Trial Oversight

The trial was designed under the auspices of the Cancerology Committee of the French Association of Urology and the Urogenital Tumors Study Group and was sponsored by Assistance Publique–Hôpitaux de Paris. The protocol (available with the full text of this article at NEJM.org) was approved by the French National Agency for the Safety of Medicines and Health Products (Agence Nationale de Sécurité du Médicament et des Produits de Santé).

The sponsor and their representatives collected and analyzed the data. All the authors had full access to the trial data. Trial oversight was provided by the first and second authors and by an independent data and safety monitoring board (see the Supplementary Appendix, available at NEJM.org). Sunitinib was purchased at full cost from Pfizer per standard pharmacy practice at each institute. Pfizer was not involved in the design or implementation of the protocol, the analysis of the data, or the preparation or review of the manuscript. Four of the authors wrote the first draft of the manuscript, and medical writing and editorial assistance was funded by the sponsor. All the authors made the decision to submit the manuscript for publication. The authors vouch for the accuracy and completeness of the data and the analyses and for the adherence of the trial to the protocol.

The conduct of the trial conformed with the International Conference on Harmonisation E6 guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki. All the patients provided written informed consent before undergoing any trial procedures.

Patients

Eligible patients were adults (≥18 years of age) with clear-cell renal-cell carcinoma confirmed on mandatory biopsy and documented metastatic disease. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1, an absence of brain metastases or treated brain metastases without recurrence 3 weeks after treatment, and acceptable organ function. ECOG scores range from 0 to 5, with higher numbers indicating greater disability and a score of 5 indicating death. Patients had to be suitable candidates for nephrectomy and eligible for treatment with sunitinib. Patients were assessed by the treating urologist before enrollment regarding the feasibility of primary tumor resection; in cases in which there was doubt regarding feasibility, computed tomographic (CT) scans of the abdomen were referred to the steering committee for a decision. Patients were excluded if they had received previous systemic treatment for kidney cancer (including VEGF-targeted therapy) or anticoagulants or if they had any medical condition, including cardiovascular disease, that ruled them out as candidates for treatment.

Trial Design

In this prospective, multicenter, open-label, randomized, phase 3 trial, patients were randomly assigned in a 1:1 ratio to undergo nephrectomy followed by sunitinib treatment or to receive sunitinib alone. Randomization was stratified according to risk group (classified according to the Memorial Sloan Kettering Cancer Center [MSKCC] prognostic model) and center.5 The MSKCC prognostic factors were a Karnofsky performance status score of less than 80 (on a scale from 0 to 100, with lower scores indicating greater disability), a lactate dehydrogenase level of 1.5 times the upper limit of the normal range, a hemoglobin level that was less than the lower limit of the normal range, a corrected serum calcium level of more than 10 mg per deciliter (2.5 mmol per liter), and a time from diagnosis to treatment of less than 1 year. Patients with one or two prognostic factors were classified as having intermediate-risk disease and those with three or more were classified as having poor-risk disease (Table S1 in the Supplementary Appendix).

Nephrectomy was performed within 28 days after randomization, according to the normal procedures of the institute. In the sunitinib-only group, sunitinib treatment was initiated within 21 days after randomization and was given at an initial dose of 50 mg daily in cycles of 28 days on followed by 14 days off every 6 weeks. In the nephrectomy–sunitinib group, sunitinib treatment was initiated between 3 and 6 weeks after nephrectomy. Dose reductions or interruptions of sunitinib treatment were permitted to manage adverse events. After recruitment and randomization, each patient was followed for a minimum of 2 years.

End Points and Assessments

The primary end point was overall survival, which was defined as the time from randomization until death from any cause or until the date of last contact for living patients. Secondary end points included investigator-assessed progression-free survival, the objective response rate, clinical benefit (see below), adherence to treatment, nephrectomy in the sunitinib-only group, postoperative morbidity and mortality, and safety. Progression-free survival was calculated, in months, from the date of randomization to the date of progression or the start date of a second-line treatment. Events in the analysis of progression-free survival included progression in patients undergoing treatment or during follow-up, the start of a new line of treatment, and death from cancer-related causes. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1, and considered all lesions (target, nontarget, and primary). The objective response rate was defined as the percentage of patients with a complete response or partial response. Clinical benefit was defined as the percentage of patients with a complete response, partial response, or stable disease for more than 12 weeks. Postoperative morbidity was evaluated according to the Clavien–Dindo classification of surgical complications14 (Table S2 in the Supplementary Appendix), and postoperative mortality was evaluated as the percentage of deaths in the 30 days after nephrectomy. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 3.0, of the National Cancer Institute. Radiographic tumor evaluation (CT scan or magnetic resonance imaging [MRI] of the thorax, abdomen, and pelvis) was performed after every two cycles of sunitinib treatment; CT or MRI scans of the head were performed only if clinically indicated.

Statistical Analysis

To assess the hypothesis that nephrectomy is not necessary in patients presenting with metastatic kidney cancer, we considered that treatment with sunitinib alone from the outset would be considered to be clinically acceptable if the upper boundary of the 95% confidence interval for the hazard ratio for death was 1.20 or less (noninferiority margin). The trial was designed to have 80% power at a one-sided significance level of 5%. To show noninferiority, we planned to enroll 576 patients in order to observe 456 deaths, on the basis of an expected recruitment of 12 patients per month over a period of 48 months. This allowed for two interim analyses — one after the observation of 152 deaths and another after 304 deaths — and for a final analysis to be scheduled either 80 months after the initiation of the trial or 32 months after the enrollment of the last patient. O’Brien–Fleming sequential boundaries were used for decisions regarding early halting of the trial. The second interim analysis after the observation of 326 events at the cutoff date of December 12, 2017, reported here, showed that the O’Brien–Fleming boundary was not reached, so the trial was allowed to continue recruitment. However, in parallel to this second interim analysis, the sponsor made the decision to close the trial early because of slow recruitment, and the steering committee considered the results from this interim analysis sufficient to meet the objectives of the trial.

The rates and 95% confidence intervals for the analyses of overall survival and progression-free survival were estimated by the Kaplan–Meier method in the intention-to-treat population. Tumor response and safety data were analyzed in patients who received sunitinib. Two per-protocol analyses were performed: the first included only patients in the nephrectomy–sunitinib group who had undergone nephrectomy and patients in the sunitinib-alone group who had received sunitinib; and the second included only patients in the nephrectomy–sunitinib group who had undergone nephrectomy and also received sunitinib and patients in the sunitinib-alone group who had received sunitinib.