This retrospective, observational chart review study aimed to determine the real-world effectiveness of common targeted systemic therapies for patients with mRCC within routine UK clinical practice. Baseline characteristics of the study population were comparable to the demographics of the UK renal cancer population in terms of sex and the proportion of patients with clear cell mRCC , however our cohort were notably younger than the average UK kidney cancer population. In this study, only 35% of patients were aged 70 and older, whereas UK statistics indicate that approximately half of newly diagnosed patients are ≥70 years old . This may be because the focus of this study was on those newly diagnosed with mRCC (as opposed to non-metastatic RCC) and was limited to patients treated with targeted systemic therapies.
During the study period (2008–2015), NICE technical advisory guidance outlined recommendations for sunitinib (TA169) and pazopanib (TA215) at first line from 2009 and 2011 respectively, and for everolimus (TA219) and axitinib (TA333) at second line from 2011 and 2015 respectively . Treatment pathways agreed by NICE indicate that approved 2LOT therapies are also used for 3LOT . Data were analysed in this study to align with the NICE pathways for advanced and/or metastatic RCC, therefore the received treatments were consistent with NICE-recommended systemic therapies. The majority of patients in this study received sunitinib or pazopanib at 1LOT (98.5%) and everolimus and axitinib at 2LOT (99.0%) and 3LOT (94.4%).
Only 28% of 1LOT patients received a 2LOT, and only 3% of 1LOT patients received a 3LOT. Figures published more recently (2012–2016) by one of the sites involved in this study are 48 and 16% respectively , which likely reflect the lower numbers of favourable prognosis patients included in this study and an increase in available treatments over time. Indeed, since the beginning of the study period, several newer therapies for mRCC patients have been approved (i.e. tivozanib (TA512), cabozantinib (TA542) and nivolumab with ipilimumab (TA581) at 1LOT; lenvatinib with everolimus (TA498), cabozantinib (TA463), and nivolumab (TA417) at 2 + LOT) . Furthermore, no patients received a 4LOT treatment, which may reflect the fact that no fourth-line treatments have been approved by NICE, therefore limiting the therapeutic options for mRCC patients post-3LOT.
Both 1-year and 5-year survival within the study period (2008–2015) were higher than the available estimates for England (from 2013 to 2015; 1 year: 52.4% vs 37.5%  and 5-year: 10.8% vs 5.2–6.6% ), and comparable to a Swedish real-world study over a similar period . However, the OS observed in this study was lower than that reported in an earlier retrospective multi-centre UK database study (Renal Cell Carcinoma Outcomes Research Dataset, RECCORD) , and in real-world studies from other countries over a similar timeframe [21,22,23,24]. The RECCORD study included only patients with clear cell renal cancer (80% of our cohort), and included patients on clinical trials and a small number of patients receiving IL-2 or IFN-α. Median age was also younger (61 years). Subgroup analyses (Supplementary Fig. 3, Additional File 1) of the 89 patients excluded from the main analysis because they received IL-2 or IFN-α at any point during the study revealed a median OS of almost four-times longer (47.5 vs. 12.9 months at 1LOT) than patients treated exclusively with NICE/CDF-recommended systemic therapies and reflects the fact that the Manchester Centre is a national treatment centre for high-dose IL-2 which, in carefully selected patients, can have an excellent outcome . In addition, a further 72 patients were excluded because they participated in clinical trials where systemic therapies were not administered within standard of care. These patients were excluded as they would have biased OS in favour of better outcomes and may partly explain the shorter OS observed in this analysis compared with similar studies.
Survival prognoses within the study were strongly linked with MSKCC risk score. This method is a frequently utilised  and validated [27, 28] scoring system for prediction of patient survival and was reliable in this cohort of mRCC patients. Favourable-risk patients achieved a 6.6-fold increase in OS (compared with poor-risk patients) at 1LOT and a 4.3-fold increase at 2LOT. Although this association remained in 1LOT patients, the improvement was somewhat diminished from 18 months onwards in the 2LOT cohort, probably reflecting the lack of suitable subsequent approved therapies within this disease area. It is however important to note that all analyses are descriptive in nature and confounding variables not controlled for. In this study, the proportion of patients in the favourable risk category was lower (11% vs 25%) and poor risk patients slightly higher (27% vs 22%) compared with a reference mRCC population . This finding is likely due to variations in the characteristics of the study populations and our exclusion of patients receiving cytokine therapies from the main analysis, who had significantly longer OS and more favourable distribution of MSKCC scores.
The nature of real-world research means there is heterogeneity across treatments used at each LOT and across patient characteristics involved in each study, and therefore comparison between study outcomes should be done with caution. Our study focused on patients for whom a full medical history was available and had one or more treatments, therefore becoming susceptible to immortal time bias. Furthermore, participation was limited to two specialist RCC centres and inclusion was limited to patients who received NICE-recommended targeted systemic therapies alone (not in conjunction with cytokine therapy or within a clinical trial), therefore it is unclear how generalisable the study findings are to alternative patient populations or settings.
Despite the limitations associated with this study, including the large numbers of excluded patients, the study remains the largest real-world study on the treatment patterns and outcomes of mRCC patients in the UK. The study was limited to an assessment of the treatment patterns and outcomes of patients receiving targeted systemic therapies; however, with increasing use of immunotherapy in recent years, the impact of this group of therapies in the treatment of mRCC warrants investigation in future studies.