Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN)

A multicentre, open-label, randomised phase 2 trial

Andrew J. Armstrong, Susan Halabi, Tim Eisen, Samuel Broderick, Walter M. Stadler, Robert J. Jones, Jorge A. Garcia, Ulka N. Vaishampayan, Joel Picus, Robert E. Hawkins, John D. Hainsworth, Christian K. Kollmannsberger, Theodore F. Logan, Igor Puzanov, Lisa M. Pickering, Christopher Ryan, Andrew Protheroe, Christine M. Lusk, Sadie Oberg, Daniel J. George

    Research output: Contribution to journalArticle

    124 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)378-388
    Number of pages11
    JournalThe Lancet Oncology
    Volume17
    Issue number3
    DOIs
    StatePublished - Mar 1 2016

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    Disease-Free Survival
    Renal Cell Carcinoma
    Therapeutics
    Hand-Foot Syndrome
    Everolimus
    sunitinib
    Clear-cell metastatic renal cell carcinoma
    Stomatitis
    Vascular Endothelial Growth Factor Receptor
    Kidney Neoplasms
    Poisons
    Random Allocation
    Disease Progression
    Diarrhea
    Pneumonia
    Histology
    Hypertension
    Safety
    Infection
    Population

    ASJC Scopus subject areas

    • Oncology

    Cite this

    Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN) : A multicentre, open-label, randomised phase 2 trial. / Armstrong, Andrew J.; Halabi, Susan; Eisen, Tim; Broderick, Samuel; Stadler, Walter M.; Jones, Robert J.; Garcia, Jorge A.; Vaishampayan, Ulka N.; Picus, Joel; Hawkins, Robert E.; Hainsworth, John D.; Kollmannsberger, Christian K.; Logan, Theodore F.; Puzanov, Igor; Pickering, Lisa M.; Ryan, Christopher; Protheroe, Andrew; Lusk, Christine M.; Oberg, Sadie; George, Daniel J.

    In: The Lancet Oncology, Vol. 17, No. 3, 01.03.2016, p. 378-388.

    Research output: Contribution to journalArticle

    Armstrong, AJ, Halabi, S, Eisen, T, Broderick, S, Stadler, WM, Jones, RJ, Garcia, JA, Vaishampayan, UN, Picus, J, Hawkins, RE, Hainsworth, JD, Kollmannsberger, CK, Logan, TF, Puzanov, I, Pickering, LM, Ryan, C, Protheroe, A, Lusk, CM, Oberg, S & George, DJ 2016, 'Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): A multicentre, open-label, randomised phase 2 trial', The Lancet Oncology, vol. 17, no. 3, pp. 378-388. https://doi.org/10.1016/S1470-2045(15)00515-X
    Armstrong, Andrew J. ; Halabi, Susan ; Eisen, Tim ; Broderick, Samuel ; Stadler, Walter M. ; Jones, Robert J. ; Garcia, Jorge A. ; Vaishampayan, Ulka N. ; Picus, Joel ; Hawkins, Robert E. ; Hainsworth, John D. ; Kollmannsberger, Christian K. ; Logan, Theodore F. ; Puzanov, Igor ; Pickering, Lisa M. ; Ryan, Christopher ; Protheroe, Andrew ; Lusk, Christine M. ; Oberg, Sadie ; George, Daniel J. / Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN) : A multicentre, open-label, randomised phase 2 trial. In: The Lancet Oncology. 2016 ; Vol. 17, No. 3. pp. 378-388.
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    abstract = "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.",
    author = "Armstrong, {Andrew J.} and Susan Halabi and Tim Eisen and Samuel Broderick and Stadler, {Walter M.} and Jones, {Robert J.} and Garcia, {Jorge A.} and Vaishampayan, {Ulka N.} and Joel Picus and Hawkins, {Robert E.} and Hainsworth, {John D.} and Kollmannsberger, {Christian K.} and Logan, {Theodore F.} and Igor Puzanov and Pickering, {Lisa M.} and Christopher Ryan and Andrew Protheroe and Lusk, {Christine M.} and Sadie Oberg and George, {Daniel J.}",
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    TY - JOUR

    T1 - Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN)

    T2 - A multicentre, open-label, randomised phase 2 trial

    AU - Armstrong, Andrew J.

    AU - Halabi, Susan

    AU - Eisen, Tim

    AU - Broderick, Samuel

    AU - Stadler, Walter M.

    AU - Jones, Robert J.

    AU - Garcia, Jorge A.

    AU - Vaishampayan, Ulka N.

    AU - Picus, Joel

    AU - Hawkins, Robert E.

    AU - Hainsworth, John D.

    AU - Kollmannsberger, Christian K.

    AU - Logan, Theodore F.

    AU - Puzanov, Igor

    AU - Pickering, Lisa M.

    AU - Ryan, Christopher

    AU - Protheroe, Andrew

    AU - Lusk, Christine M.

    AU - Oberg, Sadie

    AU - George, Daniel J.

    PY - 2016/3/1

    Y1 - 2016/3/1

    N2 - 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.

    AB - 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.

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