Updated European Association of Urology Guidelines: Recommendations for the Treatment of First-line Metastatic Clear Cell Renal Cancer
Powles, Thomas; Albiges, Laurence; Staehler, Michael; Bensalah, Karim; Dabestani, Saeed; Giles, Rachel H.; Hofmann, Fabian; Hora, Milan; Kuczyk, Markus A.; Lam, Thomas B.; Marconi, Lorenzo; Merseburger, Axel S.; Fernández-Pello, Sergio; Tahbaz, Rana; Volpe, Alessandro; Ljungberg, Börje; Bex, Axel
(2018) European Urology, volume 73, issue 3, pp. 311 - 315
(Article)
Abstract
The randomised phase III clinical trial Checkmate-214 showed a survival superiority for the combination of ipilimumab and nivolumab when compared with the previous standard of care in first-line metastatic/advanced clear cell renal cell carcinoma (RCC) (Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab
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plus ipilimumab vs sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. LBA5, ESMO 2017, 2017). These results change the frontline standard of care for this disease and have implications for the selection of subsequent therapies. For this reason the European Association of Urology RCC guidelines have been updated. Patient summary: The European Association of Urology guidelines will be updated based on the results of the phase III Checkmate-214 clinical trial. The trial showed superior survival for a combination of ipilimumab and nivolumab (IN), compared with the previous standard of care, in intermediate- and poor-risk patients with metastatic clear cell renal cell carcinoma. When IN is not safe or feasible, alternative agents such as sunitinib, pazopanib, and cabozantinib should be considered. Furthermore, at present, the data from the trial are immature in favourable-risk patients. Therefore, sunitinib or pazopanib remains the favoured agent for this subgroup of patients. Based on the Checkmate-214 trial, the European Association of Urology guidelines, which will be updated, recommend ipilimumab and nivolumab (IN) as the standard of care in intermediate- and poor-risk patients with metastatic clear cell renal cell carcinoma. Alternative agents such as sunitinib, pazopanib, and cabozantinib should be considered when IN is not safe or feasible. At present, in favourable-risk patients, the data from the trial are immature. Therefore, sunitinib or pazopanib remains the preferred agent in this subgroup of patients.
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Keywords: European Association of Urology guidelines, Ipilimumab, Nivolumab, Renal cell carcinoma, Urology
ISSN: 0302-2838
Publisher: Elsevier
Note: Funding Information: Sequencing of targeted therapies is established in mRCC and maximises outcomes , which is weak due to a lack of high-level data. [10] . IN is a new standard of care for frontline therapy. Its impact on subsequent therapies is unclear, although OS with IN in the CheckMate-214 trial is longer than one would predict from PFS, suggesting significant activity of subsequent agents. The Guidelines Panel provides the recommendation, as listed in Table 3 Subsequent therapy for patients with IN-refractory disease in first line has not been prospectively tested. However, progression of disease while receiving IN should result in subsequent sequencing of targeted therapy ( Fig. 1 ). VEGF-targeted therapies have the most robust efficacy record of activity in mRCC [2] . These agents should be initially prioritised. The Guidelines Panel was unable to specify which VEGF-targeted therapy to use. Axitinib has positive data in VEGF and cytokine-refractory disease for PFS [11] . Cabozantinib has positive trials in multiple settings in mRCC, including OS [12] . Sunitinib and pazopanib were the standard first-line VEGF-targeted therapies in unselected patients justifying their use [1] . Tivozanib, sorafenib, and bevacizumab/interferon are less favoured and not widely used [2] . The panel does not favour the use of mTOR inhibitors unless VEGF-targeted therapy is contraindicated, as they have been outperformed by other VEGF-targeted therapies in mRCC [2] . The combination of bevacizumab and interferon alpha would involve rechallenge with immune therapy, which requires further data prior to a positive recommendation [13] . Drug choice in the third-line setting, after IN and subsequent VEGF-targeted therapy, is unknown. The panel recommends a subsequent agent that is approved in VEGF-refractory disease, with the exception of a rechallenge with nivolumab. Cabozantinib is the only agent in VEGF-refractory disease with a survival advantage in a randomised phase III trial and should be used preferentially [12] . Axitinib has positive PFS data in VEGF-refractory disease. Both sorafenib and everolimus have been outperformed by other agents in VEGF-refractory disease and are therefore less attractive [2] . Lenvatinib and everolimus has regulatory approval based on randomised phase II data and is an alternative despite the fact that only phase II data are available [14] . There is no evidence for sequencing of immune therapies, which remains within the realm of clinical trials. Patients should only receive individual immune checkpoint inhibition once, in the opinion of the panel. Rechallenge with nivolumab or IN is not recommended at this stage. While data with the combination of VEGF-targeted therapy and immune checkpoint inhibition are promising, further randomised data will be needed before any recommendations can be provided. Author contributions: Thomas Powles had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Powles, Albiges, Ljungberg, Bex. Acquisition of data: Powles, Albiges, Bex. Analysis and interpretation of data: Powles, Albiges, Ljungberg, Bex. Drafting of the manuscript: Powles, Bex. Critical revision of the manuscript for important intellectual content: Staehler, Bensalah, Dabestani, Giles, Hofmann, Hora, Kuczyk, Lam, Marconi, Merseburger, Fernández-Pello, Tahbaz, Volpe, Ljungberg. Statistical analysis: None. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Powles, Bex, Ljungberg. Other: None. Financial disclosures: Thomas Powles certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Thomas Powles is a company consultant for Novartis, Pfizer, and GlaxoSmithKline; has received company speaker honoraria from Novartis, Pfizer, GlaxoSmithKline, and Genentech; has participated in trials for GlaxoSmithKline, Pfizer, BMS, Genentech, and Genetech; and has received grants/research support from GlaxoSmithKline, Pfizer, and Novartis. Laurence Albiges has received consulting/advisory fees from BMS, Pfizer, Novartis, Sanofi, Amgen, Bristol-Myers Squibb, Bayer, and Cerulean, and has received research funding from Pfizer and Novartis. Michael Staehler is a company consultant for Pfizer, Novartis, GlaxoSmithKline, Roche, Astellas, and Bayer; has received company speaker honoraria from Pfizer, Novartis, GlaxoSmithKline, Roche, Astellas, Bayer, and Aveo; has participated in trials for Pfizer, Novartis, GlaxoSmithKline, Roche, Bayer, Aveo, Wilex, and Immatics; has received fellowships and travel grants from Pfizer, Novartis, GlaxoSmithKline, Roche, and Bayer; has received grants/research support from Pfizer, Novartis, GlaxoSmithKline, Roche, Bayer, and Aveo; and also took part in the S-TRAC trial as an investigator and is an author on the S-TRAC publication. Karim Bensalah has received grants/research support from Pfizer and honoraria or consultation fees from Intuitive Surgical. Milan Hora has received company speaker honoraria from Covidien, Olympus, Janssen, and Astellas; has participated in trials for Janssen; and has received grants/research support from Ipsen. Markus A. Kuczyk is a stock shareholder of Bayer Healthcare, Astellas, Storz, Pfizer, Wyeth, and Novartis; is a company consultant for Karl Storz, Coloplast, AstraZeneca, Astellas, Storz, and Hexal; has received company speaker honoraria from Pfizer, Astellas, Bayer, GlaxoSmithKline, Pierre Fabre, Janssen Cilag, and Hexal; has participated in trials for the ProtecT Study, Millenium Study C21004, Millenium Study C21005, Astellas, Ipsen, and Janssen; and has received grants/research support from Wyeth and Pfizer. Thomas B. Lam is a company consultant for and has received company speaker honoraria from Pfizer, GlaxoSmithKline, Astellas, and Ipsen. Axel S. Merseburger is a company consultant for Ipsen Pharma, Bayer, Astellas, Janssen Cilag, Novartis, and Pfizer; has received company speaker honoraria from Ipsen Pharma, Wyeth, Astellas, Novartis, Pfizer, and SEP; has participated in trials for AstraZeneca, Bayer, Pfizer, TEVA, Novartis, and Astellas; has received grants/research support from Wyeth; and has participated in a company-sponsored speakers bureau for TEVA, Janssen, Pfizer, Astellas, Ferring, and Novartis. Börje Ljungberg has received company speaker honoraria from GlaxoSmithKline, Roche, Pfizer, and Novartis; has participated in trials for GlaxoSmithKline, Medivation, Pfizer, and Janssen R&D; and has been on advisory boards for Pfizer and GlaxoSmithKline. Axel Bex has received company speaker honoraria from Pfizer; has participated in trials for Pfizer Europe; has participated in advisory boards for GlaxoSmithKline and Novartis; is a company consultant for Pfizer and Novartis; and has received grants/research support from Pfizer. Saeed Dabestani, Rachel H. Giles, Fabian Hofmann, Lorenzo Marconi, Sergio Fernéndez-Pello, Rana Tahbaz, and Alessandro Volpe have nothing to disclose. Funding/Support and role of the sponsor: None. Publisher Copyright: © 2017 European Association of Urology
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