Pazopanib in the treatment of advanced renal cell carcinoma

Abstract

Pazopanib is an orally available multitargeted tyrosine kinase inhibitor (a class of targeted therapies) that inhibits tumor angiogenesis and cell proliferation. The safety and efficacy of pazopanib (noninferior to sunitinib for progression-free survival) in patients with advanced or metastatic renal cell carcinoma (mRCC) have been demonstrated in several clinical trials. However, in addition to therapeutic efficacy, treatment choices should also take into account health-related quality of life (HRQoL) aspects of cancer therapy. Here, we summarize the HRQoL findings related to pazopanib use, based on patient-reported outcome measures; pazopanib has been shown to be superior to sunitinib on several HRQoL domains (including patient preference). A further consideration for treatment choice is how well the findings from clinical trials correlate with evidence from general clinical practice. This review therefore includes descriptions of real-world experience of pazopanib use in the treatment of patients with mRCC, following its approval by medical regulatory authorities in a number of countries. Naturalistic observational studies demonstrate that the efficacy of pazopanib in patients with mRCC is consistent with clinical trial findings. Similarly, consistent results were observed for the safety profile of pazopanib between observational studies and clinical trials, with most treatment-associated adverse events being mild to moderate in severity, and manageable.

Introduction

Renal cell carcinoma (RCC) is the most common tumor type that originates in the kidney, with 85% of RCC tumors classified as clear-cell subtype [National Comprehensive Cancer Network, 2015]. The 5-year relative survival rate for patients diagnosed with advanced or metastatic RCC (mRCC) is discouraging, at only 12.1% according to the Surveillance, Epidemiology, and End Results Program database for the period 2004–2010 [National Cancer Institute, 2014]. Over the past few years, the introduction of molecular ‘targeted therapies’ (TTs), referring to drugs that target pathways in the growth and development of a tumor cell, has greatly improved the prognosis of patients with mRCC. These TTs include small-molecule tyrosine kinase inhibitors (TKIs) (sorafenib, sunitinib, pazopanib, and axitinib), mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus), and an anti-angiogenic antibody (bevacizumab, usually in combination with interferon alpha) [National Comprehensive Cancer Network, 2015]. Pazopanib (Votrient^®) is an orally available multi-TKI that has been approved for the treatment of mRCC in many regions worldwide including the USA (2009) [GlaxoSmithKline, 2014], Europe (2010, first line and in patients who have received prior cytokine therapy) [Novartis Europharm Limited, 2015], and Australia (2010) [Novartis Pharmaceuticals Australia Pty Limited, 2015]. Pazopanib binds to and inhibits kinase receptors involved in tumor cell angiogenesis and proliferation, such as vascular endothelial growth factor (VEGF) receptors, platelet-derived growth- factor receptors, and the stem cell-factor receptor c-Kit. This results in the inhibition of angiogenesis, and cell growth and survival, thereby preventing tumor growth and proliferation [Pick and Nystrom, 2012].

The therapeutic efficacy of pazopanib in patients with mRCC has primarily been demonstrated in three phase III randomized controlled trials: the VEG105192 [Sternberg et al. 2010] and COMPARZ trials [Motzer et al. 2013], and a crossover trial (PISCES) investigating patient preference [Escudier et al. 2014]. In the VEG105192 double-blind efficacy trial, treatment-naïve or cytokine-pretreated patients received either pazopanib 800 mg once daily or placebo [Sternberg et al. 2010]. The study reported a significant improvement in median progression-free survival (PFS) with pazopanib compared with placebo in the overall study population (9.2 months versus 4.2 months), treatment-naïve population (11.1 months versus 2.8 months), as well as the cytokine-pretreated subpopulation (7.4 months versus 4.2 months). The objective response rate (ORR) with pazopanib was 30% versus 3% with placebo [Sternberg et al. 2010]. No statistical difference in overall survival (OS) was observed between patients treated with pazopanib (22.9 months) and placebo (20.5 months); however, these results were confounded by early and extensive crossover of placebo-treated patients to pazopanib and prolonged duration of crossover treatment [Sternberg et al. 2013]. Pazopanib demonstrated a tolerable safety profile with the most common (incidence of > 20%) adverse events (AEs) being diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting [Sternberg et al. 2010]. In total, 14% of patients on pazopanib discontinued the study due to AEs. In an extension study (VEG107769), 79 patients who had disease progression while on placebo in study VEG105192 went on to receive pazopanib [Sternberg et al. 2014]. At the time of analysis, all patients had discontinued pazopanib, with the most common reason for discontinuation being disease progression. The most common AEs were hypertension, diarrhea, hair color changes, anorexia, and nausea (incidence ranging from 25% to 45%). The ORR was 37.5% and median PFS was 9.2 months, while median OS was 23.5 months. Results of this extension study of patients with mRCC previously treated with placebo demonstrated that the efficacy and safety profiles for pazopanib were very similar to those observed for pazopanib-treated patients in the pivotal VEG105192 study [Sternberg et al. 2014].

The open-label, noninferiority COMPARZ trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy in 1110 patients with clear-cell mRCC [Motzer et al. 2013]. The noninferiority of pazopanib to sunitinib was demonstrated based on the independent review committee-assessed PFS (8.4 months versus 9.5 months, respectively). In an updated report, OS was found to be similar in both the pazopanib and sunitinib groups (28.3 months versus 29.1 months) [Motzer et al. 2014]. More patients treated with pazopanib had increased levels of alanine aminotransferase (60% versus 43%), while more patients receiving sunitinib had (all-grade) fatigue (63% versus 55%), hand–foot syndrome (50% versus 29%), and thrombocytopenia (78% versus 41%) compared with patients receiving pazopanib. In total, 24% of patients in the pazopanib group discontinued the study because of AEs [Motzer et al. 2013].

The phase IIIb PISCES trial was a double-blind, crossover study evaluating patient preference for sunitinib or pazopanib [Escudier et al. 2014]. Patients with mRCC were randomly assigned to pazopanib 800 mg/day for 10 weeks, then a 2-week washout followed by sunitinib 50 mg/day for 10 weeks (4 weeks on, 2 weeks off, 4 weeks on), or the reverse sequence. Although this study was not designed to compare efficacy, the ORR was similar for sunitinib (21%) and pazopanib (19%) in the first treatment period; assessment of efficacy was limited by the inclusion of patients with nonmeasurable and nonclear-cell disease as well as the small study sample. Diarrhea, fatigue, and nausea were the most common AEs reported with either drug (all-grade incidence ranging from 29% to 42%) [Escudier et al. 2014]. This study also demonstrated a significant patient preference for pazopanib versus sunitinib based on their differential effects on health-related quality of life (HRQoL) (discussed below), and occurrence of AEs.

Aside from evidence for efficacy and safety in clinical trials, it is important to consider which other factors may influence the use of pazopanib in general clinical practice. In recent years, patient-reported outcomes (PRO) of symptom benefit or HRQoL endpoints have become important considerations. In the context of long-term treatment, consideration of patient preference and HRQoL become very important [Mitchell and Parikh, 2014]; although they are related to efficacy and safety endpoints, they cannot be accurately estimated or understood without directly asking patients. Another consideration for treatment choice is the evidence of efficacy outside the clinical trial setting. In this review we address both of these factors. Following an overview of studies describing HRQoL findings in relation to pazopanib treatment, we describe efficacy outcomes, persistence and compliance, and treatment patterns among the wider population by discussing experience outside the clinical-trial context.

HRQoL outcomes

In the VEG105192 study, the following instruments were used to assess HRQoL in patients with mRCC receiving pazopanib or placebo: EuroQoL-5D questionnaire (EQ-5D), the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) scales, and the EQ-5D visual analog scale [Sternberg et al. 2010]. The results showed that there was no significant difference in HRQoL between pazopanib and placebo treatments over the course of the 48-week evaluation period for the three HRQoL assessments. A subsequent post hoc analysis was carried out to evaluate time to HRQoL deterioration and whether tumor response/stabilization was associated with HRQoL improvement [Cella et al. 2012]. The analysis demonstrated that both treatment-naïve and cytokine-pretreated patients receiving pazopanib tended to have a lower risk of experiencing at least 20% HRQoL deterioration in EORTC QLQ-C30 global health status/QoL scale than the placebo group (hazard ratio = 0.77, 95% confidence interval [CI]: 0.51–1.03); however, these differences were not statistically significant. Based on the EORTC QLQ-C30 global health status/QoL scale, an association between changes in HRQoL and clinical response was observed: patients whose best response was ‘complete or partial response’ (CR/PR) or ‘stable disease’ (SD) experienced significantly less HRQoL deterioration compared with patients whose best response was ‘progressive disease’ (p < 0.001 and p = 0.0024, respectively). Similarly, patients whose best response was CR/PR experienced less deterioration of HRQoL than patients with SD (p = 0.012). Results were found to be generally consistent within treatment arms and for EQ-5D summary scores. Therefore, in addition to the significantly prolonged PFS and generally well-tolerated safety profile previously reported for pazopanib, the benefit of pazopanib is further supported by evidence in this study that HRQoL is not compromised, compared with placebo treatment [Cella et al. 2012].

HRQoL was also assessed in the COMPARZ trial evaluating pazopanib versus sunitinib [Motzer et al. 2013], using the following instruments: Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) [Cella et al. 2002], the Functional Assessment of Cancer Therapy (FACT) Kidney Symptom Index (FKSI-19) [Rao et al. 2009], which evaluated cancer symptoms, the Cancer Therapy Satisfaction Questionnaire [Trask et al. 2008], and the Supplementary Quality of Life Questionnaire (SQLQ), a customized questionnaire tailored to the expected major side effects of treatments of the COMPARZ trial such as mouth/throat and hand/foot soreness symptoms and related functional limitations. The SQLQ, now known as the Hand–foot and Mucositis Symptom and Impact Questionnaire (HAMSIQ), is part of the FACIT measurement system [FACIT, 2015], and has been shown to be a feasible, valid, reliable and responsive instrument for assessing the impact of hand–foot and mucositis symptoms in patients receiving TKIs [Lai et al. in press]. During the first 6 months of treatment, HRQoL scores for the pazopanib group were better than those in the sunitinib group in 11 out of 14 HRQoL domains (p < 0.05 for all 11 comparisons), particularly those related to fatigue or soreness in the mouth, throat, hands, or feet. These analyses demonstrated that patients receiving pazopanib had less fatigue, fewer side effects (e.g. soreness of the hand or foot, and soreness of the mouth or throat), and better satisfaction with treatment than patients who received sunitinib, consistent with reported AE results [Motzer et al. 2013]. Post hoc analysis of up to 12 months of treatment demonstrated an increase in treatment differences for fatigue scores, with sunitinib scores remaining relatively unchanged but pazopanib scores improving [Cella et al. 2013]. Similarly, the difference in limitations due to foot soreness between the two treatments (favoring pazopanib) also increased over 12 months. These results indicate that patients on pazopanib experienced less worsening of fatigue, as well as less mouth/throat, hands, and feet soreness, and fewer limitations due to soreness, compared with patients receiving sunitinib.

Subsequent post hoc analyses of COMPARZ data evaluated overall treatment differences using the quality-adjusted time without symptoms of progression or toxicity of treatment (Q-TWiST) analysis [Beaumont et al. 2014]. Q-TWiST examines OS in terms of time spent with grade 3/4 toxicity, time without symptoms of progression or toxicity, and time after progression or relapse. Time spent in each state was weighted by a health-state utility associated with that state (where 0 = close to death and 1 = perfect health); Q-TWiST was calculated as the sum of these values. Patients randomized to pazopanib (n = 557) had slightly longer Q-TWiST compared with patients who received sunitinib (n = 553); this was largely due to patients in the pazopanib group having fewer days with grade 3/4 toxicities compared with the sunitinib group [Beaumont et al. 2014].

In the patient preference crossover (PISCES) study, HRQoL was evaluated in patients receiving pazopanib and sunitinib using the FACT-Fatigue (FACT-F) and the HAMSIQ [Escudier et al. 2014] In this study, a statistically significant difference in mean fatigue score (using the FACT-F) was observed, favoring pazopanib over sunitinib (p = 0.002). Based on the HAMSIQ, treatment differences between pazopanib and sunitinib in worst mouth/throat soreness (p < 0.001), hand soreness (p = 0.026), worst foot soreness (p = 0.005), limitations as a result of mouth/throat soreness (p < 0.001), and limitations as a result of foot soreness scores (p = 0.003) significantly favored pazopanib. These assessments showed that patients treated with pazopanib experienced less mouth/throat, hand and foot soreness, and limitations due to these symptoms compared with sunitinib [Escudier et al. 2014]. The results of these assessments were highly consistent with those from the COMPARZ study [Motzer et al. 2013].

Patient preference

In parallel to PROs, patient preference for a particular treatment is an important consideration when it comes to therapy choice and could impact on persistence and adherence. The PISCES trial was specifically designed with a unique early crossover design to allow patients to express their preference for pazopanib or sunitinib [Escudier et al. 2014]. All patients were scheduled to receive both drugs sequentially over a 5-month period, then to choose which they preferred. Out of 169 treatment-naïve patients, significantly more patients (p < 0.001) preferred pazopanib (70%; 95% CI 60.9–78.4), compared with sunitinib (22%; 95% CI 14.7–30.6), while 8% expressed no preference [Escudier et al. 2014]. The most common reasons for preferring pazopanib included better overall QoL and less fatigue, whereas the most common reason for preferring sunitinib was less diarrhea [Escudier et al. 2014]. In alignment with patient preference, more physicians preferred to continue their patients on pazopanib (61%) than sunitinib (22%) while 17% had no preference [Escudier et al. 2014].

As noted, pazopanib had performed significantly better than sunitinib in QoL measures evaluating fatigue, hand/foot soreness, and mouth/throat soreness [Escudier et al. 2014]. In previous studies, patients with RCC ranked fatigue/tiredness as the most troublesome tolerability effect of treatment [Mohamed et al. 2011; Wong et al. 2012], therefore less fatigue associated with pazopanib may contribute to patient preference for it. Diarrhea was the most common AE for both therapies (42% with pazopanib and 32% with sunitinib), and hypertension was the most common grade 3/4 AE with both treatments (8% with pazopanib and 9% with sunitinib).

Use of pazopanib outside clinical trials

The efficacy of pazopanib is well established in clinical trials but the question of clinical experience outside controlled trials is less clear. The observational studies described below are limited to those where pazopanib was used as first-line treatment (or second line after cytokine therapy) in accordance with the licensed indications. However, some studies have been published that detail the use of pazopanib as second-line, or even third-line treatment, to another TT [Matrana et al. 2013a; Schmidinger et al. 2012; Tan et al. 2012; Yick et al. 2015]. These studies are not included in this review.

Efficacy and safety

Consistent with guideline treatment recommendations, the majority of real-world studies identified evaluated efficacy and safety of pazopanib in a first-line setting. In a study involving 31 centers in Spain, 159 patients with mRCC who had received pazopanib during the first 18 months following its approval, were retrospectively reviewed to examine its use and efficacy [Sanchez et al. 2013]. At diagnosis, 78.6% and 71.7% of patients were of good/intermediate risk (Memorial Sloan Kettering Cancer Center [MSKCC] and Heng criteria, respectively). Pazopanib was used as first- and second-line treatment in 81 (50.9%) and 32 (20.1%; in most cases given after sunitinib) patients, respectively, or as third-line treatment (or greater) in 46 (29%) patients. When used as first-line treatment, there were statistically significant differences in outcomes between risk subgroups in terms of median time to treatment failure (10 months versus 6 months for good/intermediate [n = 60] and poor [n = 21] risk, respectively) and 1-year OS (74% versus 55% for good/intermediate and poor risk, respectively). Thus in daily clinical practice, pazopanib appeared to be as effective for first-line treatment in patients with good/intermediate risk as it was in clinical trials. Pazopanib also showed efficacy in patients with poor risk, as second-line treatment (particularly after disease progression or intolerance to sunitinib), and following treatment with two or more TKIs. Safety findings were as expected [Sanchez et al. 2013].

A number of retrospective observational studies have also been carried out in Italy. Although small, two studies found pazopanib had similar efficacy to that demonstrated in COMPARZ and showed treatment-associated AEs were manageable [Germone, 2014; Ricotta and Di Bella, 2014]. In the first study, 11 out of 15 patients with mRCC receiving pazopanib achieved a PR after 3 months of therapy while three had SD [Germone, 2014]. The median PFS of 10.5 months was similar to that of the COMPARZ study (8.4 months). In the second study, eight of nine patients with mRCC receiving pazopanib had disease control, and a PR was reported for two of them. The median PFS was 9.9 months (95% CI 9.45–10.4). In both studies, the AEs reported were mostly mild or moderate (with a profile consistent with clinical trial-based results) with the most frequent being diarrhea, fatigue, hypertension, and nausea. These results suggest that treatment with pazopanib in daily clinical practice is feasible and is associated with a manageable toxicity profile and efficacy similar to that observed in the experimental setting [Germone, 2014]. Another study from Italy involving 21 centers evaluated 269 patients with late relapsing RCC (more than 5 years after initial nephrectomy) [Santoni et al. 2015]. These patients were treated with the following TKIs between January 2005 and July 2013 pazopanib (n = 21, 8%), sunitinib (n = 190, 71%), or sorafenib (n = 58, 21%) as first-line therapy at recurrence. Median PFS was 20.0 months for sunitinib and 14.1 months for both sorafenib and pazopanib. There was no significant difference between treatments in terms of median OS, PFS, or disease control rate suggesting that the efficacy of the three treatments was equivalent among this cohort [Santoni et al. 2015].

In a study conducted by the Christie National Health Services Foundation Trust in the UK, 104 patients with mRCC who had been treated with pazopanib were evaluated [Galvis et al. 2013]. The patients were described as generally frail, elderly, and had comorbidities that reflected the mRCC patient population. OS and PFS for the whole population were 19 and 13 months, respectively. OS for the favorable/intermediate prognostic groups (according to MSKCC criteria) was not reached (NR)/12 months while PFS was 25/17 months. For the favorable/intermediate prognostic groups as assessed according to Heng criteria, OS was NR/12 months while PFS was NR/25 months. These survival data were similar to that reported in clinical trials. All patients experienced treatment-related AEs and 16 (15%) patients discontinued pazopanib due to toxicity. No statistical difference in the discontinuation rate due to toxicity was observed in the different prognostic groups (favorable, intermediate, and poor according to MSKCC and Heng criteria); pazopanib treatment was generally well tolerated with discontinuation rates similar to clinical trial data [Galvis et al. 2013].

In a study from the MD Anderson Cancer Center in the USA, records of 100 patients with mRCC treated with first-line pazopanib (between 2009 and 2012) were retrospectively reviewed [Matrana et al. 2013b]. Median OS and PFS for all patients were 32.3 months (95% CI 23.3–NA) and 11.5 months (95% CI 8.13–17.1), respectively; PFS for patients with clear-cell carcinoma (87%) was 13.7 months (95% CI 8.16–18.3). AEs were mainly grade 1/2 (88%) and overall, the most frequently reported included fatigue (55%), diarrhea (36%), hypertension (26%), nausea/vomiting (25%), anorexia (20%), and increased liver function tests (LFTs) (16%). At the time of study analysis, 32% of patients were still receiving pazopanib; 48% and 9% had discontinued pazopanib due to progressive disease and AEs (mainly increased LFTs), respectively. This retrospective observational study supports the efficacy and manageable toxicity profile of first-line pazopanib in mRCC [Matrana et al. 2013b].

In another study from the USA, the outcomes of first-line pazopanib, and pazopanib followed by mTOR inhibitors (everolimus or temsirolimus), were retrospectively evaluated in patients with advanced RCC in a community oncology setting [Vogelzang et al. 2015]. Analysis of eligible patients (treated between 1 November 2009 and 31 August 2012) in the US iKnowMed electronic health records database showed that the median OS and PFS in patients who had received pazopanib as first-line therapy (n = 177) was 22 months (95% CI 16.9–not computed) and 8.5 months (95% CI 7.1–11.2), respectively. Significant differences in median OS (p < 0.001) were associated with Eastern Cooperative Oncology Group Performance Status (ECOG PS; 0 versus 1; 31.9 versus 12.4 months, respectively) and previous nephrectomy (yes versus no; 28.2 versus 13.4 months, respectively). Significant differences in median PFS were also associated with ECOG PS (0 versus 1, 11.1 versus 7.2 months, respectively; p < 0.007), but not with previous nephrectomy. Cox analyses demonstrated that decreased OS and the risk of disease progression were significantly associated with poorer baseline ECOG PS (p < 0.002 and p = 0.047, respectively). The most common toxicities were fatigue (56%), diarrhea (52%), vomiting (44%), and nausea (40%). Median treatment duration was 151 days, with most of the patients not requiring dose adjustments, and low usage of healthcare resources. In total, 125 patients discontinued pazopanib during the study period, due primarily to disease progression. For patients who had received pazopanib followed by everolimus (n = 24) or temsirolimus (n = 11), median OS and PFS was 16 months and 5.7 months, respectively, with fatigue (51%) and nausea (34%) being the most common AEs. The results of this study suggest that the clinical and safety outcomes of patients with advanced RCC treated with first-line pazopanib in a real-world setting are generally consistent with those observed in other real-world studies as well as clinical trials [Vogelzang et al. 2015].

While the majority of naturalistic observational studies support the findings of the clinical trials, one retrospective, multicenter registry of patients with mRCC in two US centers suggests that clinical trial safety data may not reflect patient experience outside clinical trials [Hirsch et al. 2014]. Treatment data for 466 patients who received first-line therapy (sunitinib [n = 275], temsirolimus [n = 60], sorafenib [n = 53], pazopanib [n = 25], and ‘other’ [n = 58]) from 2007 to 2011 in either an academic (Duke University Medical Center) or community (ACORN Research) setting were analyzed. Based mainly on results drawn from the cohort of patients receiving sunitinib (as it was the most frequently used TT), this study illustrated that the frequency and severity of AEs that occur after drug approval in the setting of everyday practice may differ significantly from those observed in controlled clinical trials, thus demonstrating the need for patients to be monitored closely to allow their AEs to be managed for an optimal outcome [Hirsch et al. 2014]. In patients receiving pazopanib, frequently reported AEs included fatigue (64%), diarrhea (48%), and vomiting (60%). A higher incidence of fatigue and vomiting but lower incidence of diarrhea were observed compared with the COMPARZ clinical trial: fatigue (55%), diarrhea (63%), and vomiting (28%) [Motzer et al. 2013].

Persistence and compliance

Aside from efficacy and safety, persistence and compliance are also important considerations in the choice of treatments for patients with mRCC. In two studies from the USA, these have been evaluated using information from medical claims databases. A retrospective claims analysis of two databases (Optum Research Database and Impact National Benchmark Database) compared the real-world persistence and compliance of patients with mRCC receiving pazopanib with those receiving sunitinib [DaCosta Byfield et al. 2015]. Adults with more than two RCC diagnoses and evidence of first-line therapy with at least one pharmacy claim for pazopanib or sunitinib (October 2009–July 2012) were eligible for inclusion. In total, 84 matched pairs were identified from 446 patients receiving pazopanib (n = 97) and sunitinib (n = 349). This analysis demonstrated a similar persistence and compliance with pazopanib and sunitinib during the first 6 months of treatment [DaCosta Byfield et al. 2015]. Similarly, another retrospective, observational study in the USA using the Truven Health MarketScan databases examined pazopanib persistence and adherence in treatment-naïve patients (n = 62) and previously treated patients (n = 81) [Hackshaw et al. 2014]. Both cohorts demonstrated high compliance and high persistence with more than 50% of patients receiving continuous pazopanib for 90 days [Hackshaw et al. 2014]. In this study, the median treatment duration was 111.5 days in patients receiving first-line pazopanib and 123.0 days in previously treated patients [Hackshaw et al. 2014]; this is shorter than that seen in the VEG105192 and COMPARZ studies [Motzer et al. 2013; Sternberg et al. 2010].

Treatment patterns

Following on from the approval of pazopanib and subsequent use in the clinic, a number of studies have evaluated the treatment patterns of mRCC. A study carried out in nine oncology sites in Belgium investigated the use of first-line therapies for the treatment of mRCC between October 2009 and November 2012 [Cornelis et al. 2014]. For 96 patients, the following were prescribed as first-line therapies: sunitinib (43%), pazopanib (33%), temsirolimus (14%), everolimus (7%), and sorafenib (3%). This demonstrated that in accordance with guidelines for RCC treatment, TKIs were first-line treatment choice (with pazopanib being the second most frequently prescribed) for the majority of patients [Cornelis et al. 2014]. In the USA, a retrospective cohort analysis of de-identified Truven Health MarketScan medicare supplemental claims data examined real-world treatment patterns and healthcare utilization of TTs for RCC [Harnett et al. 2015]. By evaluating treatment-naïve patients with RCC receiving sunitinib or pazopanib, the impact of treatment schedules on persistence was assessed. Eligible patients were adults with RCC with more than one prescription for sunitinib or pazopanib between October 2009 and September 2013; 291 patients who initiated sunitinib (76.6%) and pazopanib (23.4%) were identified. No significant differences in treatment persistence and costs for patients with RCC receiving sunitinib or pazopanib were demonstrated [Harnett et al. 2015]. In another study from the USA, a comparison of treatment patterns of patients with mRCC receiving a second TT following a first TKI was carried out using two retrospective chart review studies performed in 2012 (n = 306) and 2014 (n = 1173) [Perez et al. 2015]. Of the first-line TTs, sunitinib was the most frequently prescribed treatment (74% in both years) and the prescription of pazopanib increased over time (10–13%). As a second-line treatment, everolimus remained the most prescribed TT in both years (49% and 28%), but use of axitinib and sorafenib increased from 2012 to 2014 (from 3% to 11% and from 7% to 22%, respectively). This study showed that sunitinib and everolimus remained the most commonly prescribed TTs in the first- and second-line settings, respectively. In addition, use of pazopanib as first-line TT, and axitinib and sorafenib as second-line TTs increased over time [Perez et al. 2015].

Conclusion

The introduction of molecular TTs, including VEGF TKIs like pazopanib have dramatically changed the mRCC treatment landscape over the past 10 years. Research is in progress to investigate optimal sequencing and combinations of TTs to maximize their clinical efficacy, and the outlook and options for treatment of patients with mRCC has never been better. In recent years, PROs and patient preference have become increasingly important in the evaluation of treatment choice for patients.

In clinical trials, pazopanib has demonstrated superior efficacy outcomes compared with placebo and noninferiority compared with sunitinib in treatment-naïve patients with mRCC. In addition, pazopanib has demonstrated a tolerable safety profile and superior PROs compared with sunitinib in this patient cohort.

Outside the clinical trial research setting, efficacy results and the toxicity profile of pazopanib were largely found to be consistent with the results of clinical trials in terms of first-line treatment. Pazopanib treatment was generally well tolerated with mild/moderate AEs that were clinically manageable. Patients receiving pazopanib demonstrated high treatment persistence. In clinical practice, open discussion with patients about comparable efficacy of pazopanib versus sunitinib, including discussion of different side-effect probabilities, promises to offer patients more participation in treatment decision-making.