Everolimus versus Sunitinib for Patients with Metastatic Non-clear Cell Renal Cell Carcinoma (ASPEN): a Multicentre, Open-label, Randomised Phase 2 Trial

BACKGROUND: Non-clear cell renal cell carcinomas are histologically and genetically diverse kidney cancers with variable prognoses and their optimum initial treatment are 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. 

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.

This study is registered with ClinicalTrials.gov, number NCT01108445.

LANCET. 2016, January 12, [Epub ahead of print]

Andrew J Armstrong, MD,1  Susan Halabi, PhD,1  Tim Eisen, MD,2  Samuel Broderick, MS,3  Walter M Stadler, MD,4  Robert J Jones, MD,5  Jorge A Garcia, MD,6  Ulka N Vaishampayan, MD,7  Joel Picus, MD,8  Robert E Hawkins, MD,9  John D Hainsworth, MD,10  Christian K Kollmannsberger, MD,11  Theodore F Logan, MD,12  Igor Puzanov, MD,13  Lisa M Pickering, MD,14  Christopher W Ryan, MD,15  Andrew Protheroe, MD,16  Christine M Lusk, MPH,16  Sadie Oberg, BS,16  Daniel J George, MD,1

1. Duke University and the Duke Cancer Institute, Durham, North Carolina
2. University of Cambridge, Cambridge, United Kingdom
3. Duke Clinical Research Institute, Durham, North Carolina
4. University of Chicago, Chicago, Illinois
5. The University of Glasgow, The Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
6. Cleveland Clinic, Cleveland, Ohio
7. Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
8. Washington University in St Louis, St Louis, Missouri
9. Christie Cancer Research Centre, Manchester, United Kingdom
10. Sarah Cannon Research Institute, Nashville, Tennessee
11. BC Cancer Agency, Vancouver Cancer Centre, Vancouver, British Columbia, Canada
12. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana
13. Vanderbilt University Medical Center, Nashville, Tennessee
14. Royal Marsden Hospital, London, United Kingdom
15. Oregon Health & Science University, OHSU Knight Cancer Institute, Portland, Oregon
16. inVentiv Health Clinical, Princeton, New Jersey

THE LANCET, volume 17, issue 3, P378-388, March 01, 2016; DOI: 10.1016/S1470-2045(15)00515-X
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