BACKGROUND: It is well known that patient characteristics and survival outcomes in randomized trials may not necessarily be similar to those in real-life clinical practice. The aim of the present study was to analyse second line treatment strategies in the real-world practice and to estimate the outcomes of patients treated with second-line targeted therapy for metastatic renal cell carcinoma (mRCC). METHODS: This is a retrospective, registry-based study using data from the national registry of targeted therapies for mRCC. The RENIS registry contains data on 3049 patients who started the therapy with at least one targeted agent before 31 December, 2014. Of these patients, 1029 had a record of at least two different targeted therapies and sufficient data for analysis. Survival analysis was carried out using the Kaplan-Meier method. Statistical significance of differences in survival between subgroups was assessed using the log-rank test. RESULTS: The median overall survival from the start of second-line treatment was 17.0 months (95% confidence interval [CI] 14.5-19.5 months), 17.1 months (95% CI 14.5-19.8), and 15.4 months (95% CI 11.0-19.7) for second-line everolimus, sorafenib, and sunitinib, respectively. Patients receiving second-line everolimus were older at the start of second-line treatment, more likely to have metachronous disease, and less likely to be previously treated with cytokines or to continue to third-line treatment than patients treated with second-line sunitinib or sorafenib. Progression-free survival (PFS) correlated with PFS on first-line treatment only for everolimus. CONCLUSIONS: In this retrospective study, no significant differences in survival were observed between the cohorts treated with different second-line agents including everolimus, sorafenib, and sunitinib.

Department of Comprehensive Cancer Care and Faculty of Medicine Masaryk Memorial Cancer Institute and Masaryk University Brno Czech Republic

Department of Oncology 1st Faculty of Medicine Charles University and General University Hospital U Nemocnice 499 2 128 08 Prague Czech Republic

Department of Oncology 1st Faculty of Medicine Charles University and Thomayer Hospital Videnska 800 140 59 Prague Czech Republic

Department of Oncology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Oncology Charles University and University Hospital Svobody 80 304 60 Pilsen Czech Republic

Department of Oncology Hradec Králové University Hospital and Faculty of Medicine Charles University Hradec Králové Sokolská 581 50005 Hradec Králové Czech Republic

Department of Oncology Palacky University Medical School and Teaching Hospital 1 P Pavlova 6 775 20 Olomouc Czech Republic

Institute of Biostatistics and Analyses Faculty of Medicine Masaryk University Brno Czech Republic

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Escudier B, Porta C, Schmidinger M, Rioux-Leclercq N, Bex A, et al. Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27(Suppl 5):v58–v68. doi: 10.1093/annonc/mdw328. PubMed DOI

Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer. 2010;116:4256–4265. doi: 10.1002/cncr.25219. PubMed DOI

Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013;14:552–562. doi: 10.1016/S1470-2045(13)70093-7. PubMed DOI

Mitchell AP, Harrison MR, Walker MS, George DJ, Abernethy AP, Hirsch BR. Clinical trial participants with metastatic renal cell carcinoma differ from patients treated in real-world practice. J Oncol Pract. 2015;11:491–497. doi: 10.1200/JOP.2015.004929. PubMed DOI

Poprach A, Bortlicek Z, Buchler T, Melichar B, Lakomy R, Vyzula R, et al. Patients with advanced and metastatic renal cell carcinoma treated with targeted therapy in the Czech Republic: twenty cancer centres, six agents, one database. Med Oncol. 2012;29:3314–3320. doi: 10.1007/s12032-012-0286-9. PubMed DOI

Poprach A, Pavlik T, Melichar B, Puzanov I, Dusek L, Bortlicek Z, et al. Skin toxicity and efficacy of sunitinib and sorafenib in metastatic renal cell carcinoma: a national registry-based study. Ann Oncol. 2012;23:3137–3143. doi: 10.1093/annonc/mds145. PubMed DOI

Buchler T, Klapka R, Melichar B, Brabec P, Dusek L, Vyzula R, Abrahamova J. Sunitinib followed by sorafenib or vice versa for metastatic renal cell carcinoma--data from the Czech registry. Ann Oncol. 2012;23:395–401. doi: 10.1093/annonc/mdr065. PubMed DOI

Buchler T, Pavlik T, Bortlicek Z, Poprach A, Vyzula R, Abrahamova J, Melichar B. Objective response and time to progression on sequential treatment with sunitinib and sorafenib in metastatic renal cell carcinoma. Med Oncol. 2012;29:3321–3324. doi: 10.1007/s12032-012-0293-x. PubMed DOI

Buchler T, Bortlicek Z, Poprach A, Kubackova K, Kiss I, Zemanova M, et al. Efficacy of everolimus in second- and third-line therapy for metastatic renal cell carcinoma: a registry-based analysis. Urol Oncol. 2014;32:569–575. doi: 10.1016/j.urolonc.2013.12.007. PubMed DOI

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026. PubMed DOI

Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol. 2003;13:176–181. doi: 10.1016/S1053-4296(03)00031-6. PubMed DOI

Bergmann L, Kube U, Doehn C, Steiner T, Goebell PJ, Kindler M, et al. Everolimus in metastatic renal cell carcinoma after failure of initial anti-VEGF therapy: final results of a noninterventional study. BMC Cancer. 2015;15:303. doi: 10.1186/s12885-015-1309-7. PubMed DOI PMC

Eichelberg C, Vervenne WL, De Santis M, Fischer von Weikersthal L, Goebell PJ, Lerchenmüller C, et al. SWITCH: a randomised, sequential, open-label study to evaluate the efficacy and safety of sorafenib-sunitinib versus sunitinib-sorafenib in the treatment of metastatic renal cell cancer. Eur Urol. 2015;68:837–847. doi: 10.1016/j.eururo.2015.04.017. PubMed DOI

Pal SK, Signorovitch JE, Reichmann WM, Li N, Koo V, Liu Z, et al. Real-world effectiveness of everolimus subsequent to different first targeted therapies for the treatment of metastatic renal cell carcinoma: synthesis of retrospective chart reviews. Clin Genitourin Cancer. 2016;14:160–167. doi: 10.1016/j.clgc.2015.11.011. PubMed DOI

Ko JJ, Xie W, Kroeger N, Lee JL, Rini BI, Knox JJ, et al. 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. Lancet Oncol. 2015;16:293–300. doi: 10.1016/S1470-2045(14)71222-7. PubMed DOI

Harrison MR, Hirsch BR, George DJ, Walker MS, Chen C, Korytowsky B, et al. Real-world outcomes in metastatic renal cell carcinoma: insights from a joint community-academic registry. J Oncol Pract. 2014;10:e63–e72. doi: 10.1200/JOP.2013.001180. PubMed DOI

Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014;32:2765–2772. doi: 10.1200/JCO.2013.54.6911. PubMed DOI PMC

Busch J, Seidel C, Kempkensteffen C, Johannsen M, Wolff I, Hinz S, et al. Sequence therapy in patients with metastatic renal cell carcinoma: comparison of common targeted treatment options following failure of receptor tyrosine kinase inhibitors. Eur Urol. 2011;60:1163–1170. doi: 10.1016/j.eururo.2011.07.037. PubMed DOI

Iacovelli R, Carteni G, Sternberg CN, Milella M, Santoni M, Di Lorenzo G, et al. Clinical outcomes in patients receiving three lines of targeted therapy for metastatic renal cell carcinoma: results from a large patient cohort. Eur J Cancer. 2013;49:2134–2142. doi: 10.1016/j.ejca.2013.02.032. PubMed DOI

Heng DY, Signorovitch J, Swallow E, Li N, Zhong Y, Qin P, et al. Comparative effectiveness of second-line targeted therapies for metastatic renal cell carcinoma: a systematic review and meta-analysis of real-world observational studies. PLoS One. 2014;9:e114264. doi: 10.1371/journal.pone.0114264. PubMed DOI PMC

Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1814–1823. doi: 10.1056/NEJMoa1510016. PubMed DOI PMC

Davis ID, Xie W, Pezaro C, Donskov F, Wells JC, Agarwal N, et al. Efficacy of second-line targeted therapy for renal cell carcinoma according to change from baseline in international metastatic renal cell carcinoma database consortium prognostic category. Eur Urol. 2017;71:970–978. doi: 10.1016/j.eururo.2016.09.047. PubMed DOI

Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–1813. doi: 10.1056/NEJMoa1510665. PubMed DOI PMC

Al-Marrawi MY, Rini BI, Harshman LC, Bjarnason G, Wood L, Vaishampayan U, et al. The association of clinical outcome to first-line VEGF-targeted therapy with clinical outcome to second-line VEGF-targeted therapy in metastatic renal cell carcinoma patients. Target Oncol. 2013;8:203–209. doi: 10.1007/s11523-012-0252-7. PubMed DOI PMC

Vogelzang NJ, Pal SK, Signorovitch JE, Reichmann WM, Li N, Yang C, et al. Comparative effectiveness of everolimus and axitinib as second targeted therapies for metastatic renal cell carcinoma in the US: a retrospective chart review. Curr Med Res Opin. 2016;32:741–747. doi: 10.1185/03007995.2016.1140028. PubMed DOI

Albiges L, Choueiri T, Escudier B, Galsky M, George D, Hofmann F, et al. A systematic review of sequencing and combinations of systemic therapy in metastatic renal cancer. Eur Urol. 2015;67:100–110. doi: 10.1016/j.eururo.2014.04.006. PubMed DOI

Heng DY, Mackenzie MJ, Vaishampayan UN, Bjarnason GA, Knox JJ, Tan MH, et al. Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy. Ann Oncol. 2012;23:1549–1555. doi: 10.1093/annonc/mdr533. PubMed DOI PMC

Levy A, Menard J, Albiges L, Loriot Y, Di Palma M, Fizazi K, et al. Second line treatment of metastatic renal cell carcinoma: the Institut Gustave Roussy experience with targeted therapies in 251 consecutive patients. Eur J Cancer. 2013;49:1898–1904. doi: 10.1016/j.ejca.2013.02.003. PubMed DOI

Beisland C, Johannesen TB, Klepp O, Axcrona U, Torgersen KM, Kowalski J, et al. Overall survival in renal cell carcinoma after introduction of targeted therapies: a Norwegian population-based study. Onco Targets Ther. 2017;10:371–385. doi: 10.2147/OTT.S123061. PubMed DOI PMC

Alimohamed N, Lee JL, Srinivas S, Bjarnason GA, Knox JJ, Mackenzie MJ, et al. A population-based overview of sequences of targeted therapy in metastatic renal cell carcinoma. Clin Genitourin Cancer. 2014;12:e127–e131. doi: 10.1016/j.clgc.2013.12.003. PubMed DOI

Wagstaff J, Jones R, Hawkins R, Porfiri E, Pickering L, Bahl A, et al. Treatment patterns and clinical outcomes in patients with renal cell carcinoma in the UK: insights from the RECCORD registry. Ann Oncol. 2016;27:159–165. doi: 10.1093/annonc/mdv504. PubMed DOI PMC