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Background: Non-clear cell renal cell carcinomas are histologically and genetically diverse kidney cancers with variable prognoses, and their optimum initial treatment is unknown. We aimed to compare the mTOR inhibitor everolimus and the VEGF receptor inhibitor sunitinib in patients with non-clear cell renal cell carcinoma.Methods: We enrolled patients with metastatic papillary, chromophobe, or unclassified non-clear cell renal cell carcinoma with no history of previous systemic treatment. Patients were randomly assigned (1:1) to receive everolimus (10 mg/day) or sunitinib (50 mg/day; 6-week cycles of 4 weeks with treatment followed by 2 weeks without treatment) administered orally until disease progression or unacceptable toxicity. Randomisation was stratified by Memorial Sloan Kettering Cancer Center risk group and papillary histology. The primary endpoint was progression-free survival in the intention-to-treat population using the RECIST 1.1 criteria. Safety was assessed in all patients who were randomly assigned to treatment. This study is registered with ClinicalTrials.gov, number NCT01108445.Findings: Between Sept 23, 2010, and Oct 28, 2013, 108 patients were randomly assigned to receive either sunitinib (n=51) or everolimus (n=57). As of December, 2014, 87 progression-free survival events had occurred with two remaining active patients, and the trial was closed for the primary analysis. Sunitinib significantly increased progression-free survival compared with everolimus (8·3 months [80% CI 5·8-11·4] vs 5·6 months [5·5-6·0]; hazard ratio 1·41 [80% CI 1·03-1·92]; p=0·16), although heterogeneity of the treatment effect was noted on the basis of histological subtypes and prognostic risk groups. No unexpected toxic effects were reported, and the most common grade 3-4 adverse events were hypertension (12 [24%] of 51 patients in the sunitinib group vs one [2%] of 57 patients in the everolimus group), infection (six [12%] vs four [7%]), diarrhoea (five [10%] vs one [2%]), pneumonitis (none vs five [9%]), stomatitis (none vs five [9%]), and hand-foot syndrome (four [8%] vs none).Interpretation: In patients with metastatic non-clear cell renal cell carcinoma, sunitinib improved progression-free survival compared with everolimus. Future trials of novel agents should account for heterogeneity in disease outcomes based on genetic, histological, and prognostic factors.Funding: Novartis and Pfizer. [ABSTRACT FROM AUTHOR]

BACKGROUND The current study was conducted to investigate the dependence between progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) and to explore whether PFS can be used as an intermediate endpoint of OS in this patient population. METHODS A total of 1381 patients from 2 prospective phase 3 trials (Cancer and Leukemia Group B [CALGB] 90206 and AVOREN) of interferon-alpha with or without bevacizumab were analyzed. Both trials recruited previously untreated patients with clear cell mRCC with an Eastern Cooperative Oncology Group performance status of 0 to 2; adequate bone marrow, hepatic, cardiac, and renal function; and controlled blood pressure. The CALGB study served as the training data set, and the AVOREN study served as the testing data set. The dependence between PFS and OS was investigated using the Kendall tau for bivariate time-to-event endpoints. RESULTS In the training data set, the median OS times among patients who experienced progressive disease at 3 months or 6 months were 6 months and 8 months, respectively, compared with 25 months and 30 months, respectively, ( P < .001) in patients who did not develop disease progress. The adjusted hazard ratios (HR) were 2.6 ( P < .0001) and 2.8 ( P < .0001), respectively, for patients who did and did not progress at 3 months or 6 months. The dependence between PFS and OS was 0.53. These associations were confirmed in the testing data set. CONCLUSIONS In patients with mRCC who were treated with interferon-alpha with or without bevacizumab, the PFS at 3 months and 6 months was found to be predictive of OS. A high dependence between PFS and OS was observed, suggesting that PFS may be used as a surrogate endpoint for OS. Although this is a novel observation for RCC, these findings require validation in patients with mRCC who are treated with other targeted agents. Cancer 2014;120:52-60. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]