Corresponding Author: Sien Chow, The Clatterbridge Cancer Centre NHS Foundation Trust, England, United Kingdom.
Background: The use of multi-receptor tyrosine kinase inhibitor (TKI) targeting the tumor angiogenesis pathway has shifted the treatment paradigm as well as improved outcomes among patients with mRCC. Sunitinib (S) and pazopanib (P) are two widely used TKIs options among treatment naïve patients. Here, we present our experience and survival outcomes of these two drugs used in a UK tertiary cancer center.
Methods: mRCC patients who had received either of these agents as first line therapy were identified through the Renal Cancer Database (2005-2015). Outcomes of interest include response rate, progression free survival (PFS) and overall survival (OS). Subgroup analysis was performed based on prognostic variables to assess survival impact.
Results: A total of 665 patients were identified (S=397, P=268). The majority of patients were categorized as having worse (intermediate to poor) prognostic risk groups (93% IMDC; 71% MSKCC). Cytoreductive nephrectomy rate in this population was 62%. Objective response rate (ORR) was 22%; ORR 25% (S) v 20% (P). Median PFS and OS of the entire cohort was 10.5 and 16.1 months respectively. Median OS in good-risk IMDC group reached 47 months but 21 and 7 months in the intermediate and poor-risk groups respectively. Survival outcomes for both drug groups were comparable when stratified by prognostic risks.
Conclusion: In this large population-based retrospective review, the survival performance of either TKI was impressive and comparable to published evidence among favorable-risk patients. However, the overall survival is lower than expected for the entire cohort and is likely attributable to the high proportion of patients with less than favorable prognostic risk in this real world cohort and the correspondingly lower benefits of this subgroups to these drugs.
Renal cell carcinoma is the most common cancer of the kidney and its incidence is increasing rapidly worldwide. In England, kidney cancer is the third most common urological cancer after prostate and bladder cancer with an incidence in excess of 4000 and 2500 per 100,000 cases per year for male and female respectively.1 Unfortunately, around 30% of patients present with advanced or metastatic disease and relapse rate despite curative surgery is as high as 40%.2,3 The understanding of tumor angiogenesis pathway in RCC has led to the successful utilization of anti-angiogenic agents in the last decade. This signalling process is mediated by binding of stimulatory protein such as vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) to the external domain of transmembrane receptor which in turn activates the subsequent intracellular tyrosine kinase activity with cascading effect on cancer cell proliferation and metastasis. Sunitinib is a first generation small molecule that inhibits multiple receptor tyrosine kinases. Targets of sunitinib include vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3), platelet-derived growth factor receptors (PDGFRα and PDGFRβ), and several other kinase receptors. It received FDA approval for use in mRCC in 2006. Pazopanib is a second-generation small-molecule TKI with higher selective activity against similar receptors range and was FDA-approved in 2009. For a long while, sunitinib and pazopanib were the only two approved oral TKIs for patients with treatment-naïve mRCC in the UK. Consistent PFS benefits have been demonstrated in separate randomized controlled clinical studies of sunitinib (versus Interferon alpha)4 and pazopanib (versus placebo)5 as the first-line treatment of mRCC. Pazopanib was later compared directly to sunitinib in the COMPARZ trial showing essentially non-inferior efficacy among 1110 patients. Investigator-led median PFS and OS were similar for both agents at around 10 and 29 months respectively.6
There are several reports on the real world outcomes of the use of targeted therapies in mRCC. Ruiz-morales et al7 documented the use of pazopanib versus sunitinib in the first-line setting using data from the International mRCC Database Consortium (IMDC), but the UK is not part of this consortium. In this article, we report the outcomes on the use of these two drugs in a large tertiary referral center between 2005 - 2015 with the aim to evaluate and compare their population-based efficacy and extent of survival benefits and this will serve as an important benchmark for future outcome comparisons in this region.
Patient selection, treatment and methods
Patients who received pazopanib or sunitinib as first-line therapy for mRCC (from April 2005 to August 2015) were identified from our Renal Cancer database. Patients who had previous cytokines therapy or were treated with either of these agents as monotherapy within a clinical trial of first-line setting were included in this analysis. Patient demographics and relevant clinical data were retrieved from electronic patient record. Treatment response was evaluated using CT scan assessments based on RECIST criteria approximately every 3 months. Progression-free survival (PFS) was calculated from start of treatment to date of progression or death or last date patient known to be progression-free. Overall survival (OS) was calculated from start of treatment to date of death of any cause or last date patient known to be alive. Last observation date was September 2, 2016.
Survivals were analysed using Kaplan-Meier method and Log-rank tests were used to compare difference between covariates (SPSS software version 20).
The assessment of treatment response reflects that of standard clinical practice and therefore will not be as robust as that in a clinical trial setting and may have an impact on interpretation of PFS result. Also, due to the retrospective nature of a clinical audit, the complete and accurate assessment of adverse events was not feasible and therefore not presented here.
This is a retrospective clinical review with no intervention beyond standard of care; therefore ethics committee approval is not required. This project was approved and registered with The Christie NHS Trust Foundation trust audit department (Registration reference: SE17/1957).
A total of 665 patients were identified from The Christie Renal Cancer Database. Of these, 577 (86.8%) patients were treated within standard clinical practice while 88 (13.2%) received pazopanib or sunitinib within a clinical trial. Higher proportions of patients within the pazopanib group were of worse prognosis and performance status. Sixty-two percent of this patient series had cytoreductive nephrectomies. Other patient characteristics and demographics are as outlined in Table 1. Clear cell was the predominant histology subtype seen in both treatment populations (85% pazopanib, 77% sunitinib). A higher percentage of patients with non-clear cell (papillary, chromophobe, or translocation) and unclassified RCC received treatment with sunitinib. Histology detail was not available in less than 10% of both cohorts (Table 2).
Treatment and subsequent therapy
Only 52% and 59% of patients in the sunitinib and pazopanib groups started treatment at full dose. Median duration on treatment was 6.5 and 6.2 months for sunitinib and pazopanib group, respectively. Forty-two percent (42%) of patients who discontinued first line sunitinib or pazopanib received second line treatment. Subsequent treatments were predominantly axitinib (P 51%, S 40%) and everolimus (P 35%, S 38%) while very small number (less than 5%) of patients received other treatment such as nivolumab, HD IL-2 or treatment within clinical trial during this period. Proportionately more patients in the pazopanib group were able to receive any subsequent treatment (58%) compared to sunitinib group (42%).
Overall Response Rate (ORR) was 22% of which 2% were complete; 43% of patients had SD as best response while over a quarter had PD. ORR was 25% and 21% in Sunitinib and pazopanib arm respectively.
Median follow up was to 40.2 months. One year survival estimated to be above 60%. Median PFS and OS of the entire cohort are 10.5 and 15.8 months respectively (see Tables 3,4).
Median PFS of pazopanib cohort (8.3 months) was lower than Sunitinib (10.4 months P = 0.02) but median OS was not significantly different (S 17.7 v P 14.8 months P = 0.67). Figure 1 and 2 respectively. No statistically significant difference in PFS or OS was detected among patients with matched prognostic risk receiving the different drug type on univariate analysis (Figures 3, 4). Median OS of patient with Favorable risk was 47.3 months (36 months and 47 months in the sunitinib and pazopanib groups, respectively, P = 0.18). This was significantly lower at 20.8 months and 7.4 months for intermediate and poor-risk groups, respectively. See Table 3 and 4 for PFS and OS OF different risk groups.
Figures 1 and 2. Median PFS of pazopanib cohort (8.3 months) was lower than Sunitinib (10.4 months P = 0.02) but median OS was not significantly different (S 17.7 v P 14.8 months P = 0.67).
Figure 3. Kaplan-Meier curves comparing PFS between Pazopanib versus Sunitinib according to MSKCC a) good b) intermediate and c) poor prognostic subgroups. No statistical difference shown.
Figure 4. Kaplan-Meier curves comparing OS between Pazopanib versus Sunitinib according to MSKCC a) good b) intermediate and c) poor prognostic subgroups. No statistical difference shown.
The median OS in our study population is notably lower compared to contemporary trial or real-world reports of similar treatment setting (16 versus 23-28 months). Of significance, only about 7% of patients in our study population had favorable IMDC risk category which is in stark contrast to at least 25-27% in COMPARZ or IMDC report. The proportion of patients with non-clear cell pathology, which is usually associated with poorer outcome, was also comparatively higher in this study cohort. In a review done by Kidney Cancer UK in 2016,8 survival outcomes in the UK as a whole is poorer compared to other western advanced countries or European counterparts. The possible contributing factors highlighted was the low proportion of patients receiving more than one line of treatment and the generally restricted overall number of approved and effective treatment available during the study period. Another relevant factor to the poor survival outcome in this region is likely the very high proportion (41%) of highly deprived neighborhoods served by this referral center compared to only 6-7% in other parts of England (ONS 2015).9 The findings here indirectly highlighted the absolute importance of public awareness and early diagnosis to further improve survival outcome of kidney cancer. The approval of several newer agents by NICE in recent times including cabozantinib and ipilimumab and nivolumab combination immunotherapy among patients with I/P prognostic risk, for example, is extremely timely and will likely bring about improvement in survival outcome in general and for this region.
The outcome of mRCC patients with favorable prognostic risk (IMDC or MSKCC) in this series is excellent (median survival of more than 3 years similar to that of COMPARZ trial) irrespective of TKI type. The median PFS is also comparable to COMPARZ (investigator review) at around 10 months. Taking the unequal distribution of patient with poorer risks between the two drug types into consideration, efficacy and survival are comparable between sunitinib and pazopanib and remaining true when compared among matched prognostic subgroups. This real world evidence reaffirms the important role of VEGF pathway inhibition as one the main therapeutic strategy in mRCC, particularly among patients with favorable prognostic risk. The lower benefits among patients belonging to intermediate and poor prognostic risk categories in this real world data set is in keeping with published research data and represents an on-going challenge in mRCC.
Results from Checkmate-214 study represent a breakthrough in this area. In this phase 3 randomized controlled trial comparing ipilimumab and nivolumab with sunitinib among patient populations of predominantly I/P prognostic risk category, combination checkpoint inhibitors showed superior PFS in patients with less than favorable risk group while patients with favorable risk achieved better outcome with sunitinib. At 30 months update review, median OS was not reached in the combination group (versus 37.9 months) and a complete response rate of 11%.10,11 Translational work done in the IMMOTION 150 and151 study by Rini et al12 found that patients with favorable prognostic risk is characterized by a predominantly angiogenesis gene expression signature which correlated with improved PFS when exposed to VEGF-directed therapy. Patients with a predominantly immune underlying gene expression signature fared better when exposed to immunotherapy in these trials. These early findings provided some insight into the differential susceptibility of tumors to VEGF or immune checkpoint pathway blockade or even both among the different clinical prognostic risk categories although the full understanding is still evolving.
There is other progress in the management of patients with I/P risk categories. Following positive results of the METEOR trial in second line setting,13 the CABOSUN study was set up to evaluate the efficacy of Cabozantinib compared to sunitinib among mRCC patients with Intermediate or Poor IMDC risk group (~20% Poor IMDC risk). Cabozantinib is a third generation VEGF pathway directed tyrosine kinase inhibitor poised with additional target activity against AXL and MET receptor. In CABOSUN, ORR was significantly higher in Cabozantinib group at 46% versus 18% and an impressive 34% reduction in risk of progression or death (hazard ratio 0.66; 95% CI 0.46-0.95 P =0.012) was seen with Cabozantinib.14 This represents another significant stride given the unmet need of this adverse risk group.
There has been definite stride in the survival outcome among patients mRCC through therapeutic exploitation of the VEGF-pathway in recent decade. However the benefit of the commonly utilised agents such as sunitinib and pazopanib so far has been largely limited to patients with Favourable prognostic risk. The strikingly discrepant outcome defined by prognostic risks emphasises the importance of risk-stratifying mRCC patients in clinical practice and personalising appropriate treatment based on this.
The arrival of newer and more effective treatments and combination offers optimism to improving survival outcomes of mRCC patients particular those of I/P risk groups. Better understanding of differential underlying immune versus vascular-driven disease process through relentless translational research and biomarker-based treatment personalisation will be the next crucial step in advancing the care of our patients.
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List of Abbreviations
TKI = Tyrosine Kinase Inhibitor; NHS = National Health Service; NICE= National Institute for Health and Care Excellence; ECOG PS = Eastern Cooperative Oncology Group Performance status; mRCC= Metastatic Renal Cell Carcinoma; VEGF= Vascular Endothelial Growth Factor; MSKCC= Memorial Sloan-Kettering Cancer Centre; ORR= Overall Response Rate; ONS = Office for National Statistic; CR = Complete Response; CRR= Complete Response Rate; SD= Stable Disease; PR = Partial Response; PD = Progressive Disease; PD1 = Programmed cell death 1; EORTC= European Organisation for Research and Treatment of Cancer;HD-IL2 = High Dose Interleukin 2; UK = United Kingdom. KCJ