With the approval of a number of different drugs for the treatment of metastatic renal cell carcinoma, a major issue is how to sequence these drugs to optimize outcome. A large, randomized phase II study called RECORD-3 shows that the standard sequence of the multitargeted tyrosine kinase inhibitor sunitinib (Sutent) followed by the mTOR inhibitor everolimus (Afinitor) extended survival compared with the reverse sequence of first-line everolimus followed by sunitinib.
“The study failed to meet the prespecified level for noninferiority between the two strategies. The sequence of sunitinib followed by everolimus is supported by overall survival and progression-free survival results. The standard first-line paradigm remains first-line sunitinib followed by everolimus at progression,” stated lead author Robert J. Motzer, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center, New York. Dr. Motzer presented results of the study at the 2013 ASCO Annual Meeting.1
RECORD-3 was an international, randomized, open-label study that enrolled 471 patients from 83 sites in 19 countries between October 2009 and June 2011. All patients had metastatic renal cell carcinoma of clear cell or non-clear cell histology and had had no prior systemic therapy.
Patients were randomly assigned to first-line therapy with everolimus vs sunitinib and treated until progression. After a 2- to 6-week washout period, they could switch to the alternative drug. More than 50% of patients were unable to cross over to the second-line therapy, but they were followed anyway, Dr. Motzer explained.
The primary endpoint was progression-free survival on first-line therapy, and the study was designed to show noninferiority of everolimus followed by sunitinib to the standard sequence. The data cutoff was in September 2012.
At the time of the progression-free survival analysis of first-line therapy, 201 patients in the everolimus arm and 192 in the sunitinib arm discontinued treatment, mainly due to progressive disease. Crossover to second-line therapy was possible in less than 50% of patients—108 assigned to first-line everolimus and 99 assigned to first-line sunitinib.
Median progression-free survival on first-line therapy was superior with sunitinib: 7.85 months for everolimus vs 10.71 months for sunitinib. The hazard ratio favoring sunitinib was 1.43, and the study failed to meet the primary objective of a 1.1 hazard ratio for the noninferiority margin.
Sunitinib as first-line therapy achieved longer progression-free survival regardless of risk group or histology. Results of the primary progression-free survival analysis were consistent in all three prespecified risk groups: poor, intermediate, and favorable risk according to Memorial Sloan-Kettering criteria. Progression-free survival results in clear cell vs non–clear cell histology were consistent with the primary analysis.
An analysis of combined progression-free survival for first- and second-line therapy was censored for patients who did not cross over to second-line therapy. A trend was seen in the combined progression-free survival analysis favoring the standard paradigm of sunitinib followed by everolimus. Median progression-free survival for first-line everolimus followed by sunitinib was 21.13 months vs 29.79 months for sunitinib followed by everolimus.
The final analysis of overall survival will be available in a year or so.
Deaths were similar: 45% for the first-line everolimus sequence and 41% for the first-line sunitinib sequence. Median overall survival was 22.4 and 32.4 months, respectively, for the two sequences.
The adverse event profiles of both drugs were similar to what has been previously described. The incidence of noninfectious pneumonitis was lower than reported previously, Dr. Motzer said. ■
Disclosure: Dr. Motzer has had a consultant or advisory role with Pfizer and has received research funding from Astellas Pharma, AVEO, GlaxoSmithKline, Novartis, and Pfizer.
1. Motzer RJ, Barrios CH, Kim TM, et al: 2013 ASCO Annual Meeting. Abstract 4504. Presented June 1, 2013.