Elsevier

European Urology

Volume 60, Issue 6, December 2011, Pages 1163-1170
European Urology

Platinum Priority – Kidney Cancer
Editorial by Camillo Porta on pp. 1171–1172 of this issue
Sequence Therapy in Patients with Metastatic Renal Cell Carcinoma: Comparison of Common Targeted Treatment Options Following Failure of Receptor Tyrosine Kinase Inhibitors

https://doi.org/10.1016/j.eururo.2011.07.037Get rights and content

Abstract

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.

Introduction

During the last few years, efficacious therapeutic options have been developed for patients with metastatic renal cell carcinoma (mRCC). Most patients are treated with receptor tyrosine kinase inhibitors (rTKIs), particularly sunitinib (Sun), based on the results obtained in two meta-analyses [1], [2]. Inevitably, most of the patients develop tumour resistance to the first rTKI therapy and therefore require further sequential therapy.

Based on a phase 3 trial, everolimus (EV) is an efficacious treatment option after failure of vascular endothelial growth factor receptor (VEGFr) targeted therapy, particularly rTKI treatment [3]. Current guidelines for the treatment of mRCC have adopted EV as the treatment of choice after VEGF failure [4], [5]. However, some limited evidence suggests that following failure of one VEGFr targeted agent, patients may still have the potential to respond to another VEGFr inhibitor. Particularly rTKIs such as Sun and sorafenib (Sor) have been applied in sequence, although the data of a phase 2 study suggested limited efficacy of this sequencing regimen [6]. Largely retrospective data form the basis for the sequential use of Sun and Sor or vice versa [7], [8], [9], [10], [11], [12]. However, studies sufficiently comparing different sequence options are still lacking.

In the context of insufficient comparative data on the best sequence of targeted treatments in mRCC patients, we collected the data of patients treated with two common sequence options: rTKI therapy followed by EV (rTKI-EV) versus rTKI therapy followed by another rTKI (rTKI-rTKI) in two treatment centres. The aim of our retrospective study was to compare these sequence options in terms of efficacy and toxicity.

Section snippets

Patients and methods

We retrospectively reviewed patients treated with first rTKI therapy (Sun or Sor) at two large academic centres between 2005 and 2010. Patients receiving the sequence rTKI-EV or rTKI-rTKI were included in this study. Either Sun or Sor was allowed as first rTKI treatments, so the rTKI-rTKI sequence subgroup included patients treated with Sun-Sor or vice versa, and the rTKI-EV subgroup included Sun-EV or Sor-EV. Further therapy lines were individualised and included EV, temsirolimus, dovitinib,

Patient characteristics

A total of 108 patients with first rTKI treatment were included in the study. Of these 46 received the rTKI-rTKI sequence, and 62 individuals received the rTKI-EV sequence. The rTKI-rTKI group included Sun-Sor (n = 35) and Sor-Sun (n = 11); the rTKI-EV group consisted of Sun-EV (n = 50) and Sor-EV (n = 12). All patients underwent nephrectomy before targeted therapy. Table 1 depicts the main patient characteristics of the study population and by sequence group. There were no statistical significant

Discussion

Despite significant improvements in the efficacy of systemic treatment of mRCC patients, the best strategy of sequencing targeted therapies remains a matter of debate. Literally all patients with mRCC inevitably experience tumour progression during first-line treatment necessitating sequential therapy.

In this study we compared frequent sequence strategies. Our data support the notion that both efficacy and safety of the most frequently applied sequential targeted therapies (ie, switching rTKI

Conclusions

EV remains the preferred option in rTKI-resistant mRCC according to the evidence available to date. Sequential rTKI therapy with Sun or Sor may provide similar efficacy in terms of PFS and response rate. The trend towards superior OS for the rTKI-EV sequence needs further confirmation in prospective randomised trials. Results from such trials comparing different sequence options are urgently needed to better define the treatment algorithms in rTKI-resistant disease.

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    Both authors contributed equally to this work.

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