Optimisation of the tumour response threshold in patients treated with everolimus for metastatic renal cell carcinoma: Analysis of response and progression-free survival in the RECORD-1 study

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Abstract

Background and objectives

Objective response as determined by Response Evaluation Criteria in Solid Tumors (RECIST) is low among patients with metastatic renal cell carcinoma (mRCC) treated with targeted agents, despite significantly improved progression-free survival (PFS). A modified response threshold may be more clinically meaningful than RECIST for identifying patients who may derive a PFS benefit from targeted therapy.

Patients and methods

We performed a retrospective analysis of data from the phase III RECORD-1 trial of everolimus versus placebo in patients with mRCC who had failed sunitinib or sorafenib (ClinicalTrials.gov identifier: NCT00410124). A series of tumour response thresholds, defined by the best change in the sum of the longest tumour diameters (ΔSLD) of target lesions, was evaluated to distinguish ‘responders’ from ‘non-responders’ with respect to significant improvement in PFS.

Results

The optimal threshold for determining a response to everolimus was −5% ΔSLD. At this threshold, median PFS was 8.4 months in responders and 5.0 months in non-responders (hazard ratio [HR] 2.4, 95% confidence interval [CI] 1.6–3.7).

Conclusion

In patients who have failed vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFr-TKI) therapy, everolimus affords superior PFS to placebo, regardless of change in tumour burden. However, a ⩾5% reduction in SLD is a better predictor of PFS benefit than the classical ⩾30% reduction used with RECIST.

Introduction

In clinical trials evaluating cytotoxic therapy, an objective response is often determined using the Response Evaluation Criteria in Solid Tumors (RECIST).1 RECIST relies primarily on the change in the sum of the longest tumour diameters (ΔSLD) of target lesions as a measure of tumour response. An objective response requires at least a 30% decrease in the SLD from baseline (ΔSLD below −30%). Progressive disease is defined by a 20% or greater increase in observed SLD (ΔSLD above +20%). Stable disease is reported for any change in tumour burden that does not meet the criteria for an objective response or progressive disease (ΔSLD between −30% and +20%).

Despite its widespread use, RECIST has a limited ability to reflect the activity of recently developed targeted therapies. The investigators who developed RECIST note that ‘therapies are being developed that may work by mechanisms unlikely to cause tumour regression’ and that the major end-points in definitive clinical trials should consist of other measures of clinical benefit (including survival, progression-free survival [PFS], or symptom control).1

Treatment with targeted agents has improved survival outcomes in patients with metastatic renal cell carcinoma (mRCC); however, response rates with these agents have been variable. In pivotal trials, the anti-angiogenic agents sunitinib and sorafenib produced response rates of 47% (in previously untreated patients) and 10% (in previously treated patients), respectively.2, 3 Since these agents inhibit tumour growth by decreasing tumour perfusion rather than by a direct cytotoxic effect on tumour cells, tumour size may not be significantly reduced despite good anti-tumour activity.4

Similarly, treatment with the mammalian target of rapamycin (mTOR) inhibitor everolimus is infrequently associated with objective tumour responses in patients with mRCC, despite providing a significant PFS benefit.5, 6, 7 In patients who failed prior therapy with sunitinib or sorafenib, everolimus significantly prolonged PFS compared with placebo (to a median of 4.9 months versus 1.9 months with placebo, P < 0.001, hazard ratio [HR] 0.33). However, an objective response was observed in only 2% of patients treated with everolimus (versus 0% in those receiving placebo), with the majority achieving stable disease as their best response (63% versus 32% with placebo).

We hypothesise that a modified threshold for response to everolimus may be more clinically meaningful than standard RECIST criteria. In this study, we aim to optimise the tumour response threshold for the identification of patients who are likely to derive a survival benefit from treatment with everolimus.

Section snippets

Patients

We performed a retrospective analysis of data from the randomised, phase III RECORD-1 trial comparing everolimus versus placebo in patients with mRCC who progressed during or within 6 months of discontinuing vascular endothelial growth factor receptor–tyrosine kinase inhibitors (VEGFr-TKIs). In RECORD-1, patients were randomised 2:1 to receive best supportive care plus either oral everolimus 10 mg/day (n = 277) or placebo (n = 139). The protocol was approved by the institutional review boards of the

Response according to RECIST

In the everolimus-treated group (n = 196), an objective response according to RECIST (best ΔSLD below −30%) was documented in seven patients (4%), whereas stable disease (best ΔSLD between −30% and +20%) was reported in 162 patients (83%). Twenty-seven patients (14%) experienced progressive disease (best ΔSLD above +20%). The standard RECIST threshold for response did not separate the everolimus-treated patients by outcome: the median PFS among RECIST responders (n = 7) was 7.3 months compared with

Discussion

The 30% reduction in tumour size specified as the threshold for a RECIST response has demonstrated limited sensitivity when evaluating the efficacy of everolimus. With RECIST, most patients in the pivotal trial were classed as non-responsive, with many ‘non-responsive’ patients nevertheless deriving a PFS benefit. The use of a smaller relative reduction in tumour size as a threshold for response may be more clinically appropriate when evaluating everolimus therapy. In the present study, a ⩾5%

Role of the funding source

This work was supported by Novartis Pharmaceuticals Corporation. Novartis-affiliated authors had a role in formulating the study concepts and design, coordinating data acquisition, performing quality control, data analysis and interpretation, and statistical analysis, and editing and reviewing the manuscript. All authors participated in the decision to submit this manuscript for publication.

Conflict of interest statement

S. Oudard has received honoraria from Bayer, Novartis, Pfizer, Roche, and Sanofi-Aventis. D. Kim and E. Kpamegan are employees of and own stock in Novartis. A. Panneerselvam is an employee of Novartis. R. Thiam, L. Fournier, J. Medioni, M. Lauraglia, F. Scotte, E. Fabre, and C. Cuenod have no conflicts of interest to declare.

Acknowledgements

Third-party medical writing assistance was provided by ApotheCom (Yardley, PA), and funded by Novartis Pharmaceuticals Corporation.

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