www.thelancet.com/oncology Published online February 12, 2015 http://dx.doi.org/10.1016/S1470-2045(14)71222-7 1 Articles Lancet Oncol 2015 Published Online February 12, 2015 http://dx.doi.org/10.1016/ S1470-2045(14)71222-7 See Online/Comment http://dx.doi.org/10.1016/ S1470-2045(15)70009-4 *Contributed equally †Contributed equally Department of Medical Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada (J J Ko MD, D Y C Heng MD); Dana-Farber Cancer Institute, Boston, MA, USA (W Xie MS, T K Choueiri MD); Department of Urology, University Hospital Greifswald, Ernst Moritz Arndt University, Greifswald, Germany (N Kroeger MD); Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea (J-L Lee MD); Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH, USA (B I Rini MD); Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada (J J Knox MD); Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada (G A Bjarnason MD); Division of Oncology, Stanford Medical Center, Stanford, CA, USA (S Srinivas MD); City of Hope Comprehensive Cancer Center, Medical Oncology & Experimental Therapeutics, Duarte, CA, USA (S K Pal MD); Department of Urology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan (T Yuasa MD); Department of Medical Oncology, British Columbia Cancer Agency, The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study Jenny J Ko*, Wanling Xie*, Nils Kroeger, Jae-lyun Lee, Brian I Rini, Jennifer J Knox, Georg A Bjarnason, Sandy Srinivas, Sumanta K Pal, Takeshi Yuasa, Martin Smoragiewicz, Frede Donskov, Ravindran Kanesvaran, Lori Wood, D Scott Ernst, Neeraj Agarwal, Ulka N Vaishampayan, Sun-young Rha, Toni K Choueiri†, Daniel Y C Heng† Summary Background Previous prognostic models for second-line systemic therapy in patients with metastatic renal cell carcinoma have not been studied in the setting of targeted therapy. We sought to validate the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model in patients with metastatic renal cell carcinoma receiving next-line targeted therapy after progression on first-line targeted therapy. Methods In this population-based study, we analysed patients who received second-line targeted therapy for metastatic renal cell carcinoma at 19 centres in Canada, USA, Greece, Japan, Singapore, South Korea, and Denmark. The primary endpoint was overall survival since the initiation of second-line therapy. We compared the prognostic performance of the IMDC model with the three-factor MSKCC model used for previously treated patients for overall survival since the start of second-line targeted therapy. Findings Between Jan 1, 2005, and Nov 30, 2012, we included 1021 patients treated with second-line targeted therapy. Median overall survival since the start of second-line targeted therapy was 12·5 months (95% CI 11·3–14·3). Five of six predefined factors in the IMDC model (anaemia, thrombocytosis, neutrophilia, Karnofsky performance status [KPS] <80, and <1 year from diagnosis to first-line targeted therapy) were independent predictors of poor overall survival on multivariable analysis. The concordance index using all six prognostic factors (ie, also including hypercalcaemia) was 0·70 (95% CI 0·67–0·72) with the IMDC model and was 0·66 (95% CI 0·64–0·68) with the three-factor MSKCC model. When patients were divided into three risk categories using IMDC criteria, median overall survival was 35·3 months (95% CI 28·3–47·8) in the favourable risk group (n=76), 16·6 months (14·9–17·9) in the intermediate risk group (n=529), and 5·4 months (4·7–6·8) in the poor risk group (n=261). Interpretation The IMDC prognostic model can be applied to patients previously treated with targeted therapy, in addition to previously validated populations in first-line targeted therapy. The IMDC prognostic model in the second- line targeted therapy setting has an improved prognostic performance and is applicable to a more contemporary patient cohort than that of the three-factor MSKCC model. Funding DF/HCC Kidney Cancer SPORE P50 CA101942-01, Kidney Cancer Research Network of Canada, Canadian Institute for Health Research, Trust Family, Loker Pinard, Michael Brigham, and Gerald DeWulf. Introduction Systemic treatment for metastatic renal cell carcinoma has historically consisted mainly of immunotherapies such as interferon α and interleukin 2. The advent of targeted therapy has substantially changed the treatment and prognosis of metastatic renal cell carcinoma in the past decade, with many drugs—eg, sorafenib, sunitinib, bevacizumab, axitinib, pazopanib, everolimus, and temsirolimus—now available for use in the clinic. The standard of care in metastatic renal cell carcinoma for most eligible patients now consists of sequential treatment with targeted therapy, including anti-VEGF drugs and mTOR inhibitors, aiming to increase both survival and quality of life; 1–5 immunotherapy with interferon α or interleukin 2 is now rarely used. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model (Heng criteria 6 ) has been developed and validated for patients diagnosed with metastatic renal cell carcinoma receiving first-line targeted therapy, with six readily available clinical and laboratory factors: Karnofsky performance status (KPS), time from diagnosis to first-line targeted therapy, haemoglobin concentration, neutrophil count, platelet count, and serum calcium concentration. This model has since been externally validated in a separate cohort. 7 Prognostic models for second-line systemic therapy in patients with metastatic renal cell carcinoma have not been studied in the setting of contemporary sequential targeted therapy. The only pre-existing large-scale model in the era of immunotherapy is the Memorial Sloan Kettering Cancer