Sequence Therapy in Patients with Metastatic Renal Cell Carcinoma: Comparison of Common Targeted Treatment Options Following Failure of Receptor Tyrosine Kinase Inhibitors

Background: The best sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been sufficiently defined. Objective: To describe the efficacy and toxicity of sequential everolimus (EV) versus receptor tyrosine kinase inhibitor (rTKI) following failure of first rTKI treatment. Design, setting, and participants: Retrospective study of 108 patients receiving rTKI or EV after progression on rTKI therapy at two German academic centres. Intervention: Sequence of systemic targeted treatment with sunitinib (n = 85) or sorafenib (n = 23) followed by EV (n = 62) or another rTKI (n = 46; sorafenib, n = 35; sunitinib, n = 11). Measurements: We measured response rate (Response Evaluation Criteria in Solid Tumours 1.0) and toxicity. Survival analysis (Kaplan-Meier method and Cox regression) was conducted for progression-free survival (PFS) and overall survival (OS). Results and limitations: Main patient characteristics did not significantly differ by sequence of treatment groups (rTKI-rTKI vs rTKI-EV). Response rate following first rTKI failure was not significantly different between sequential therapies with a disease control rate of 51.6% (EV) and 43.5% (rTKI). The corresponding median PFS was 3.6 mo (95% confidence interval [CI], 1.8-5.4) for EV and 4.0 mo (3.2-4.9) for rTKI treatment. The estimated OS was longer for the rTKI-EV group (43 mo; 95% CI, 33.9-52.1) than for the rTKI-rTKI group (29 mo; 95% CI, 18.6-39.5; p = 0.03), but this difference lost statistical significance in multivariable-adjusted analyses. Intrinsic rTKI resistance was independently associated with inferior subsequent PFS (hazard ratio [HR]: 1.79; 95% CI, 1.15-3.62; p = 0.015) and OS (HR: 6.54; 95% CI, 3.01-14.20; p < 0.001). Limitations are the retrospective design, limited numbers of cases, and residual confounding factors. Conclusions: The sequence therapies rTKI-EV and rTKI-rTKI may be equally efficacious in terms of PFS and response rate, whereas a tendency towards superior survival was observed for the rTKI-EV sequence. These data, particularly the potential benefit of an early change of mode of action, need confirmation in randomised comparative trials. (C) 2011 European Association of Urology. Published by Elsevier B. V. All rights reserved.