Sequence therapy in patients with metastatic renal cell carcinoma

TY - JOUR

T1 - Sequence therapy in patients with metastatic renal cell carcinoma

T2 - comparison of common targeted treatment options following failure of receptor tyrosine kinase inhibitors

AU - Busch, Jonas

AU - Seidel, Christoph

AU - Kempkensteffen, Carsten

AU - Johannsen, Manfred

AU - Wolff, Ingmar

AU - Hinz, Stefan

AU - Magheli, Ahmed

AU - Miller, Kurt

AU - Grünwald, Viktor

AU - Weikert, Steffen

N1 - Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

PY - 2011/12

Y1 - 2011/12

N2 - 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.

AB - 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.

KW - Academic Medical Centers

KW - Aged

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Benzenesulfonates

KW - Carcinoma, Renal Cell

KW - Chi-Square Distribution

KW - Disease-Free Survival

KW - Drug Administration Schedule

KW - Drug Resistance, Neoplasm

KW - Female

KW - Germany

KW - Humans

KW - Indoles

KW - Kaplan-Meier Estimate

KW - Kidney Neoplasms

KW - Male

KW - Middle Aged

KW - Molecular Targeted Therapy

KW - Niacinamide

KW - Phenylurea Compounds

KW - Proportional Hazards Models

KW - Protein Kinase Inhibitors

KW - Pyridines

KW - Pyrroles

KW - Receptor Protein-Tyrosine Kinases

KW - Retrospective Studies

KW - Risk Assessment

KW - Risk Factors

KW - Sirolimus

KW - Survival Rate

KW - Time Factors

KW - Treatment Failure

U2 - 10.1016/j.eururo.2011.07.037

DO - 10.1016/j.eururo.2011.07.037

M3 - SCORING: Journal article

C2 - 21802830

VL - 60

SP - 1163

EP - 1170

JO - EUR UROL

JF - EUR UROL

SN - 0302-2838

IS - 6

ER -