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What Do International Guidelines Say About First-line Therapy for Clear-cell Metastatic Renal Cell Carcinoma?
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Guidelines – Kidney Cancer
What Do International Guidelines Say About First-line Therapy for Clear-cell Metastatic Renal Cell Carcinoma? Myuran Thana a,b,*, Lori Anne Wood a,b a
Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; b Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada
Article info
Abstract
Article history: Accepted September 20, 2019
Treatment options for clear-cell metastatic renal cell carcinoma (mRCC) have increased significantly. Clinical practice guidelines aim to aid with decision-making about treatment selection through evidence-based recommendations. In this article, recommendations on first-line treatment for clear-cell mRCC in guidelines from three international organizations are reviewed and summarized. Future guideline development should focus on dynamic updates based on practice-changing data and guidance regarding therapy selection. Patient summary: International guidelines for first-line treatment of metastatic renal cell carcinoma are reviewed in this article. The main differences between guidelines appear to be how quickly the newest evidence is included. © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Gratzke
Editor:
Christian
Keywords: Clear-cell renal cell carcinoma Clinical practice guidelines First line Metastatic Checkpoint inhibitors Targeted therapy Cytokine therapy Active surveillance
* Corresponding author. Queen Elizabeth II Health Sciences Centre, 1276 South Park Street, Halifax, Nova Scotia B3H 2Y9, Canada. Tel.: +1 902 4738317; Fax: +1 902 4736186. E-mail address: [email protected] (M. Thana).
1.
Introduction
Systemic therapy options for metastatic renal cell carcinoma (mRCC) have increased dramatically with the introduction of VEGF-targeted therapy, immune checkpoint inhibitors (CPI), and now combinations of these agents. However, as the number of options increases, the more challenging it can be to decide on the optimal choice for a given patient. Clinical practice guidelines can aid in standardizing care, ensuring that clinicians are aware of up-todate data, and provide recommendations that can temper
some of the potential uncertainty in selecting a treatment strategy. Many national and international societies develop and publish their own mRCC recommendations independently to tailor content to clinicians practicing in similar situations. In this article, we review recommendations for first-line therapy for clear-cell mRCC from English-language guidelines updated since 2018, including the European Association of Urology (EAU) [1,2], the European Society of Medical Oncology (ESMO) [3], and the National Comprehensive Cancer Network (NCCN) [4] in the USA. This timeframe
https://doi.org/10.1016/j.euf.2019.09.014 2405-4569/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Thana M, Wood LA, What Do International Guidelines Say About First-line Therapy for Clearcell Metastatic Renal Cell Carcinoma?. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.09.014
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was chosen to include guidelines that incorporate recent data on first-line CPI regimens, and thus excludes certain guidelines such as the Kidney Cancer Research Network of Canada, Spanish Society of Medical Oncology, and Saudi Oncology Society/Saudi Urological Association guidelines, which were all published in 2017. The recommendations for first-line systemic therapy from the EAU, ESMO, and NCCN guidelines are summarized (Table 1) and salient similarities and differences are highlighted. 2.
4.
CPI therapy
4.1.
Ipilimumab plus nivolumab
Risk stratification
All three guidelines recommend that treatment decisions should be based on a risk assessment with a validated scoring system, most commonly the Memorial Sloan Kettering Cancer Center (MSKCC) [5] and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) [6] criteria. Both stratify patients into favorable-, intermediate-, or poor-risk categories on the basis of prognostic factors (Table 2). The ESMO guidelines advocate using either system. The NCCN presents both the IMDC and MSKCC criteria, but bases treatment recommendations on the IMDC system. The EAU guideline recommends using the IMDC risk groups but acknowledges that the MSKCC criteria are “also widely used”. 3.
While the ESMO guidelines indicate that surveillance should be considered for patients with “limited disease and few symptoms”, the NCCN does not provide specific recommendations as to who should be considered for this strategy. The EAU guidelines do not mention active surveillance.
Active surveillance
A certain subset of patients may not require immediate systemic therapy and may benefit from a period of observation, referred to as active surveillance. This approach is supported by a phase 2 prospective trial [7]. In this singlearm trial, 52 asymptomatic, treatment-naïve patients with mRCC underwent surveillance and the time to initiation of first-line therapy was determined. The median time on surveillance was 14.9 mo, with none of the patients experiencing symptomatic progression during that time.
Coinciding with recently published data, the recommendations for first-line therapy have undergone significant changes, predominantly with regard to CPI therapies. The CheckMate 214 trial has changed the standard of care for intermediate- and poor-risk disease. This trial showed that ipilimumab plus nivolumab improved overall survival (OS) and objective response rates over sunitinib in patients with IMDC intermediate and poor risk [8]. These data are reflected in the NCCN, ESMO, and EAU guidelines, all of which strongly recommend ipilimumab plus nivolumab as first-line therapy for intermediate- and poor-risk disease. The NCCN also recommends the combination of ipilimumab plus nivolumab for favorable-risk disease as an “alternative” regimen. No other guidelines recommend the use of this regimen in patients with favorable risk; while CheckMate 214 included this patient cohort, the favorable-risk subgroup was not included in the primary endpoints. The NCCN does not provide specific direction regarding the situations for which this regimen should be considered in favorablerisk disease. 4.2.
Axitinib plus pembrolizumab
The NCCN and EAU both recommend the combination of axitinib plus pembrolizumab as a preferred regimen. This combination was found to be superior to sunitinib in terms
Table 1 – Summary of recommendations for treatment-naïve metastatic clear-cell renal cell carcinoma from three international guidelines. Guideline
Favorable risk Preferred
NCCN 2019 Axitinib + PMB Pazopanib Sunitinib
ESMO 2019 EAU 2019
Sunitinib Pazopanib Bevacizumab + IFN Tivozanib
Axitinib + PMB
Intermediate risk
Alternatives
Preferred
Ipilimumab + nivolumab Pazopanib Axitinib + PMB Sunitinib Cabozantinib Axitinib + avelumab Axitinib High-dose IL-2 Bevacizumab + IFN Temsirolimus Ipilimumab + nivolumab Sunitinib Pazopanib Cabozantinib Tivozanib Bevacizumab + IFN Ipilimumab + nivolumab Cabozantinib Axitinib + PMB Sunitinib Pazopanib
Ipilimumab + nivolumab Cabozantinib Axitinib + avelumab Axitinib High-dose IL-2 Bevacizumab + IFN Surveillance High-dose IL-2 Surveillance
Sunitinib Pazopanib
Alternative
Poor risk Preferred
Alternative
Ipilimumab + nivolumab Pazopanib Axitinib + PMB Sunitinib Cabozantinib Axitinib + avelumab Axitinib High-dose IL-2 Bevacizumab + IFN Temsirolimus Ipilimumab + nivolumab Temsirolimus Cabozantinib Sunitinib Pazopanib Ipilimumab + nivolumab Cabozantinib Axitinib + PMB Sunitinib Pazopanib
NCCN = National Comprehensive Cancer Network; ESMO = European Society of Medical Oncology; EAU = European Association of Urology; PMB = pembrolizumab; IFN = interferon; IL-2 = interleukin-2.
Please cite this article in press as: Thana M, Wood LA, What Do International Guidelines Say About First-line Therapy for Clearcell Metastatic Renal Cell Carcinoma?. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.09.014
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Table 2 – Prognostic risk factors for the IMDC and MSKCC criteria.a IMDC
MSKCC
Low hemoglobin (ULN) Elevated neutrophil count (>ULN) Hypercalcemia (>ULN) KPS <80% Less than 1 yr from time of diagnosis to treatment
Low hemoglobin (ULN) Elevated neutrophil count (>ULN) Hypercalcemia (>ULN) KPS <80% Less than 1 yr from time of diagnosis to treatment
IMDC = International Metastatic Renal Cell Carcinoma Database Consortium; MSKCC = Memorial Sloan-Kettering Cancer Center; LLN = lower limit of normal; ULN = upper limit of normal; KPS = Karnofsky performance status. a No risk factors = favorable risk; 1–2 risk factors = intermediate risk; 3–6 risk factors = poor risk.
of OS and progression-free survival (PFS) in the KEYNOTE426 phase 3 trial [9]. This benefit was seen across all subgroups, including all IMDC risk categories. The NCCN guidelines do not state whether axitinib plus pembrolizumab is favored over the former standards of care for favorable-risk disease (sunitinib or pazopanib), and all three options are currently listed as “preferred regimens”. Conversely, the EAU specifies that axitinib plus pembrolizumab is the standard of care for favorable-risk disease, with sunitinib and pazopanib being alternatives for patients who cannot receive or tolerate CPI. Notably, this regimen has not been compared to ipilimumab plus nivolumab, and there is a lack of direct evidence as to which treatment should be used in intermediate- or poor-risk disease. Accordingly, neither the NCCN nor EAU guidelines recommend one regimen over the other for these patients. The recent ESMO guidelines do not yet include the CPI plus axitinib combination data in their recommendations. 4.3.
Axitinib plus avelumab
The combination of axitinib plus avelumab was also compared to sunitinib in the JAVELIN Renal 101 phase 3 trial [10]. While one of the primary endpoints in the clinical trial (PFS in the PD-L1–positive patient population) was positive, the other primary endpoint of OS in PD-L1–positive patients did not show a statistically significant improvement at the data cutoff. The NCCN is the only guideline currently recommending this option for all risk groups as an “other recommended regimen”. In their recent update, the EAU specifically did not recommend using axitinib plus avelumab because of the lack of an OS benefit. 5.
Molecularly targeted therapy
Before CPI therapies, anti-VEGF treatments constituted the mainstay of mRCC therapy. Sunitinib and pazopanib are still both commonly used as first-line therapy. Accordingly, the NCCN and ESMO both strongly recommend either for favorable-risk disease. The recent EAU guideline update, however, recommends axitinib plus pembrolizumab over sunitinib or pazopanib for favorable-risk mRCC. For patients with intermediate- and poor-risk disease, the EAU, ESMO, and NCCN have all relegated sunitinib and pazopanib to alternative regimens in favor of ipilimumab plus nivolumab
and (in the case of the EAU and NCCN) axitinib plus pembrolizumab on the basis of the CheckMate 214 and KEYNOTE-426 results, respectively. The NCCN recommends cabozantinib as a “preferred regimen” for intermediate- and poor-risk disease on the basis of randomized phase 2 data [11]. No other guidelines list cabozantinib as a preferred regimen in the first-line setting. However, the EAU and ESMO do list it as an alternative regimen in certain scenarios (Table 1). Tivozanib, another anti-VEGF tyrosine kinase inhibitor, is only mentioned in the ESMO and EAU guidelines, with conflicting recommendations. The EAU makes a weak recommendation against offering tivozanib, noting it is “considered inferior over existing options”. ESMO lists tivozanib as a “standard” option, but notes it has the lowest score using the ESMO Magnitude of Clinical Benefit Scale [12]. Several other targeted therapies are listed as alternative regimens (Table 1). 6.
Cytokine therapy
The combination of the anti-VEGF monoclonal antibody bevacizumab with interferon is provided as a standard option in the ESMO guidelines, with the NCCN also listing this regimen as “useful under certain circumstances”. Both also mention high-dose interleukin-2 as an alternative option. Conversely, the EAU makes a weak recommendation against using both regimens. 7.
Discussion
First-line treatment for clear-cell mRCC is rapidly evolving, with practice-changing results from phase 3 trials being presented at nearly every recent major oncology conference. The three guidelines reviewed here provide clinicians with relevant recommendations that incorporate recent data. The three guidelines take somewhat different approaches to providing recommendations. The NCCN frequently updates their guidelines, and was the first to include CPI plus axitinib combinations. Conversely, the ESMO guidelines are yet to provide an update stating their position on these new regimens. With an impressive pace of advances in this field, groups that create guidelines should
Please cite this article in press as: Thana M, Wood LA, What Do International Guidelines Say About First-line Therapy for Clearcell Metastatic Renal Cell Carcinoma?. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.09.014
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use a dynamic process to provide updates as breakthroughs are made, as opposed to at set time intervals. It is also of interest that the NCCN and ESMO guidelines add newer regimens to a list including previous standard-of-care recommendations, instead of replacing them or providing guidance on when to select an older regimen. This can create challenges, especially for clinicians who do not see a high volume of mRCC patients. The EAU guidelines make some attempt at prioritizing, by providing several “weak” recommendations against the use of older options. While these guidelines highlight the benefit of outlining treatment options, there are inherent limitations that preclude clinicians from completely relying on guidelines for all aspects of decision-making, leaving many aspects of mRCC care unaddressed. These include factors, other than IMDC and MSKCC criteria, to help in guiding choice of a firstline therapy. One of the major dilemmas that clinicians will soon face is what option to choose for patients with intermediate- or poor-risk mRCC: the combination of ipilimumab plus nivolumab or axitinib plus pembrolizumab. Based on the format and information in current guidelines, both will be listed as options for these patients, with minimal direction on how to choose one over the other. Without direct comparisons between these two regimens, the use of indirect comparative methods has been proposed. For example, a network meta-analysis indicated that axitinib plus pembrolizumab is likely to provide longer survival compared to other options [13]. However, indirect statistical comparisons from heterogeneous trials must be done with caution, and should have a limited role both in informing guideline recommendations and in the clinician’s decisionmaking process. As noted above, active surveillance has supportive prospective evidence and is mentioned in two of the three guidelines, but there is only limited guidance as to which patients should be considered for this strategy. The aforementioned phase 2 trial did not have specific criteria for selecting patients other than being asymptomatic and treatment-naïve [7]. Multivariable analysis indicated that solitary organ system involvement and fewer IMDC risk factors were associated with longer surveillance duration, but presumably other key factors would be important to consider, such as growth kinetics and sites of metastases. Other factors that can aid in selecting a first-line treatment, such as cost-effectiveness, quality of life, risk of toxicities (especially for certain subpopulations, such as those with pre-existing autoimmune disorders), hereditary RCC, and poor performance status are not discussed in detail in most guidelines. In situations where multiple options exist without direct comparison to indicate superior efficacy, these factors can help clinicians select an appropriate regimen, and should be highlighed in guidelines.
clinical assessment and shared decision-making that occur in the clinic. Understanding the strengths and shortcomings of these recommendations is essential to incorporating them into daily practice.
Author contributions: Myuran Thana 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: Wood, Thana. Acquisition of data: Thana, Wood. Analysis and interpretation of data: Wood, Thana. Drafting of the manuscript: Thana, Wood. Critical revision of the manuscript for important intellectual content: Wood, Thana. Statistical analysis: None. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Wood. Other: None.
Financial disclosures: Myuran Thana 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: Lori Anne Wood is an unpaid advisory board member for Astellas, Novartis, and Pfizer, and has participated in clinical trials with Aragon, AstraZeneca, BMS, Exelixis, Merck, Pfizer, and Roche. Myuran Thana has nothing to disclose.
Funding/Support and role of the sponsor: None.
References [1] Ljungberg B, Albiges L, Abu-Ghanem Y, et al. European Association of Urology guidelines on renal cell carcinoma: the 2019 update. Eur Urol 2019;75:799–810. [2] Albiges L, Powles T, Staehler M, et al. Updated European Association of Urology guidelines on renal cell carcinoma: immune checkpoint inhibition is the new backbone in first-line treatment of metastatic clear-cell renal cell carcinoma. Eur Urol 2019;76:151–6. [3] Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2019;30:706–20. [4] National Comprehensive Cancer Network. Kidney cancer (version 2.2020). www.nccn.org/professionals/physician_gls/pdf/ kidney.pdf. [5] Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004;22:454–63. [6] Heng DYC, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic RenalCell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol 2013;14:141–8. [7] Rini BI, Dorff TB, Elson P, et al. Active surveillance in metastatic
8.
Conclusions
renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol 2016;17:1317–24. [8] Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipili-
Ultimately, the aim of guidelines is to provide evidencebased guidance for clinicians and cannot substitute for the
mumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277–90.
Please cite this article in press as: Thana M, Wood LA, What Do International Guidelines Say About First-line Therapy for Clearcell Metastatic Renal Cell Carcinoma?. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.09.014
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[9] Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1116–27. [10] Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1103–15. [11] Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus suni-
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cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol 2017;35:591–7. [12] Cherny NI, Dafni U, Bogaerts J, et al. ESMO-Magnitude of Clinical Benefit Scale version 1.1. Ann Oncol 2017;28:2340–66. [13] Klaassen Z, Satkunasivam R, Wallis CJD. Immune checkpoint blockade plus axitinib for renal-cell carcinoma. N Engl J Med 2019;380:2581–2.
tinib as initial targeted therapy for patients with metastatic renal
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available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Guidelines – Kidney Cancer
What Do International Guidelines Say About First-line Therapy for Clear-cell Metastatic Renal Cell Carcinoma? Myuran Thana a,b,*, Lori Anne Wood a,b a
Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; b Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada
Article info
Abstract
Article history: Accepted September 20, 2019
Treatment options for clear-cell metastatic renal cell carcinoma (mRCC) have increased significantly. Clinical practice guidelines aim to aid with decision-making about treatment selection through evidence-based recommendations. In this article, recommendations on first-line treatment for clear-cell mRCC in guidelines from three international organizations are reviewed and summarized. Future guideline development should focus on dynamic updates based on practice-changing data and guidance regarding therapy selection. Patient summary: International guidelines for first-line treatment of metastatic renal cell carcinoma are reviewed in this article. The main differences between guidelines appear to be how quickly the newest evidence is included. © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Gratzke
Editor:
Christian
Keywords: Clear-cell renal cell carcinoma Clinical practice guidelines First line Metastatic Checkpoint inhibitors Targeted therapy Cytokine therapy Active surveillance
* Corresponding author. Queen Elizabeth II Health Sciences Centre, 1276 South Park Street, Halifax, Nova Scotia B3H 2Y9, Canada. Tel.: +1 902 4738317; Fax: +1 902 4736186. E-mail address: [email protected] (M. Thana).
1.
Introduction
Systemic therapy options for metastatic renal cell carcinoma (mRCC) have increased dramatically with the introduction of VEGF-targeted therapy, immune checkpoint inhibitors (CPI), and now combinations of these agents. However, as the number of options increases, the more challenging it can be to decide on the optimal choice for a given patient. Clinical practice guidelines can aid in standardizing care, ensuring that clinicians are aware of up-todate data, and provide recommendations that can temper
some of the potential uncertainty in selecting a treatment strategy. Many national and international societies develop and publish their own mRCC recommendations independently to tailor content to clinicians practicing in similar situations. In this article, we review recommendations for first-line therapy for clear-cell mRCC from English-language guidelines updated since 2018, including the European Association of Urology (EAU) [1,2], the European Society of Medical Oncology (ESMO) [3], and the National Comprehensive Cancer Network (NCCN) [4] in the USA. This timeframe
https://doi.org/10.1016/j.euf.2019.09.014 2405-4569/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Thana M, Wood LA, What Do International Guidelines Say About First-line Therapy for Clearcell Metastatic Renal Cell Carcinoma?. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.09.014
EUF-806; No. of Pages 5 2
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was chosen to include guidelines that incorporate recent data on first-line CPI regimens, and thus excludes certain guidelines such as the Kidney Cancer Research Network of Canada, Spanish Society of Medical Oncology, and Saudi Oncology Society/Saudi Urological Association guidelines, which were all published in 2017. The recommendations for first-line systemic therapy from the EAU, ESMO, and NCCN guidelines are summarized (Table 1) and salient similarities and differences are highlighted. 2.
4.
CPI therapy
4.1.
Ipilimumab plus nivolumab
Risk stratification
All three guidelines recommend that treatment decisions should be based on a risk assessment with a validated scoring system, most commonly the Memorial Sloan Kettering Cancer Center (MSKCC) [5] and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) [6] criteria. Both stratify patients into favorable-, intermediate-, or poor-risk categories on the basis of prognostic factors (Table 2). The ESMO guidelines advocate using either system. The NCCN presents both the IMDC and MSKCC criteria, but bases treatment recommendations on the IMDC system. The EAU guideline recommends using the IMDC risk groups but acknowledges that the MSKCC criteria are “also widely used”. 3.
While the ESMO guidelines indicate that surveillance should be considered for patients with “limited disease and few symptoms”, the NCCN does not provide specific recommendations as to who should be considered for this strategy. The EAU guidelines do not mention active surveillance.
Active surveillance
A certain subset of patients may not require immediate systemic therapy and may benefit from a period of observation, referred to as active surveillance. This approach is supported by a phase 2 prospective trial [7]. In this singlearm trial, 52 asymptomatic, treatment-naïve patients with mRCC underwent surveillance and the time to initiation of first-line therapy was determined. The median time on surveillance was 14.9 mo, with none of the patients experiencing symptomatic progression during that time.
Coinciding with recently published data, the recommendations for first-line therapy have undergone significant changes, predominantly with regard to CPI therapies. The CheckMate 214 trial has changed the standard of care for intermediate- and poor-risk disease. This trial showed that ipilimumab plus nivolumab improved overall survival (OS) and objective response rates over sunitinib in patients with IMDC intermediate and poor risk [8]. These data are reflected in the NCCN, ESMO, and EAU guidelines, all of which strongly recommend ipilimumab plus nivolumab as first-line therapy for intermediate- and poor-risk disease. The NCCN also recommends the combination of ipilimumab plus nivolumab for favorable-risk disease as an “alternative” regimen. No other guidelines recommend the use of this regimen in patients with favorable risk; while CheckMate 214 included this patient cohort, the favorable-risk subgroup was not included in the primary endpoints. The NCCN does not provide specific direction regarding the situations for which this regimen should be considered in favorablerisk disease. 4.2.
Axitinib plus pembrolizumab
The NCCN and EAU both recommend the combination of axitinib plus pembrolizumab as a preferred regimen. This combination was found to be superior to sunitinib in terms
Table 1 – Summary of recommendations for treatment-naïve metastatic clear-cell renal cell carcinoma from three international guidelines. Guideline
Favorable risk Preferred
NCCN 2019 Axitinib + PMB Pazopanib Sunitinib
ESMO 2019 EAU 2019
Sunitinib Pazopanib Bevacizumab + IFN Tivozanib
Axitinib + PMB
Intermediate risk
Alternatives
Preferred
Ipilimumab + nivolumab Pazopanib Axitinib + PMB Sunitinib Cabozantinib Axitinib + avelumab Axitinib High-dose IL-2 Bevacizumab + IFN Temsirolimus Ipilimumab + nivolumab Sunitinib Pazopanib Cabozantinib Tivozanib Bevacizumab + IFN Ipilimumab + nivolumab Cabozantinib Axitinib + PMB Sunitinib Pazopanib
Ipilimumab + nivolumab Cabozantinib Axitinib + avelumab Axitinib High-dose IL-2 Bevacizumab + IFN Surveillance High-dose IL-2 Surveillance
Sunitinib Pazopanib
Alternative
Poor risk Preferred
Alternative
Ipilimumab + nivolumab Pazopanib Axitinib + PMB Sunitinib Cabozantinib Axitinib + avelumab Axitinib High-dose IL-2 Bevacizumab + IFN Temsirolimus Ipilimumab + nivolumab Temsirolimus Cabozantinib Sunitinib Pazopanib Ipilimumab + nivolumab Cabozantinib Axitinib + PMB Sunitinib Pazopanib
NCCN = National Comprehensive Cancer Network; ESMO = European Society of Medical Oncology; EAU = European Association of Urology; PMB = pembrolizumab; IFN = interferon; IL-2 = interleukin-2.
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Table 2 – Prognostic risk factors for the IMDC and MSKCC criteria.a IMDC
MSKCC
Low hemoglobin (
Low hemoglobin (
IMDC = International Metastatic Renal Cell Carcinoma Database Consortium; MSKCC = Memorial Sloan-Kettering Cancer Center; LLN = lower limit of normal; ULN = upper limit of normal; KPS = Karnofsky performance status. a No risk factors = favorable risk; 1–2 risk factors = intermediate risk; 3–6 risk factors = poor risk.
of OS and progression-free survival (PFS) in the KEYNOTE426 phase 3 trial [9]. This benefit was seen across all subgroups, including all IMDC risk categories. The NCCN guidelines do not state whether axitinib plus pembrolizumab is favored over the former standards of care for favorable-risk disease (sunitinib or pazopanib), and all three options are currently listed as “preferred regimens”. Conversely, the EAU specifies that axitinib plus pembrolizumab is the standard of care for favorable-risk disease, with sunitinib and pazopanib being alternatives for patients who cannot receive or tolerate CPI. Notably, this regimen has not been compared to ipilimumab plus nivolumab, and there is a lack of direct evidence as to which treatment should be used in intermediate- or poor-risk disease. Accordingly, neither the NCCN nor EAU guidelines recommend one regimen over the other for these patients. The recent ESMO guidelines do not yet include the CPI plus axitinib combination data in their recommendations. 4.3.
Axitinib plus avelumab
The combination of axitinib plus avelumab was also compared to sunitinib in the JAVELIN Renal 101 phase 3 trial [10]. While one of the primary endpoints in the clinical trial (PFS in the PD-L1–positive patient population) was positive, the other primary endpoint of OS in PD-L1–positive patients did not show a statistically significant improvement at the data cutoff. The NCCN is the only guideline currently recommending this option for all risk groups as an “other recommended regimen”. In their recent update, the EAU specifically did not recommend using axitinib plus avelumab because of the lack of an OS benefit. 5.
Molecularly targeted therapy
Before CPI therapies, anti-VEGF treatments constituted the mainstay of mRCC therapy. Sunitinib and pazopanib are still both commonly used as first-line therapy. Accordingly, the NCCN and ESMO both strongly recommend either for favorable-risk disease. The recent EAU guideline update, however, recommends axitinib plus pembrolizumab over sunitinib or pazopanib for favorable-risk mRCC. For patients with intermediate- and poor-risk disease, the EAU, ESMO, and NCCN have all relegated sunitinib and pazopanib to alternative regimens in favor of ipilimumab plus nivolumab
and (in the case of the EAU and NCCN) axitinib plus pembrolizumab on the basis of the CheckMate 214 and KEYNOTE-426 results, respectively. The NCCN recommends cabozantinib as a “preferred regimen” for intermediate- and poor-risk disease on the basis of randomized phase 2 data [11]. No other guidelines list cabozantinib as a preferred regimen in the first-line setting. However, the EAU and ESMO do list it as an alternative regimen in certain scenarios (Table 1). Tivozanib, another anti-VEGF tyrosine kinase inhibitor, is only mentioned in the ESMO and EAU guidelines, with conflicting recommendations. The EAU makes a weak recommendation against offering tivozanib, noting it is “considered inferior over existing options”. ESMO lists tivozanib as a “standard” option, but notes it has the lowest score using the ESMO Magnitude of Clinical Benefit Scale [12]. Several other targeted therapies are listed as alternative regimens (Table 1). 6.
Cytokine therapy
The combination of the anti-VEGF monoclonal antibody bevacizumab with interferon is provided as a standard option in the ESMO guidelines, with the NCCN also listing this regimen as “useful under certain circumstances”. Both also mention high-dose interleukin-2 as an alternative option. Conversely, the EAU makes a weak recommendation against using both regimens. 7.
Discussion
First-line treatment for clear-cell mRCC is rapidly evolving, with practice-changing results from phase 3 trials being presented at nearly every recent major oncology conference. The three guidelines reviewed here provide clinicians with relevant recommendations that incorporate recent data. The three guidelines take somewhat different approaches to providing recommendations. The NCCN frequently updates their guidelines, and was the first to include CPI plus axitinib combinations. Conversely, the ESMO guidelines are yet to provide an update stating their position on these new regimens. With an impressive pace of advances in this field, groups that create guidelines should
Please cite this article in press as: Thana M, Wood LA, What Do International Guidelines Say About First-line Therapy for Clearcell Metastatic Renal Cell Carcinoma?. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.09.014
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use a dynamic process to provide updates as breakthroughs are made, as opposed to at set time intervals. It is also of interest that the NCCN and ESMO guidelines add newer regimens to a list including previous standard-of-care recommendations, instead of replacing them or providing guidance on when to select an older regimen. This can create challenges, especially for clinicians who do not see a high volume of mRCC patients. The EAU guidelines make some attempt at prioritizing, by providing several “weak” recommendations against the use of older options. While these guidelines highlight the benefit of outlining treatment options, there are inherent limitations that preclude clinicians from completely relying on guidelines for all aspects of decision-making, leaving many aspects of mRCC care unaddressed. These include factors, other than IMDC and MSKCC criteria, to help in guiding choice of a firstline therapy. One of the major dilemmas that clinicians will soon face is what option to choose for patients with intermediate- or poor-risk mRCC: the combination of ipilimumab plus nivolumab or axitinib plus pembrolizumab. Based on the format and information in current guidelines, both will be listed as options for these patients, with minimal direction on how to choose one over the other. Without direct comparisons between these two regimens, the use of indirect comparative methods has been proposed. For example, a network meta-analysis indicated that axitinib plus pembrolizumab is likely to provide longer survival compared to other options [13]. However, indirect statistical comparisons from heterogeneous trials must be done with caution, and should have a limited role both in informing guideline recommendations and in the clinician’s decisionmaking process. As noted above, active surveillance has supportive prospective evidence and is mentioned in two of the three guidelines, but there is only limited guidance as to which patients should be considered for this strategy. The aforementioned phase 2 trial did not have specific criteria for selecting patients other than being asymptomatic and treatment-naïve [7]. Multivariable analysis indicated that solitary organ system involvement and fewer IMDC risk factors were associated with longer surveillance duration, but presumably other key factors would be important to consider, such as growth kinetics and sites of metastases. Other factors that can aid in selecting a first-line treatment, such as cost-effectiveness, quality of life, risk of toxicities (especially for certain subpopulations, such as those with pre-existing autoimmune disorders), hereditary RCC, and poor performance status are not discussed in detail in most guidelines. In situations where multiple options exist without direct comparison to indicate superior efficacy, these factors can help clinicians select an appropriate regimen, and should be highlighed in guidelines.
clinical assessment and shared decision-making that occur in the clinic. Understanding the strengths and shortcomings of these recommendations is essential to incorporating them into daily practice.
Author contributions: Myuran Thana 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: Wood, Thana. Acquisition of data: Thana, Wood. Analysis and interpretation of data: Wood, Thana. Drafting of the manuscript: Thana, Wood. Critical revision of the manuscript for important intellectual content: Wood, Thana. Statistical analysis: None. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Wood. Other: None.
Financial disclosures: Myuran Thana 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: Lori Anne Wood is an unpaid advisory board member for Astellas, Novartis, and Pfizer, and has participated in clinical trials with Aragon, AstraZeneca, BMS, Exelixis, Merck, Pfizer, and Roche. Myuran Thana has nothing to disclose.
Funding/Support and role of the sponsor: None.
References [1] Ljungberg B, Albiges L, Abu-Ghanem Y, et al. European Association of Urology guidelines on renal cell carcinoma: the 2019 update. Eur Urol 2019;75:799–810. [2] Albiges L, Powles T, Staehler M, et al. Updated European Association of Urology guidelines on renal cell carcinoma: immune checkpoint inhibition is the new backbone in first-line treatment of metastatic clear-cell renal cell carcinoma. Eur Urol 2019;76:151–6. [3] Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2019;30:706–20. [4] National Comprehensive Cancer Network. Kidney cancer (version 2.2020). www.nccn.org/professionals/physician_gls/pdf/ kidney.pdf. [5] Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004;22:454–63. [6] Heng DYC, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic RenalCell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol 2013;14:141–8. [7] Rini BI, Dorff TB, Elson P, et al. Active surveillance in metastatic
8.
Conclusions
renal-cell carcinoma: a prospective, phase 2 trial. Lancet Oncol 2016;17:1317–24. [8] Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipili-
Ultimately, the aim of guidelines is to provide evidencebased guidance for clinicians and cannot substitute for the
mumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277–90.
Please cite this article in press as: Thana M, Wood LA, What Do International Guidelines Say About First-line Therapy for Clearcell Metastatic Renal Cell Carcinoma?. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.09.014
EUF-806; No. of Pages 5 E U R O P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X
[9] Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1116–27. [10] Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1103–15. [11] Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus suni-
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cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol 2017;35:591–7. [12] Cherny NI, Dafni U, Bogaerts J, et al. ESMO-Magnitude of Clinical Benefit Scale version 1.1. Ann Oncol 2017;28:2340–66. [13] Klaassen Z, Satkunasivam R, Wallis CJD. Immune checkpoint blockade plus axitinib for renal-cell carcinoma. N Engl J Med 2019;380:2581–2.
tinib as initial targeted therapy for patients with metastatic renal
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