Christian Eichelberg1, Walter L Vervenne2, Maria De Santis3, Ludwig Fischer von Weikersthal4, Peter J Goebell5, Christian Lerchenmüller6, Uwe Zimmermann7, Monique M E M Bos8, Werner Freier9, Silke Schirrmacher-Memmel10, Michael Staehler11, Sascha Pahernik12, Maartje Los13, Marcus Schenck14, Anne Flörcken15, Cornelis van Arkel16, Kirsten Hauswald17, Martin Indorf17, Dana Gottstein18, Maurice S Michel19. 1. Universitätsklinikum Hamburg-Eppendorf, Hamburg and Caritas-St. Josef Medical Centre, University of Regensburg, Regensburg, Germany. Electronic address: christian.eichelberg@ukr.de. 2. Deventer Ziekenhuis, Deventer, The Netherlands. 3. Ludwig Boltzmann Institute for Applied Cancer Research, Centre for Oncology and Haematology, Kaiser Franz Josef-Spital, Vienna, Austria. 4. Gesundheitszentrum Klinikum Amberg, Amberg, Germany. 5. Urologische Klinik und Klinik für Hämatologie und Onkologie, Universitätsklinikum Erlangen, Erlangen, Germany. 6. Onkologisches Zentrum Münster, Münster, Germany. 7. Urologische Universitätsklinik Greifswald, Greifswald, Germany. 8. Reinier de Graaf Gasthuis, Delft, The Netherlands. 9. Onkologische Praxis, Hildesheim, Germany. 10. Klinikum Fulda, Germany. 11. Universitätsklinikum Grosshadern, Munich, Germany. 12. Universitätsklinikum Heidelberg, Heidelberg, Germany. 13. St. Antonius Ziekenhuis, Nieuwegein, The Netherlands. 14. Urologische Universitätsklinik Essen, Essen, Germany. 15. Charité Universitätsmedizin Berlin, Berlin, Germany. 16. Slingeland Ziekenhuis, Doetinchem, The Netherlands. 17. iOMEDICO AG, Freiburg, Germany. 18. ICRC Weyer GmbH, Berlin, Germany. 19. University Medical Centre Mannheim, Mannheim, Germany.
Abstract
BACKGROUND: Understanding how to sequence targeted therapies for metastatic renal cell carcinoma (mRCC) is important for maximisation of clinical benefit. OBJECTIVES: To prospectively evaluate sequential use of the multikinase inhibitorssorafenib followed by sunitinib (So-Su) versus sunitinib followed by sorafenib (Su-So) in patients with mRCC. DESIGN, SETTING, AND PARTICIPANTS: The multicentre, randomised, open-label, phase 3 SWITCH study assessed So-Su versus Su-So in patients with mRCC without prior systemic therapy, and stratified by Memorial Sloan Kettering Cancer Center risk score (favourable or intermediate). INTERVENTION: Patients were randomised to sorafenib 400mg twice daily followed, on progression or intolerable toxicity, by sunitinib 50mg once daily (4 wk on, 2 wk off) (So-Su), or vice versa (Su-So). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was improvement in progression-free survival (PFS) with So-Su versus Su-So, assessed from randomisation to progression or death during second-line therapy. Secondary endpoints included overall survival (OS) and safety. RESULTS AND LIMITATIONS: In total, 365 patients were randomised (So-Su, n=182; Su-So, n=183). There was no significant difference in total PFS between So-Su and Su-So (median 12.5 vs 14.9 mo; hazard ratio [HR] 1.01; 90% confidence interval [CI] 0.81-1.27; p=0.5 for superiority). OS was similar for So-Su and Su-So (median 31.5 and 30.2 mo; HR 1.00, 90% CI 0.77-1.30; p=0.5 for superiority). More So-Su patients than Su-So patients reached protocol-defined second-line therapy (57% vs 42%). Overall, adverse event rates were generally similar between the treatment arms. The most frequent any-grade treatment-emergent first-line adverse events were diarrhoea (54%) and hand-foot skin reaction (39%) for sorafenib; and diarrhoea (40%) and fatigue (40%) for sunitinib. CONCLUSIONS:Total PFS was not superior with So-Su versus Su-So. These results demonstrate that sorafenib followed by sunitinib and vice versa provide similar clinical benefit in mRCC. PATIENT SUMMARY: We investigated if total progression-free survival (PFS) is improved in patients with advanced/metastatic kidney cancer who are treated with sorafenib and then with sunitinib (So-Su), compared with sunitinib and thensorafenib (Su-So). We found that total PFS was not improved with So-Su compared with Su-So, but both treatment options were similarly effective in patients with advanced/metastatic kidney cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00732914, www.clinicaltrials.gov.
RCT Entities:
BACKGROUND: Understanding how to sequence targeted therapies for metastatic renal cell carcinoma (mRCC) is important for maximisation of clinical benefit. OBJECTIVES: To prospectively evaluate sequential use of the multikinase inhibitors sorafenib followed by sunitinib (So-Su) versus sunitinib followed by sorafenib (Su-So) in patients with mRCC. DESIGN, SETTING, AND PARTICIPANTS: The multicentre, randomised, open-label, phase 3 SWITCH study assessed So-Su versus Su-So in patients with mRCC without prior systemic therapy, and stratified by Memorial Sloan Kettering Cancer Center risk score (favourable or intermediate). INTERVENTION: Patients were randomised to sorafenib 400mg twice daily followed, on progression or intolerable toxicity, by sunitinib 50mg once daily (4 wk on, 2 wk off) (So-Su), or vice versa (Su-So). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was improvement in progression-free survival (PFS) with So-Su versus Su-So, assessed from randomisation to progression or death during second-line therapy. Secondary endpoints included overall survival (OS) and safety. RESULTS AND LIMITATIONS: In total, 365 patients were randomised (So-Su, n=182; Su-So, n=183). There was no significant difference in total PFS between So-Su and Su-So (median 12.5 vs 14.9 mo; hazard ratio [HR] 1.01; 90% confidence interval [CI] 0.81-1.27; p=0.5 for superiority). OS was similar for So-Su and Su-So (median 31.5 and 30.2 mo; HR 1.00, 90% CI 0.77-1.30; p=0.5 for superiority). More So-Supatients than Su-Sopatients reached protocol-defined second-line therapy (57% vs 42%). Overall, adverse event rates were generally similar between the treatment arms. The most frequent any-grade treatment-emergent first-line adverse events were diarrhoea (54%) and hand-foot skin reaction (39%) for sorafenib; and diarrhoea (40%) and fatigue (40%) for sunitinib. CONCLUSIONS: Total PFS was not superior with So-Su versus Su-So. These results demonstrate that sorafenib followed by sunitinib and vice versa provide similar clinical benefit in mRCC. PATIENT SUMMARY: We investigated if total progression-free survival (PFS) is improved in patients with advanced/metastatic kidney cancer who are treated with sorafenib and then with sunitinib (So-Su), compared with sunitinib and then sorafenib (Su-So). We found that total PFS was not improved with So-Su compared with Su-So, but both treatment options were similarly effective in patients with advanced/metastatic kidney cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00732914, www.clinicaltrials.gov.