generalizable results compared to clinical trial populations. The EMR contains data from usual clinical practice, with issues such as dosing and adherence uninfluenced by a trial protocol. EMRs provide longitudinal data allowing for better capture of events compared to reliance on individual spontaneous adverse event reports. The study period duration of clinical trials is generally short compared to the present study with more extensive follow-up time for observing LC elevations. This study allows for comparison of LC elevations among a large number of patients with the same indication across different comparator drugs and multiple healthcare databases with diverse patient populations. The chart review and adjudication process by a panel of three physicians allowed for careful assessment of suspected DILI events in the VA population; this approach represents a gold standard of outcome ascertainment in retrospective studies.

Current post-marketing surveillance of pazopanib and other anti-VEGF drugs in RCC patients showed a relatively low frequency of serious liver events for approximately 4 years of data collection. More data are needed to estimate the rates of DILI or liver failure in pazopanib users. Understanding the incidence of severe liver injuries in RCC patients newly using pazopanib and other marketed anti-VEGF agents in real-world clinical practice helps inform patients’ hepatic safety profile.