Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial
Abstract
Background Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. We did a phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy.Methods Patients with metastatic renal cell carcinoma which had progressed on sunitinib, sorafenib, or both, were randomly assigned in a two to one ratio to receive everolimus 10 mg once daily (n=272) or placebo (n=138), in conjunction with best supportive care. Randomisation was done centrally via an interactive voice response system using a validated computer system, and was stratified by Memorial Sloan-Kettering Cancer Center prognostic score and previous anticancer therapy, with a permuted block size of six. The primary endpoint was progression-free survival, assessed via a blinded, independent central review. The study was designed to be terminated after 290 events of progression. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00410124.Findings All randomised patients were included in efficacy analyses. The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed (101 [37%] events in the everolimus group, 90 [65%] in the placebo group; hazard ratio 0.30, 95% CI 0.22-0.40, p<0.0001; median progression-free survival 4.0 [95% CI 3.7-5.5] vs 1.9 [1.8-1.9] months). Stomatitis (107 [40%] patients in the everolimus group vs 11 [8%] in the placebo group), rash (66 [25%] vs six [4%]), and fatigue (53 [20%] vs 22 [16%]) were the most commonly reported adverse events, but were mostly mild or moderate in severity. Pneumonitis (any grade) was detected in 22 (8%) patients in the everolimus group, of whom eight had pneumonitis of grade 3 severity.Interpretation Treatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The mTOR inhibitor everolimus can prolong progression-free survival in patients with advanced renal cell carcinoma by inhibiting mTOR's promotion of HIF-1.
“The mTOR inhibitor everolimus, which has been tested in phase III clinical trials, can prolong the progression‐free survival of patients with advanced renal cell carcinoma by inhibiting the promotion of HIF‐1 by mTOR.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [184]
Cites
1 retracted
Immunotherapy for advanced renal cell cancer
Coppin, C., Porzsolt, F., Autenrieth, M. E., Kumpf, J., Coldman, A. J., & Wilt, T. J. (2004) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd001425.pub2 · Cited by 594 · see citing works
RetractedAaronson, N. K., Ahmedzai, S., Bergman, B., Bullinger, M., Cull, A., Duez, N. J., Filiberti, A., Flechtner, H., Fleishman, S. B., Haes, J. C. J. M. D., et al. (1993) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/85.5.365 · Cited by 16,005 · see citing works
New Guidelines to Evaluate the Response to Treatment in Solid Tumors
Therasse, P., Arbuck, S. G., Eisenhauer, E. A., Wanders, J., Kaplan, R. S., Rubinstein, L., Verweij, J., Van Glabbeke, M., van Oosterom, A. T., Christian, M. C., et al. (2000) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/92.3.205 · Cited by 15,660 · see citing works
Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma
Motzer, R. J., Hutson, T. E., Tomczak, P., Michaelson, M. D., Bukowski, R. M., Rixe, O., Oudard, S. M., Négrier, S., Szczylik, C. A., Kim, S. T., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa065044 · Cited by 5,752 · see citing works
Self-citationSorafenib in Advanced Clear-Cell Renal-Cell Carcinoma
Escudier, B. J., Eisen, T. G., Stadler, W. M., Szczylik, C. A., Oudard, S. M., Siebels, M., Négrier, S., Chevreau, C., Solska, E., Desai, A. A., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa060655 · Cited by 4,802 · see citing works
Self-citationTemsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma
Hudes, G. R., Carducci, M. A., Tomczak, P., Dutcher, J. P., Figlin, R. A., Kapoor, A., Starosławska, E., Sosman, J. A., McDermott, D. F., Bodrogi, I., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa066838 · Cited by 3,645 · see citing works
Self-citationA Multiple Testing Procedure for Clinical Trials
O'Brien, P. C., & Fleming, T. R. (1979) · Biometrics · doi:10.2307/2530245 · Cited by 3,311 · see citing works
Discrete sequential boundaries for clinical trials
GORDON LAN, K. K., & DEMETS, D. L. (1983) · Biometrika · doi:10.1093/biomet/70.3.659 · Cited by 2,310 · see citing works
Discrete Sequential Boundaries for Clinical Trials
Lan, K. K. G., & DeMets, D. L. (1983) · Biometrika · doi:10.2307/2336502 · Cited by 2,310 · see citing works
Motzer, R. J., Bander, N. H., & Nanus, D. M. (1996) · New England Journal of Medicine · doi:10.1056/nejm199609193351207 · Cited by 2,239 · see citing works
Self-citationEscudier, B. J., Pluzanska, A., Koralewski, P., Ravaud, A., Sergio Bracarda, A., Szczylik, C. A., Chevreau, C., Filipek, M., Melichar, B., Bajetta, E., et al. (2007) · The Lancet · doi:10.1016/s0140-6736(07)61904-7 · Cited by 2,216 · see citing works
Self-citationAtkins, M. B., Hidalgo, M. M., Stadler, W. M., Logan, T. F., Dutcher, J. P., Hudes, G. R., Park, Y., Liou, S.-H., Marshall, B., Boni, J. P., et al. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.08.185 · Cited by 942 · see citing works
Prognostic Factors for Survival in Previously Treated Patients With Metastatic Renal Cell Carcinoma
Motzer, R. J., Bacik, J., Schwartz, L. H., Reuter, V. E., Russo, P., Marion, S., & Mazumdar, M. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.06.132 · Cited by 792 · see citing works
Self-citationHypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer
Thomas, G. V., Tran, C., Mellinghoff, I. K., Welsbie, D. S., Chan, E., Fueger, B., Czernin, J., & Sawyers, C. L. (2006) · Nature Medicine · doi:10.1038/nm1337 · Cited by 604 · see citing works
Tabernero, J. M., Rojo, F., Calvo, E., Burris, H. A., Judson, I. R., Hazell, K., Martinelli, E., y Cajal, S. R., Jones, S. F., Vidal, L., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.5482 · Cited by 537 · see citing works
Self-citationTSC2 regulates VEGF through mTOR-dependent and -independent pathways
Brugarolas, J. B., Vazquez, F., Reddy, A., Sellers, W. R., & Kaelin, W. G. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00187-9 · Cited by 528 · see citing works
End Points and United States Food and Drug Administration Approval of Oncology Drugs
Johnson, J. R., Williams, G., & Pazdur, R. M. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2003.08.072 · Cited by 480 · see citing works
O’Donnell, A. E., Faivre, S. J., Burris, H. A., Rea, D. W., Papadimitrakopoulou, V. A., Shand, N., Lane, H. A., Hazell, K., Zoellner, U., Kovarik, J. M., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.0988 · Cited by 478 · see citing works
The Von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer
Kaelin, W. G. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-sup-040025 · Cited by 316 · see citing works
Renal-Cell Carcinoma — Molecular Pathways and Therapies
Brugarolas, J. (2007) · New England Journal of Medicine · doi:10.1056/nejme068263 · Cited by 256 · see citing works
Tanaka, C., O’Reilly, T., Kovarik, J. M., Shand, N., Hazell, K., Judson, I. R., Raymond, É., Zumstein-Mecker, S., Stephan, C., Boulay, A., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.1127 · Cited by 211 · see citing works
Thurnher, M., Putz, T., Rahm, A., Gander, H., Ramoner, R. E., Bartsch, G. C., Höltl, L., & Falkensammer, C. E. (2006) · Wiley eBooks · doi:10.1002/9783527619696.ch53 · Cited by 205 · see citing works
A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC)
Amato, R. J., Misellati, A., Khan, M., & Chiang, S. B. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2006.24.18_suppl.4530 · Cited by 104 · see citing works
Targeted therapy for advanced renal cell carcinoma
Coppin, C., Le, L., Wilt, T. J., & Kollmannsberger, C. (2008) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd006017.pub2 · Cited by 97 · see citing works
Development and Validation of a Scale to Measure Disease-Related Symptoms of Kidney Cancer
Cella, D. F., Yount, S., Brucker, P. S., Du, H., Bukowski, R. M., Vogelzang, N. J., & Bro, W. P. (2007) · Value in Health · doi:10.1111/j.1524-4733.2007.00183.x · Cited by 97 · see citing works
A phase II trial of RAD001 in patients (Pts) with metastatic renal cell carcinoma (MRCC)
Jac, J., Giessinger, S., Khan, M., Willis, J., Chiang, S. B., & Amato, R. J. (2007) · Journal of Clinical Oncology · doi:10.1200/jco.2007.25.18_suppl.5107 · Cited by 53 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Comprehensive molecular characterization of clear cell renal cell carcinoma
The Cancer Genome Atlas Research Network (2013) · Nature · doi:10.1038/nature12222 · Cited by 3,485 · see citing works
Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Escudier, B., Porta, C., Schmidinger, M., Rioux-Leclercq, N., Bex, A., Khoo, V., Grünwald, V., Gillessen, S., & Horwich, A. (2019) · Annals of Oncology · doi:10.1093/annonc/mdz056 · Cited by 1,151 · see citing works
Self-citationTargeting the PI3K pathway in cancer: are we making headway?
Janku, F., Yap, T. A., & Meric-Bernstam, F. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2018.28 · Cited by 1,033 · see citing works
Targeting the translation machinery in cancer
Bhat, M., Robichaud, N., Hulea, L., Sonenberg, N., Pelletier, J., & Topisirovic, I. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4505 · Cited by 799 · see citing works
Cherny, N. I., Sullivan, R., Dafni, U., Kerst, J. M., Sobrero, A., Zielinski, C., de Vries, E. G. E., & Piccart, M. J. (2015) · Annals of Oncology · doi:10.1093/annonc/mdv249 · Cited by 818 · see citing works
Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma
Clark, D. J., Dhanasekaran, S. M., Petralia, F., Pan, J., Song, X., Hu, Y., da Veiga Leprevost, F., Reva, B., Lih, T.-S. M., Chang, H.-Y., et al. (2019) · Cell · doi:10.1016/j.cell.2019.10.007 · Cited by 730 · see citing works
Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway
Polivka, J., & Janku, F. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.12.004 · Cited by 765 · see citing works
Targeting the cancer kinome through polypharmacology
Knight, Z. A., Lin, H., & Shokat, K. M. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2787 · Cited by 674 · see citing works
Properties of FDA-approved small molecule protein kinase inhibitors
Roskoski, R. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.03.006 · Cited by 554 · see citing works
Dual role of autophagy in hallmarks of cancer
Singh, S. S., Vats, S., Chia, A. Y.-Q., Tan, T. Z., Deng, S., Ong, M. S., Arfuso, F., Yap, C. T., Goh, B. C., Sethi, G., et al. (2018) · Oncogene · doi:10.1038/s41388-017-0046-6 · Cited by 542 · see citing works
Targeting the HIF2–VEGF axis in renal cell carcinoma
Choueiri, T. K., & Kaelin, W. G. (2020) · Nature Medicine · doi:10.1038/s41591-020-1093-z · Cited by 477 · see citing works
mTOR: Role in cancer, metastasis and drug resistance
Murugan, A. K. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.07.003 · Cited by 483 · see citing works
Review: Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management
Stein, A., Voigt, W., & Jordan, K. (2010) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834009355164 · Cited by 431 · see citing works
Geissler, E. K., Schnitzbauer, A. A., Zülke, C., Lamby, P. E., Proneth, A., Duvoux, C., Burra, P., Jauch, K.-W., Rentsch, M., Ganten, T. M., et al. (2016) · Transplantation · doi:10.1097/tp.0000000000000965 · Cited by 433 · see citing works
Wander, S. A., Hennessy, B. T., & Slingerland, J. M. (2011) · Journal of Clinical Investigation · doi:10.1172/jci44145 · Cited by 427 · see citing works
Martinez-Outschoorn, U. E., Pavlides, S., Howell, A., Pestell, R. G., Tanowitz, H. B., Sotgia, F., & Lisanti, M. P. (2011) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2011.01.023 · Cited by 248 · see citing works
Demetri, G. D., Chawla, S. P., Ray-Coquard, I., Le Cesne, A., Staddon, A. P., Milhem, M. M., Penel, N., Riedel, R. F., Bui-Nguyen, B., Cranmer, L. D., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.45.5766 · Cited by 245 · see citing works
Anti-VEGF therapies in the clinic
Meadows, K. L., & Hurwitz, H. I. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006577 · Cited by 237 · see citing works
Roles of mTOR complexes in the kidney: implications for renal disease and transplantation
Fantus, D., Rogers, N. M., Grahammer, F., Huber, T. B., & Thomson, A. W. (2016) · Nature Reviews Nephrology · doi:10.1038/nrneph.2016.108 · Cited by 208 · see citing works
Adverse events associated with mTOR inhibitors
Pallet, N., & Legendre, C. (2013) · Expert Opinion on Drug Safety · doi:10.1517/14740338.2013.752814 · Cited by 198 · see citing works
Coordinate Autophagy and mTOR Pathway Inhibition Enhances Cell Death in Melanoma
Xie, X., White, E. P., & Mehnert, J. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0055096 · Cited by 150 · see citing works
Petrelli, N. J., Winer, E. P., Brahmer, J., Dubey, S., Smith, S., Thomas, C., Vahdat, L. T., Obel, J., Vogelzang, N., Markman, M., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.26.6171 · Cited by 121 · see citing works
Hypoxia signaling in cancer: Implications for therapeutic interventions
Zhuang, Y., Liu, K., He, Q., Gu, X., Jiang, C., & Wu, J. (2023) · MedComm · doi:10.1002/mco2.203 · Cited by 119 · see citing works
When are ‘positive’ clinical trials in oncology truly positive?
Ocana, A., & Tannock, I. F. (2011) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djq463 · Cited by 110 · see citing works
Fox, J. H., Connor, T., Chopra, V., Dorsey, K., Kama, J. A., Bleckmann, D., Betschart, C., Hoyer, D., Frentzel, S., DiFiglia, M., et al. (2010) · Molecular Neurodegeneration · doi:10.1186/1750-1326-5-26 · Cited by 94 · see citing works
Kordes, S., Klümpen, H. J., Weterman, M. J., Schellens, J. H. M., Richel, D. J., & Wilmink, J. W. (2015) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-015-2730-y · Cited by 71 · see citing works
Translating statistical findings into plain English
Pocock, S. J., & Ware, J. H. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60499-2 · Cited by 67 · see citing works
Wall, M., Poortinga, G., Stanley, K. L., Lindemann, R. K., Bots, M., Chan, C. J., Bywater, M. J., Kinross, K. M., Astle, M. V., Waldeck, K., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0404 · Cited by 64 · see citing works
Evangelisti, C., Cenni, V., & Lattanzi, G. (2016) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12928 · Cited by 53 · see citing works
BEZ235: When Promising Science Meets Clinical Reality
Pongas, G., & Fojo, T. (2016) · The Oncologist · doi:10.1634/theoncologist.2016-0243 · Cited by 43 · see citing works
Faes, S., Demartines, N., & Dormond, O. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.636037 · Cited by 41 · see citing works
Su, Y., Zhang, T., Lu, J., Qian, L., Fei, Y., Zhang, L., Fan, S., Zhou, J., Tang, J., Chen, H., et al. (2023) · Cells · doi:10.3390/cells12010180 · Cited by 20 · see citing works
Inhibiteurs de mTOR : temsirolimus et évérolimus dans le traitement du cancer du rein
Ravaud, A., Bernhard, J.-C., Gross-Goupil, M., Digue, L., & Ferriere, J.-M. (2010) · Bulletin du Cancer · doi:10.1684/bdc.2010.1069 · Cited by 14 · see citing works
Self-citationActivation of the Akt/mammalian target of rapamycin pathway in myxofibrosarcomas
Takahashi, Y., Kohashi, K., Yamada, Y., Endo, M., Setsu, N., Ishii, T., Yamamoto, H., Iwamoto, Y., & Oda, Y. (2014) · Human Pathology · doi:10.1016/j.humpath.2013.12.012 · Cited by 11 · see citing works
- Authors
- Motzer, R. J., Escudier, B., Oudard, S., Hutson, T. E., Porta, C., Bracarda, S., Grünwald, V., Thompson, J. A., Figlin, R. A., Hollaender, N., Urbanowitz, G., Berg, W. J., Kay, A., Lebwohl, D., & Ravaud, A.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Institut Gustave Roussy (FR)
- Hôpital Européen Georges-Pompidou (FR)
- University of Pavia (IT)
- Medizinische Hochschule Hannover (DE)
- Seattle Cancer Care Alliance (US)
- City Of Hope National Medical Center (US)
- Centre Hospitalier Universitaire de Bordeaux (FR)
- Corresponding author
- Motzer, Robert J
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 372
- Issue
- 9637
- Pages
- 449-456
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2118677643
- Cited by
- 3,019
- References
- 26
- Citations by year
- 2026: 33 · 2025: 48 · 2024: 49 · 2023: 95 · 2022: 94 · 2021: 88 · 2020: 123 · 2019: 132 · 2018: 161 · 2017: 177 · 2016: 211 · 2015: 233 · 2014: 240 · 2013: 295 · 2012: 254
- FWCI
- 239.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- Funders
- Novartis
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Health Sciences › Medicine › Surgery › Bladder and Urothelial Cancer Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- everolimus, metastatic renal cell carcinoma, mTOR inhibitors, progression-free survival, sunitinib, sorafenib, anti-VEGF therapy, pneumonitis, stomatitis, adverse events, best supportive care, early trial termination, oral anticancer therapy, survival after nephrectomy
- MeSH terms
- Everolimus, Adult, Aged, Aged, 80 and over, Carcinoma, Renal Cell, Double-Blind Method, Female, Humans, Immunosuppressive Agents, Kidney Neoplasms, Male, Middle Aged, Neoplasm Metastasis, Karnofsky Performance Status, Disease-Free Survival, Sirolimus
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
