Targeted therapy for metastatic renal cell carcinoma

Fabian Hofmann; Eu Chang Hwang; Thomas BL Lam; Axel Bex; Yuhong Yuan; Lorenzo SO Marconi; Börje Ljungberg

doi:10.1002/14651858.CD012796.pub2

Cochrane Database of Systematic Reviews

Tratamiento dirigido para el carcinoma metastásico de células renales

Información

DOI:

https://doi.org/10.1002/14651858.CD012796.pub2 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

14 octubre 2020see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Urología

Copyright:

Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Contraer

Autores

Fabian Hofmann

Correspondencia a: Department of Urology, Sunderby Sjukhus, Umeå University, Luleå, Sweden

[email protected]
Eu Chang Hwang

Department of Urology, Chonnam National University Medical School, Chonnam National University Hwasun Hospital, Hwasun, Korea, South
Thomas BL Lam

Academic Urology Unit, University of Aberdeen, Aberdeen, UK
Axel Bex

Department of Urology and UCL Division of Surgery and Interventional Science, Royal Free London NHS Foundation Trust, London, UK
Yuhong Yuan

Department of Medicine, Division of Gastroenterology, McMaster University, Hamilton, Canada
Lorenzo SO Marconi

Department of Urology and Renal Transplantation, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal
Börje Ljungberg

Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden

Contributions of authors

Contributions to the protocol

This protocol version concept and design: Fabian Hofmann, Thomas BL Lam, Axel Bex

Submitted and revised protocol: final approval by all authors.

Contributions to the review

Fabian Hofmann (FH): conception and study design, drafting the protocol, searching for trials, study selection, extracting data,
assessing risk of bias, performing data analysis, interpretation of data, and drafting the review.

Eu Chang Hwang (ECH): extracting data, assessing risk of bias, performing data analysis, interpretation of data.

Thomas BL Lam (TB): conception and study design, drafting the protocol, searching for trials, study selection, extracting data, assessing risk of bias, drafting the review and providing methodological advices on the review.

Axel Bex (AB): conception and study design, drafting the protocol, searching for trials, study selection, drafting the review and providing clinical advices on the review.

Yuhong Yuan (YY): creating search strategies, searching for trials and drafting the review.

Lorenzo SO Marconi (LM): searching for trials, study selection, extracting data, assessing risk of bias

Börje Ljungberg (BL): searching for trials, study selection, drafting the review and providing clinical advices on the review.

Sources of support

Internal sources

Fabian Hofmann, Sweden

No sources of support supplied for Fabian Hofmann
Eu Chang Hwang, Korea, South

Chonnam National University Hwasun Hospital, Hwasun, Korea, South Salary support for Eu Chang Hwang
Thomas BL Lam, UK

Aberdeen Royal Infirmary, NHS Grampian, Aberdeen, Scotland, United Kingdom provided salary support for Dr. Thomas B. L. Lam
Axel Bex, UK

No sources of support supplied for Axel Bex
Lorenzo Marconi, Portugal

No sources of support supplied for Lorenzo Marconi
Yuhong Yuan, Canada

No sources of support supplied for Yuhong Yuan
Börje Ljungberg, Sweden

Department of surgical and perioperative sciences, Umeå University, Umeå, Sweden provided salary support for Börje Ljungberg

External sources

Fabian Hofmann, Sweden

No sources of support supplied for Fabian Hofmann
Eu Chang Hwang, Korea, South

No sources of support supplied for Eu Chang Hwang
Thomas BL Lam, UK

No sources of support supplied for Dr. Lam
Axel Bex, UK

No sources of support supplied for Axel Bex
Yuhong Yuan, Canada

No sources of support supplied for Yuhong Yuan
Lorenzo Marconi, Portugal

No sources of support supplied for Lorenzo Marconi
Börje Ljungberg, Sweden

No sources of support supplied for Börje Ljungberg

Declarations of interest

F Hofmann: declares the following relevant activities outside the submitted work: employed as a urologist, serves as guideline associate of European Association of Urology Renal Cell Carcinoma Guideline Panel and reports receiving no compensation for panel membership. Received payment from Ipsen for presenting at Ipsen‐sponsored symposia and conferences.

EC Hwang: none known

LSO Marconi: none known

Yuhong Y: none known.

TBL Lam: declares the following relevant activity outside the submitted work: serves as member of European Association of Urology Renal Cell Carcinoma Guideline Panel and reports receiving no compensation for panel membership.

A Bex: declares the following relevant activities outside the submitted work: received consultancy support paid to his institution by Pfizer and Novartis for taking part in advisory boards; received payment from Pfizer and GlaxoSmithKline for presenting at Pfizer and GlaxoSmithKline sponsored symposia and conferences. These companies produce interventions (mTOR inhibitors and VEGF‐targeting therapy) that are researched in the review. Dr. Bex also reports that he is principal investigator of the European Organisation for Research and Treatment of Cancer (EORTC) SURTIME trial, a randomised phase III trial comparing immediate versus deferred nephrectomy in patients with synchronous metastatic renal cell carcinoma, which is in part supported by a grant from Pfizer to the sponsor (EORTC).

B Ljungberg: declares the following relevant activities outside the submitted work: received support from Pfizer, GlaxoSmithKline and Novartis for advisory board attendance, most recently in early 2013, on the topic of renal cell carcinoma. Most interventions assessed in the review are produced by these companies.

Acknowledgements

We thank Cochrane Urology Review Group representatives Philipp Dahm and Robert Lane for facilitating this collaboration and for editorial suggestions, and Molly M Neuberger, for administrative assistance. We wish to acknowledge additional authors contributing to previous versions of this review: Chris Coppin (Canada), Christian Kollmannsberger (Canada), Lyly Le (Canada), Franz Porzsolt (Germany), and Timothy J Wilt (USA). We also thank Fiona Stewart for the initial search methods, as well as all members of the EAU Renal Cell Cancer Guideline Panel for support and individual contributions.

We are most grateful to Federico Cayol, Arjun K Nambiar, Mark Klein and Petri Bono for their thorough and accurate feedback on this review.

Version history

Published

Title

Stage

Authors

Version

2020 Oct 14

Targeted therapy for metastatic renal cell carcinoma

Review

Fabian Hofmann, Eu Chang Hwang, Thomas BL Lam, Axel Bex, Yuhong Yuan, Lorenzo SO Marconi, Börje Ljungberg

https://doi.org/10.1002/14651858.CD012796.pub2

2017 Sep 15

Targeted therapy for metastatic renal cell carcinoma

Protocol

Fabian Hofmann, Lorenzo SO Marconi, Fiona Stewart, Thomas BL Lam, Axel Bex, Steven E Canfield, Börje Ljungberg

https://doi.org/10.1002/14651858.CD012796

Differences between protocol and review

This review is based on a published protocol (Hofmann 2017) and underwent some changes during the process of completion.

We expanded the scope to include newer immunotherapy agents. Several of these drugs have been compared to targeted agents mainly in first line treatment and the comparisons are included in this review.
We initially planned to include second and further line treatments into this review. Since the first publication of the protocol there has been a dramatic increase in available treatment options mainly in first, but also in second and further lines. We therefore chose to focus on treatment‐naïve patients to retain a manageable review scope.
We restricted the number of participants per study arm to at least 100 which we considered as sufficient to make clinically substantial conclusions and at the same time limit small study bias.

Notes

This is review is developed from the existing Cochrane Review entitled, "Targeted therapy for advanced renal cell carcinoma" (Coppin 2008).

We have based parts of the Methods section of this Cochrane protocol on a standard template established by the CMED Group.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Adult; Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Categories: green point (+) = low risk of bias; yellow point (?) = unclear risk of bias; red point (‐) = high risk of bias.

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Analysis 1.1

Comparison 1: Sorafenib versus Sunitinib, Outcome 1: Progression‐free survival

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Analysis 1.2

Comparison 1: Sorafenib versus Sunitinib, Outcome 2: Overall survival

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Analysis 1.3

Comparison 1: Sorafenib versus Sunitinib, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 1.4

Comparison 1: Sorafenib versus Sunitinib, Outcome 4: Response rate

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Analysis 1.5

Comparison 1: Sorafenib versus Sunitinib, Outcome 5: Minor adverse events (Grade 1 or 2)

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Analysis 2.1

Comparison 2: Pazopanib versus Sunitinib, Outcome 1: Progression‐free survival

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Analysis 2.2

Comparison 2: Pazopanib versus Sunitinib, Outcome 2: Overall survival

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Analysis 2.3

Comparison 2: Pazopanib versus Sunitinib, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 2.4

Comparison 2: Pazopanib versus Sunitinib, Outcome 4: Health‐related quality of life

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Analysis 2.5

Comparison 2: Pazopanib versus Sunitinib, Outcome 5: Response rate

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Analysis 2.6

Comparison 2: Pazopanib versus Sunitinib, Outcome 6: Minor adverse events (Grade 1 or 2)

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Analysis 3.1

Comparison 3: Tivozanib versus Sorafenib, Outcome 1: Progression‐free survival

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Analysis 3.2

Comparison 3: Tivozanib versus Sorafenib, Outcome 2: Overall survival

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Analysis 3.3

Comparison 3: Tivozanib versus Sorafenib, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 3.4

Comparison 3: Tivozanib versus Sorafenib, Outcome 4: Health‐related quality of life

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Analysis 3.5

Comparison 3: Tivozanib versus Sorafenib, Outcome 5: Response rate

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Analysis 3.6

Comparison 3: Tivozanib versus Sorafenib, Outcome 6: Minor adverse events (Grade 1 or 2)

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Analysis 4.1

Comparison 4: Sorafenib versus Pazopanib, Outcome 1: Progression‐free survival

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Analysis 4.2

Comparison 4: Sorafenib versus Pazopanib, Outcome 2: Overall survival

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Analysis 4.3

Comparison 4: Sorafenib versus Pazopanib, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 4.4

Comparison 4: Sorafenib versus Pazopanib, Outcome 4: Health‐related quality of life

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Analysis 4.5

Comparison 4: Sorafenib versus Pazopanib, Outcome 5: Response rate

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Analysis 4.6

Comparison 4: Sorafenib versus Pazopanib, Outcome 6: Minor adverse events (Grade 1 or 2)

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Analysis 5.1

Comparison 5: Sunitinib versus Everolimus, Outcome 1: Progression‐free survival

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Analysis 5.2

Comparison 5: Sunitinib versus Everolimus, Outcome 2: Overall survival

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Analysis 5.3

Comparison 5: Sunitinib versus Everolimus, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 5.4

Comparison 5: Sunitinib versus Everolimus, Outcome 4: Health‐related quality of life

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Analysis 5.5

Comparison 5: Sunitinib versus Everolimus, Outcome 5: Response rate

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Analysis 5.6

Comparison 5: Sunitinib versus Everolimus, Outcome 6: Minor adverse events (Grade 1 or 2)

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Analysis 6.1

Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 1: Progression‐free survival

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Analysis 6.2

Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 2: Overall survival

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Analysis 6.3

Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 6.4

Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 4: Response rate

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Analysis 6.5

Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 5: Minor adverse events (Grade 1 or 2)

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Analysis 7.1

Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 1: Progression‐free survival

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Analysis 7.2

Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 2: Overall survival

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Analysis 7.3

Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 7.4

Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 4: Response rate

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Analysis 7.5

Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 5: Minor adverse events (Grade 1 or 2)

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Analysis 8.1

Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 1: Progression‐free survival

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Analysis 8.2

Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 2: Overall survival

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Analysis 8.3

Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 8.4

Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 4: Health‐related quality of life

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Analysis 8.5

Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 5: Response rate

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Analysis 8.6

Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 6: Minor adverse events (Grade 1 or 2)

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Analysis 9.1

Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 1: Progression‐free survival

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Analysis 9.2

Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 2: Overall survival

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Analysis 9.3

Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 9.4

Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 4: Response rate

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Analysis 9.5

Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 5: Minor adverse events (Grade 1 or 2)

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Analysis 10.1

Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 1: Progression‐free survival

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Analysis 10.2

Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 2: Overall survival

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Analysis 10.3

Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 10.4

Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 4: Health‐related quality of life

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Analysis 10.5

Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 5: Response rate

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Analysis 10.6

Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 6: Minor adverse events (Grade 1 or 2)

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Analysis 11.1

Comparison 11: Temsirolimus versus IFN‐α, Outcome 1: Progression‐free survival

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Analysis 11.2

Comparison 11: Temsirolimus versus IFN‐α, Outcome 2: Overall survival

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Analysis 11.3

Comparison 11: Temsirolimus versus IFN‐α, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 11.4

Comparison 11: Temsirolimus versus IFN‐α, Outcome 4: Health‐related quality of life

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Analysis 11.5

Comparison 11: Temsirolimus versus IFN‐α, Outcome 5: Response rate

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Analysis 11.6

Comparison 11: Temsirolimus versus IFN‐α, Outcome 6: Minor adverse events (Grade 1 or 2)

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Analysis 12.1

Comparison 12: Sunitinib versus Atezolizumab, Outcome 1: Progression‐free survival

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Analysis 12.2

Comparison 12: Sunitinib versus Atezolizumab, Outcome 2: Overall survival

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Analysis 12.3

Comparison 12: Sunitinib versus Atezolizumab, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 12.4

Comparison 12: Sunitinib versus Atezolizumab, Outcome 4: Health‐related quality of life

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Analysis 12.5

Comparison 12: Sunitinib versus Atezolizumab, Outcome 5: Response rate

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Analysis 12.6

Comparison 12: Sunitinib versus Atezolizumab, Outcome 6: Minor adverse events (Grade 1 or 2)

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Analysis 13.1

Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 1: Progression‐free survival

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Analysis 13.2

Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 2: Overall survival

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Analysis 13.3

Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 13.4

Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 4: Response rate

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Analysis 13.5

Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 5: Minor adverse events (Grade 1 or 2)

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Analysis 14.1

Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 1: Progression‐free survival

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Analysis 14.2

Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 2: Overall survival

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Analysis 14.3

Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 14.4

Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 4: Health‐related quality of life

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Analysis 14.5

Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 5: Response rate

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Analysis 14.6

Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 6: Minor adverse events (Grade 1 or 2)

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Analysis 15.1

Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 1: Progression‐free survival

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Analysis 15.2

Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 2: Overall survival

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Analysis 15.3

Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 15.4

Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 4: Response rate

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Analysis 15.5

Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 5: Minor adverse events (Grade 1 or 2)

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Analysis 16.1

Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 1: Progression‐free survival

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Analysis 16.2

Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 2: Overall survival

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Analysis 16.3

Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 16.4

Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 4: Response rate

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Analysis 16.5

Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 5: Minor adverse events (Grade 1 or 2)

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Analysis 17.1

Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 1: Progression‐free survival

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Analysis 17.2

Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 2: Overall survival

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Analysis 17.3

Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 17.4

Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 4: Health‐related quality of life

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Analysis 17.5

Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 5: Response rate

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Analysis 17.6

Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 6: Minor adverse events (Grade 1 or 2)

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Analysis 18.1

Comparison 18: Pazopanib versus Placebo, Outcome 1: Progression‐free survival

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Analysis 18.2

Comparison 18: Pazopanib versus Placebo, Outcome 2: Overall survival

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Analysis 18.3

Comparison 18: Pazopanib versus Placebo, Outcome 3: Serious adverse events (Grade 3 or 4)

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Analysis 18.4

Comparison 18: Pazopanib versus Placebo, Outcome 4: Health‐related quality of life

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Analysis 18.5

Comparison 18: Pazopanib versus Placebo, Outcome 5: Response rate

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Analysis 18.6

Comparison 18: Pazopanib versus Placebo, Outcome 6: Minor adverse events (Grade 1 or 2)

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Summary of findings 1. Sorafenib compared to sunitinib (targeted agent versus targeted agent)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) Setting: Germany and the Netherlands/muticentre/likely outpatient Intervention: Sorafenib Comparison: Sunitinib
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Sunitinib	Risk difference with Sorafenib
Progression‐free survival (absolute effect size estimates based on survival rate at 10 months) follow‐up: mean 10.3 months	365 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	HR 1.19 (0.92 to 1.53)	Study population
	365 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	HR 1.19 (0.92 to 1.53)	340 per 1000	63 fewer per 1000 (148 fewer to 31 more)
Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: mean 10.3 months	365 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{3 4}	HR 0.99 (0.74 to 1.33)	Study population
	365 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{3 4}	HR 0.99 (0.74 to 1.33)	550 per 1000	3 more per 1000 (98 fewer to 92 more)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE v3.0	353 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 4}	RR 0.99 (0.85 to 1.14)	Study population
	353 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 4}	RR 0.99 (0.85 to 1.14)	670 per 1000	7 fewer per 1000 (101 fewer to 94 more)
Health‐related quality of life⁵	not reported	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 1 level for study limitations; high risk of performance and detection bias and unclear risk of other bias ² Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) ³ Downgraded by 1 level for study limitations; unclear risk of other bias ⁴ Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) ⁵ Health‐related quality of life: no available data

Summary of findings 1. Sorafenib compared to sunitinib (targeted agent versus targeted agent)

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Summary of findings 2. Pazopanib compared to sunitinib (targeted agent versus targeted agent)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) Setting: Multinational muticentre/likely outpatient Intervention: Pazopanib Comparison: Sunitinib
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Sunitinib	Risk difference with Pazopanib
Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported	1110 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	HR 1.05 (0.90 to 1.23)	Study population
	1110 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	HR 1.05 (0.90 to 1.23)	420 per 1000	18 fewer per 1000 (76 fewer to 38 more)
Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported	1110 (1 RCT)	⊕⊕⊝⊝ LOW ^{3 4}	HR 0.92 (0.80 to 1.06)	Study population
	1110 (1 RCT)	⊕⊕⊝⊝ LOW ^{3 4}	HR 0.92 (0.80 to 1.06)	550 per 1000	27 more per 1000 (19 fewer to 70 more)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE v3.0	1102 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	RR 1.01 (0.94 to 1.09)	Study population
	1102 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	RR 1.01 (0.94 to 1.09)	734 per 1000	7 more per 1000 (44 fewer to 66 more)
Health‐related quality of life (mean change value) assessed with: FACIT‐F (higher scores indicating less fatigue) Scale from: 0 to 52 follow‐up: after 4 cycle	467 (1 RCT)	⊕⊕⊝⊝ LOW ^{5 6}	‐	The mean health‐related quality of life (mean change value) was ‐6.5	MD 3.6 higher (1.76 higher to 5.44 higher)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;FACIT‐F: Functional Assessment of Chronic Illness Therapy–Fatigue scale; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 1 level for study limitations; high risk of performance and detection bias and unclear risk of other bias ² Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) ³ Downgraded by 1 level for study limitations; unclear risk of other bias ⁴ Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included no benefit and benefit) ⁵ Downgraded by 1 level for study limitations; high risk of performance, detection and attrition bias and unclear risk of other bias ⁶ Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (3 points, included benefit and little benefit)

Summary of findings 2. Pazopanib compared to sunitinib (targeted agent versus targeted agent)

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Summary of findings 3. Tivozanib compared to sorafenib (targeted agent versus targeted agent)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) Setting: Multinational muticentre/likely outpatient Intervention: Tivozanib Comparison: Sorafenib
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Sorafenib	Risk difference with Tivozanib
Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported	517 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	HR 0.79 (0.64 to 0.99)	Study population
	517 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	HR 0.79 (0.64 to 0.99)	360 per 1000	86 more per 1000 (4 more to 160 more)
Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported	517 (1 RCT)	⊕⊕⊝⊝ LOW ^{3 4}	HR 1.25 (0.95 to 1.64)	Study population
	517 (1 RCT)	⊕⊕⊝⊝ LOW ^{3 4}	HR 1.25 (0.95 to 1.64)	620 per 1000	70 fewer per 1000 (163 fewer to 15 more)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE v3.0	516 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.85 (0.74 to 0.97)	Study population
	516 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.85 (0.74 to 0.97)	689 per 1000	103 fewer per 1000 (179 fewer to 21 fewer)
Health‐related quality of life assessed with: EQ‐5D Health State Index Scale from: ‐0.59 (worst health state) to 1 (best health state) follow‐up: 12 months	506 (1 RCT)	⊕⊕⊝⊝ LOW ^{2 5}	‐	The mean health‐related quality of life was ‐0.06	MD 0.01 higher (0.05 lower to 0.07 higher)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;EQ‐5D: EuroQol‐5D; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included benefit and little benefit) ² Downgraded by 1 level for study limitations; high risk of performance, detection and other bias ³ Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) ⁴ Downgraded by 1 level for study limitations; high risk of other bias ⁵ Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (0.06 points, included benefit and no benefit)

Summary of findings 3. Tivozanib compared to sorafenib (targeted agent versus targeted agent)

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Summary of findings 4. Sorafenib compared to pazopanib (targeted agent versus targeted agent)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) Setting: Multinational muticentre/likely outpatient Intervention: Sorafenib Comparison: Pazopanib
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Pazopanib	Risk difference with Sorafenib
Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported	377 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	HR 1.92 (1.74 to 2.11)	Study population
	377 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	HR 1.92 (1.74 to 2.11)	380 per 1000	224 fewer per 1000 (250 fewer to 194 fewer)
Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported	377 (1 RCT)	⊕⊕⊝⊝ LOW ^{2 3}	HR 1.22 (0.91 to 1.64)	Study population
	377 (1 RCT)	⊕⊕⊝⊝ LOW ^{2 3}	HR 1.22 (0.91 to 1.64)	520 per 1000	70 fewer per 1000 (178 fewer to 32 more)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE v4.03	366 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 4}	RR 0.92 (0.78 to 1.09)	Study population
	366 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 4}	RR 0.92 (0.78 to 1.09)	639 per 1000	51 fewer per 1000 (141 fewer to 58 more)
Health‐related quality of life (mean change value) assessed with: FACIT‐F (higher scores indicating less fatigue) Scale from: 0 to 52 follow‐up: not reported	267 (1 RCT)	⊕⊕⊝⊝ LOW ^{5 6}	‐	The mean health‐related quality of life was ‐9.9	MD 3.1 higher (1.82 lower to 8.02 higher)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;FACIT‐F: Functional Assessment of Chronic Illness Therapy–Fatigue scale; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 1 level for study limitations; unclear risk of selection, detection, and reporting bias and high risk of performance bias ² Downgraded by 1 level for study limitations; unclear risk of selection, and reporting bias ³ Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) ⁴ Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) ⁵ Downgraded by 1 level for study limitations; unclear risk of selection, detection, and reporting bias and high risk of performance and attrition bias ⁶ Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (3 points, included benefit and no benefit)

Summary of findings 4. Sorafenib compared to pazopanib (targeted agent versus targeted agent)

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Summary of findings 5. Sunitinib compared to everolimus (targeted agent versus targeted agent)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) Setting: Multinational muticentre/likely outpatient Intervention: Sunitinib Comparison: Everolimus
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Everolimus	Risk difference with Sunitinib
Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported	471 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	HR 0.71 (0.59 to 0.87)	Study population
	471 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	HR 0.71 (0.59 to 0.87)	300 per 1000	125 more per 1000 (51 more to 191 more)
Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported	471 (1 RCT)	⊕⊕⊝⊝ LOW ^{2 3}	HR 0.90 (0.72 to 1.11)	Study population
	471 (1 RCT)	⊕⊕⊝⊝ LOW ^{2 3}	HR 0.90 (0.72 to 1.11)	470 per 1000	37 more per 1000 (37 fewer to 111 more)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE v3.0	469 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	RR 1.34 (1.14 to 1.59)	Study population
	469 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	RR 1.34 (1.14 to 1.59)	471 per 1000	160 more per 1000 (66 more to 278 more)
Health‐related quality of life assessed with: EORTC QLQ‐C30 (Global health status scale: high score represent better functioning) Scale from: 0 to 100 follow‐up: 16 weeks	288 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 4}	‐	The mean health‐related quality of life was 65.5	MD 5 lower (10.4 lower to 0.4 higher)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;EORTC QLQ‐C30: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 1 level for study limitations; high risk of performance, detection and other bias ² Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included benefit and no benefit) ³ Downgraded by 1 level for study limitations; high risk of other bias ⁴ Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (10 points, included harm and no harm)

Summary of findings 5. Sunitinib compared to everolimus (targeted agent versus targeted agent)

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Summary of findings 6. Sunitinib compared to avelumab + axitinib (targeted agent versus immunotherapy + targeted agent)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) Setting: Multinational muticentre/likely outpatient Intervention: Sunitinib Comparison: Avelumab + Axitinib
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Avelumab + Axitinib	Risk difference with Sunitinib
Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: median 10.8 months	886 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	HR 1.45 (1.17 to 1.80)	Study population
	886 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	HR 1.45 (1.17 to 1.80)	550 per 1000	130 fewer per 1000 (209 fewer to 53 fewer)
Overall survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: median 12.0 months	886 (1 RCT)	⊕⊕⊝⊝ LOW ^{2 3}	HR 1.28 (0.92 to 1.79)	Study population
	886 (1 RCT)	⊕⊕⊝⊝ LOW ^{2 3}	HR 1.28 (0.92 to 1.79)	890 per 1000	29 fewer per 1000 (78 fewer to 8 more)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE v4.03	873 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	RR 1.01 (0.93 to 1.10)	Study population
	873 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	RR 1.01 (0.93 to 1.10)	705 per 1000	7 more per 1000 (49 fewer to 71 more)
Health‐related quality of life⁴	Not reported	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 1 level for study limitations: high risk of performance bias and unclear risk of reporting bias ² Downgraded by 1 level for imprecision: confidence interval crossed the assumed threshold of a clinically important difference (included no benefit and harm) ³ Downgraded by 1 level for study limitations: unclear risk of reporting bias ⁴ Health‐related quality of life: no available data

Summary of findings 6. Sunitinib compared to avelumab + axitinib (targeted agent versus immunotherapy + targeted agent)

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Summary of findings 7. Sunitinib compared to pembrolizumab + axitinib (targeted agent versus immunotherapy + targeted agent)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) Setting: Multinational muticentre/likely outpatient Intervention: Sunitinib Comparison: Pembrolizumab + Axitinib
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Pembrolizumab + Axitinib	Risk difference with Sunitinib
Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: median 12.8 months	861 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	HR 1.45 (1.19 to 1.76)	Study population
	861 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	HR 1.45 (1.19 to 1.76)	590 per 1000	125 fewer per 1000 (195 fewer to 56 fewer)
Overall survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: median 12.8 months	861 (1 RCT)	⊕⊕⊕⊝ MODERATE ²	HR 1.90 (1.36 to 2.65)	Study population
	861 (1 RCT)	⊕⊕⊕⊝ MODERATE ²	HR 1.90 (1.36 to 2.65)	880 per 1000	96 fewer per 1000 (167 fewer to 40 fewer)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE v4.0	854 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 3}	RR 0.90 (0.81 to 1.02)	Study population
	854 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 3}	RR 0.90 (0.81 to 1.02)	604 per 1000	60 fewer per 1000 (115 fewer to 12 more)
Health‐related quality of life⁴	Not reported	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 1 level for study limitations; high risk of performance bias ² Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included harm and little harm) ³ Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included benefit and no benefit) ⁴ Health‐related quality of life: no available data

Summary of findings 7. Sunitinib compared to pembrolizumab + axitinib (targeted agent versus immunotherapy + targeted agent)

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Summary of findings 8. Sunitinib compared to atezolizumab + bevacizumab (targeted agent versus immunotherapy + targeted agent)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) Setting: Multinational muticentre/likely outpatient Intervention: Sunitinib Comparison: Atezolizumab + Bevacizumab
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Atezolizumab + Bevacizumab	Risk difference with Sunitinib
Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: range 15 months to 20.7 months	1117 (2 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	HR 1.18 (1.02 to 1.36)	Study population
	1117 (2 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	HR 1.18 (1.02 to 1.36)	480 per 1000	59 fewer per 1000 (111 fewer to 7 fewer)
Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: range 20.7 months to 24 months	1117 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{2 3}	HR 0.99 (0.73 to 1.33)	Study population
	1117 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{2 3}	HR 0.99 (0.73 to 1.33)	630 per 1000	3 more per 1000 (89 fewer to 84 more)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE v4.0	1098 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{2 4 5}	RR 1.22 (1.00 to 1.49)	Study population
	1098 (2 RCTs)	⊕⊝⊝⊝ VERY LOW ^{2 4 5}	RR 1.22 (1.00 to 1.49)	446 per 1000	98 more per 1000 (0 fewer to 218 more)
Health‐related quality of life assessed with: MDASI (high score indicates worse QoL) Scale from: 0 to 10 follow‐up: 12 weeks	691 (2 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	‐	The mean health‐related quality of life ranged from 0.56 to 1.57	MD 1 higher (0.68 higher to 1.32 higher)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; MDASI: MD Anderson Symptom Inventory; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included harm and little harm) ² Downgraded by 1 level for study limitations; high and unclear risk of 1 or more domains. ³ Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) ⁴ Downgraded by 1 level for inconsistency; moderate to substantial heterogeneity: unexplained differences between study results ⁵ Downgraded by 1 level for imprecision; confidence interval reached the line of no difference and crossed the assumed threshold of a clinically important difference (included harm and no harm)

Summary of findings 8. Sunitinib compared to atezolizumab + bevacizumab (targeted agent versus immunotherapy + targeted agent)

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Summary of findings 9. Sunitinib compared to IMA901 + sunitinib (targeted agent versus tumour vaccine + targeted agent)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) Setting: Multinational muticentre/likely outpatient Intervention: Sunitinib Comparison: IMA901 + Sunitinib
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with IMA901 + Sunitinib	Risk difference with Sunitinib
Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: median 33.27 months	339 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 2}	HR 0.95 (0.70 to 1.30)	Study population
	339 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 2}	HR 0.95 (0.70 to 1.30)	590 per 1000	16 more per 1000 (86 fewer to 101 more)
Overall survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: median 33.27 months	339 (1 RCT)	⊕⊕⊝⊝ LOW ^{3 4}	HR 0.75 (0.54 to 1.04)	Study population
	339 (1 RCT)	⊕⊕⊝⊝ LOW ^{3 4}	HR 0.75 (0.54 to 1.04)	800 per 1000	46 more per 1000 (7 fewer to 86 more)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE v4.0	334 (1 RCT)	⊕⊕⊝⊝ LOW ^{2 5}	RR 0.74 (0.59 to 0.95)	Study population
	334 (1 RCT)	⊕⊕⊝⊝ LOW ^{2 5}	RR 0.74 (0.59 to 0.95)	550 per 1000	143 fewer per 1000 (225 fewer to 27 fewer)
Health‐related quality of life⁶	Not reported	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) ² Downgraded by 1 level for study limitations; high risk of performance and other bias ³ Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included benefit and no benefit) ⁴ Downgraded by 1 level for study limitations: high risk of other bias ⁵ Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included benefit and little benefit) ⁶ Health‐related quality of life: no available data

Summary of findings 9. Sunitinib compared to IMA901 + sunitinib (targeted agent versus tumour vaccine + targeted agent)

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Summary of findings 10. Sunitinib compared to interferon‐α (IFN‐α) (targeted agent versus classic immunotherapy)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) Setting: Multinational muticentre/likely outpatient Intervention: Sunitinib Comparison: Interferon‐α (IFN‐α)
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Interferon‐α (IFN‐α)	Risk difference with Sunitinib
Progression‐free survival (absolute effect size estimates based on survival rate at 6 months) follow‐up: median 31 months	750 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	HR 0.54 (0.45 to 0.64)	Study population
	750 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	HR 0.54 (0.45 to 0.64)	400 per 1000	210 more per 1000 (156 more to 262 more)
Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: median 31 months	750 (1 RCT)	⊕⊕⊝⊝ LOW ^{2 3}	HR 0.82 (0.67 to 1.00)	Study population
	750 (1 RCT)	⊕⊕⊝⊝ LOW ^{2 3}	HR 0.82 (0.67 to 1.00)	480 per 1000	68 more per 1000 (0 fewer to 132 more)
Serious adverse events (Grade 3 or 4) assessed as: CTCAE v3.0	735 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	RR 1.75 (1.43 to 2.16)	Study population
	735 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	RR 1.75 (1.43 to 2.16)	258 per 1000	194 more per 1000 (111 more to 300 more)
Health‐related quality of life assessed with: EQ‐5D Health State Index Scale from: ‐0.59 (worst health state) to 1 (best health state) follow‐up: after 2 cycle	544 (1 RCT)	⊕⊕⊕⊝ MODERATE ⁴	‐	The mean health‐related quality of life was 0.74	MD 0.01 lower (0.05 lower to 0.03 higher)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval;EQ‐5D: EuroQol‐5D; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 1 level for study limitations; unclear risk of selection bias and high risk of performance and other bias ² Downgraded by 1 level for study limitations; unclear risk of selection bias and high risk of other bias ³ Downgraded by 1 level for imprecision; confidence interval reached the line of no difference and crossed the assumed threshold of a clinically important difference (included benefit and no benefit) ⁴ Downgraded by 1 level for study limitations; unclear risk of selection and attrition bias and high risk of performance and other bias

Summary of findings 10. Sunitinib compared to interferon‐α (IFN‐α) (targeted agent versus classic immunotherapy)

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Summary of findings 11. Temsirolimus compared to IFN‐α (targeted agent versus classic immunotherapy)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type [80% clear cell]) Setting: Multinational muticentre/likely outpatient Intervention: Temsirolimus Comparison: IFN‐α
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with IFN‐α	Risk difference with Temsirolimus
Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: up to 80 months	416 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	HR 0.74 (0.60 to 0.91)	Study population
	416 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	HR 0.74 (0.60 to 0.91)	100 per 1000	82 more per 1000 (23 more to 151 more)
Overall survival survival (absolute effect size estimates based on survival rate at 12 months ) follow‐up: up to 80 months	416 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	HR 0.78 (0.63 to 0.97)	Study population
	416 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	HR 0.78 (0.63 to 0.97)	300 per 1000	91 more per 1000 (11 more to 168 more)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE version: not reported	408 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.86 (0.76 to 0.97)	Study population
	408 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	RR 0.86 (0.76 to 0.97)	780 per 1000	109 fewer per 1000 (187 fewer to 23 fewer)
Health‐related quality of life assessed with: EQ‐5D Health State Index Scale from: ‐0.59 (worst health state) to 1 (best health state) follow‐up: not reported	401 (1 RCT)	⊕⊕⊝⊝ LOW ^{3 4}	‐	The mean health‐related quality of life was 0.66	MD 0.03 higher (0.01 lower to 0.07 higher)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;EQ‐5D: EuroQol‐5D; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included benefit and no benefit) ² Downgraded by 1 level for study limitations; high risk of performance and detection bias ³ Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included benefit and no benefit) ⁴ Downgraded by 1 level for study limitations; high risk of performance, detection and attrition bias

Summary of findings 11. Temsirolimus compared to IFN‐α (targeted agent versus classic immunotherapy)

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Summary of findings 12. Sunitinib compared to atezolizumab (targeted therapy versus immunotherapy)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) Setting: Multinational muticentre/likely outpatient Intervention: Sunitinib Comparison: Atezolizumab
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Atezolizumab	Risk difference with Sunitinib
Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: median 20.7 months	204 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 2}	HR 0.84 (0.58 to 1.22)	Study population
	204 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 2}	HR 0.84 (0.58 to 1.22)	420 per 1000	63 more per 1000 (73 fewer to 185 more)
Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: median 20.7 months	204 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 3}	HR 0.94 (0.58 to 1.54)	Moderate
	204 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 3}	HR 0.94 (0.58 to 1.54)	630 per 1000 ⁶	18 more per 1000 (139 fewer to 135 more)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE v4.0	203 (1 RCT)	⊕⊕⊕⊝ MODERATE ²	RR 1.73 (1.32 to 2.27)	Study population
	203 (1 RCT)	⊕⊕⊕⊝ MODERATE ²	RR 1.73 (1.32 to 2.27)	398 per 1000	291 more per 1000 (127 more to 506 more)
Health‐related quality of life assessed with: MDASI (high score indicates worse QoL) Scale from: 0 to 10 follow‐up: 12 weeks	157 (1 RCT)	⊕⊕⊝⊝ LOW ^{4 5}	‐	The mean health‐related quality of life was 1.04	MD 1.46 higher (0.8 higher to 2.12 higher)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; MDASI: MD Anderson Symptom Inventory; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) ² Downgraded by 1 level for study limitations; high risk of selection, performance and detection bias and unclear risk of other bias ³ Downgraded by 1 level for study limitations; high risk of selection and unclear risk of other bias ⁴ Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (1 point, included harm and little harm) ⁵ Downgraded by 1 level for study limitations; high risk of selection, performance and detection bias and unclear risk of other bias ⁶ Baseline risk for overall survival in the atezolizumab group was assumed to be 63% (moderate risk) at 24 months as reported in Rini 2019b

Summary of findings 12. Sunitinib compared to atezolizumab (targeted therapy versus immunotherapy)

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Summary of findings 13. Bevacizumab + IFN compared to IFN (+ placebo) (targeted agent + classic immunotherapy versus classic immunotherapy)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) Setting: Multinational muticentre/likely outpatient Intervention: Bevacizumab + IFN Comparison: IFN (+ placebo)
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with IFN (+ placebo)	Risk difference with Bevacizumab + IFN
Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: intervention: 13.3 months comparator: 12.8 months	1381 (2 RCTs)	⊕⊕⊕⊝ MODERATE ¹	HR 0.68 (0.60 to 0.77)	Study population
	1381 (2 RCTs)	⊕⊕⊕⊝ MODERATE ¹	HR 0.68 (0.60 to 0.77)	200 per 1000	135 more per 1000 (90 more to 181 more)
Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: intervention: 23 months comparator: 21 months	1381 (2 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	HR 0.88 (0.79 to 0.99)	Study population
	1381 (2 RCTs)	⊕⊕⊝⊝ LOW ^{1 2}	HR 0.88 (0.79 to 0.99)	500 per 1000	43 more per 1000 (3 more to 78 more)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE v3.0	1356 (2 RCTs)	⊕⊕⊕⊝ MODERATE ¹	RR 1.31 (1.20 to 1.42)	Study population
	1356 (2 RCTs)	⊕⊕⊕⊝ MODERATE ¹	RR 1.31 (1.20 to 1.42)	536 per 1000	166 more per 1000 (107 more to 225 more)
Health‐related quality of life³	Not reported	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 1 level for study limitations; high and unclear risk of 1 or more domains ² Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included benefit and little benefit) ³ Health‐related quality of life: no available data

Summary of findings 13. Bevacizumab + IFN compared to IFN (+ placebo) (targeted agent + classic immunotherapy versus classic immunotherapy)

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Summary of findings 14. Temsirolimus + IFN‐α compared to IFN‐α (targeted agent + classic immunotherapy versus classic immunotherapy)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type [80% clear cell]) Setting: Multinational muticentre/likely outpatient Intervention: Temsirolimus + IFN‐α Comparison: IFN‐α
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with IFN‐α	Risk difference with Temsirolimus + IFN‐α
Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: up to 80 months	417 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	HR 0.76 (0.62 to 0.93)	Study population
	417 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	HR 0.76 (0.62 to 0.93)	100 per 1000	74 more per 1000 (17 more to 140 more)
Overall survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: up to 80 months	417 (1 RCT)	⊕⊕⊝⊝ LOW ³	HR 0.93 (0.75 to 1.15)	Study population
	417 (1 RCT)	⊕⊕⊝⊝ LOW ³	HR 0.93 (0.75 to 1.15)	300 per 1000	26 more per 1000 (50 fewer to 105 more)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE version: not reported	408 (1 RCT)	⊕⊕⊝⊝ LOW ^{2 4}	RR 1.12 (1.02 to 1.22)	Study population
	408 (1 RCT)	⊕⊕⊝⊝ LOW ^{2 4}	RR 1.12 (1.02 to 1.22)	780 per 1000	94 more per 1000 (16 more to 172 more)
Health‐related quality of life assessed with: EQ‐5D Health State Index Scale from: ‐0.59 (worst health state) to 1 (best health state) follow‐up: not reported	394 (1 RCT)	⊕⊕⊝⊝ LOW ^{5 6}	‐	The mean health‐related quality of life was 0.66	MD 0.03 higher (0.01 lower to 0.07 higher)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;EQ‐5D: EuroQol‐5D; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included benefit and no benefit) ² Downgraded by 1 level for study limitations; high risk of performance and detection bias ³ Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) ⁴ Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included harm and no harm) ⁵ Downgraded by 1 level for study limitations; high risk of performance, detection and attrition bias ⁶ Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included benefit and no benefit)

Summary of findings 14. Temsirolimus + IFN‐α compared to IFN‐α (targeted agent + classic immunotherapy versus classic immunotherapy)

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Summary of findings 15. Temsirolimus + bevacizumab compared to bevacizumab + IFN‐α (targeted agent + targeted agent versus targeted agent + classic immunotherapy)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type [80% clear cell]) Setting: Multinational muticentre/likely outpatient Intervention: Temsirolimus + Bevacizumab Comparison: Bevacizumab + IFN‐α
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Bevacizumab + IFN‐α	Risk difference with Temsirolimus + Bevacizumab
Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported	791 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	HR 1.10 (0.90 to 1.34)	Study population
	791 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	HR 1.10 (0.90 to 1.34)	420 per 1000	35 fewer per 1000 (107 fewer to 38 more)
Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported	791 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	HR 1.08 (0.90 to 1.30)	Study population
	791 (1 RCT)	⊕⊕⊕⊝ MODERATE ¹	HR 1.08 (0.90 to 1.30)	550 per 1000	26 fewer per 1000 (90 fewer to 34 more)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE v3.0	784 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	RR 1.05 (0.98 to 1.13)	Study population
	784 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	RR 1.05 (0.98 to 1.13)	760 per 1000	38 more per 1000 (15 fewer to 99 more)
Health‐related quality of life³ assessed with: FKSI–15 Scale from: 0 to 60	no available data	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;FKSI: Functional Assessment of Cancer Therapy–Kidney Symptom Index; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) ² Downgraded by 1 level for study limitations; high risk of performance bias (we are not concerned with unclear risk of other bias) ³ Health‐related quality of life: no available data

Summary of findings 15. Temsirolimus + bevacizumab compared to bevacizumab + IFN‐α (targeted agent + targeted agent versus targeted agent + classic immunotherapy)

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Summary of findings 16. Everolimus + bevacizumab compared to IFN α‐2a + bevacizumab (targeted agent + targeted agent versus targeted agent + classic immunotherapy)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) Setting: Multinational muticentre/likely outpatient Intervention: Everolimus + Bevacizumab Comparison: IFN α‐2a + Bevacizumab
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with IFN α‐2a + Bevacizumab	Risk difference with Everolimus + Bevacizumab
Progression‐free survival (absolute effect size estimates based on survival rate at 18 months) follow‐up: not reported	365 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 2}	HR 0.91 (0.69 to 1.20)	Study population
	365 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 2}	HR 0.91 (0.69 to 1.20)	250 per 1000	33 more per 1000 (61 fewer to 134 more)
Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported	365 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{2 3}	HR 1.01 (0.75 to 1.36)	Study population
	365 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{2 3}	HR 1.01 (0.75 to 1.36)	533 per 1000	3 fewer per 1000 (108 fewer to 91 more)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE v3.0	361 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 4}	RR 1.06 (0.95 to 1.18)	Study population
	361 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 4}	RR 1.06 (0.95 to 1.18)	762 per 1000	46 more per 1000 (38 fewer to 137 more)
Health‐related quality of life⁵ assessed with: EORTC QLQ‐C30 (Global health status scale: high score represent better functioning) Scale from: 0 to 100	no available data	‐	‐	‐	‐
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;EORTC QLQ‐C30: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 1 level for study limitations; unclear risk of selection, performance and other bias and high risk of detection bias ² Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference: wide confidence interval (included both benefit and harm) ³ Downgraded by 1 level for study limitations; unclear risk of selection and other bias ⁴ Downgraded by 1 level for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included harm and no harm) ⁵ Health‐related quality of life: no available data

Summary of findings 16. Everolimus + bevacizumab compared to IFN α‐2a + bevacizumab (targeted agent + targeted agent versus targeted agent + classic immunotherapy)

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Summary of findings 17. Sunitinib compared to nivolumab + ipilimumab (targeted agent versus combinations of immunotherapy)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type); IMDC intermediate, poor risk patients only. Setting: Multinational muticentre/likely outpatient Intervention: Sunitinib Comparison: Nivolumab + Ipilimumab
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Nivolumab + Ipilimumab	Risk difference with Sunitinib
Progression‐free survival (absolute effect size estimates based on survival rate at 30 months) follow‐up: median 32.4 months	847 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	HR 1.30 (1.11 to 1.52)	Study population
	847 (1 RCT)	⊕⊕⊝⊝ LOW ^{1 2}	HR 1.30 (1.11 to 1.52)	280 per 1000	89 fewer per 1000 (136 fewer to 37 fewer)
Overall survival (absolute effect size estimates based on survival rate at 30 months) follow‐up: median 32.4 months	847 (1 RCT)	⊕⊕⊕⊕ HIGH	HR 1.52 (1.23 to 1.89)	Study population
	847 (1 RCT)	⊕⊕⊕⊕ HIGH	HR 1.52 (1.23 to 1.89)	600 per 1000	140 fewer per 1000 (219 fewer to 67 fewer)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE v4.0	1082 (1 RCT)	⊕⊕⊕⊝ MODERATE ²	RR 1.37 (1.22 to 1.53)	Study population
	1082 (1 RCT)	⊕⊕⊕⊝ MODERATE ²	RR 1.37 (1.22 to 1.53)	457 per 1000	169 more per 1000 (101 more to 242 more)
Health‐related quality of life assessed with: FKSI‐19 (higher scores indicating fewer symptoms) Scale from: 0 to 76 follow‐up: 24 weeks	460 (1 RCT)	⊕⊕⊕⊝ MODERATE ³	‐	The mean health‐related quality of life was 2.6	MD 4.1 lower (5.75 lower to 2.45 lower)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;FKSI: Functional Assessment of Cancer Therapy–Kidney Symptom IndexHR: Hazard ratio; IMDC: International Metastatic Renal Cell Carcinoma Database Consortium; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 1 level for imprecision; confidence interval crossed the assumed threshold of a clinically important difference (included harm and no harm) ² Downgraded by 1 level for study limitations; high risk of performance and detection bias ³ Downgraded by 1 level for study limitations; high risk of performance and detection bias and unclear risk of attrition bias

Summary of findings 17. Sunitinib compared to nivolumab + ipilimumab (targeted agent versus combinations of immunotherapy)

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Summary of findings 18. Pazopanib compared to placebo (targeted agent versus placebo)

Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	*Anticipated absolute effects^ (95% CI)**
Patient or population: Previous treated and treatment‐naïve (54%) metastatic renal cell carcinoma (clear cell type) Setting: Multinational muticentre/likely outpatient Intervention: Pazopanib Comparison: Placebo
Outcomes	№ of participants (studies)	Certainty of the evidence (GRADE)	Relative effect (95% CI)	Risk with Placebo	Risk difference with Pazopanib
Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: not reported	435 (1 RCT)	⊕⊕⊕⊕ HIGH	HR 0.46 (0.34 to 0.62)	Study population
	435 (1 RCT)	⊕⊕⊕⊕ HIGH	HR 0.46 (0.34 to 0.62)	180 per 1000	274 more per 1000 (165 more to 378 more)
Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported	435 (1 RCT)	⊕⊕⊝⊝ LOW ¹	HR 0.91 (0.72 to 1.16)	Study population
	435 (1 RCT)	⊕⊕⊝⊝ LOW ¹	HR 0.91 (0.72 to 1.16)	480 per 1000	33 more per 1000 (53 fewer to 110 more)
Serious adverse events (Grade 3 or 4) assessed with: CTCAE v3.0	435 (1 RCT)	⊕⊕⊕⊕ HIGH	RR 2.00 (1.40 to 2.85)	Study population
	435 (1 RCT)	⊕⊕⊕⊕ HIGH	RR 2.00 (1.40 to 2.85)	200 per 1000	200 more per 1000 (80 more to 370 more)
Health‐related quality of life assessed with: EORTC QLQ‐C30 (Global health status scale: high score represent better functioning but negative change from baseline represents a worsening condition) Scale from: 0 to 100 follow‐up: 12 weeks	300 (1 RCT)	⊕⊕⊕⊕ HIGH	‐	The mean health‐related quality of life was ‐0.5	MD 3.1 lower (7.76 lower to 1.56 higher)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CTCAE: Common Terminology Criteria for Adverse Events;EORTC QLQ‐C30: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; HR: Hazard ratio; RCT: Randomized controlled trial; RR: Risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Downgraded by 2 levels for imprecision; confidence interval crossed the line of no difference and the assumed threshold of a clinically important difference (included both benefit and harm)

Summary of findings 18. Pazopanib compared to placebo (targeted agent versus placebo)

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Table 1. Individual targeted agents to be searched

Axitinib

Bevacizumab

Dovitinib

Erlotinib

Everolimus

Lapatinib

Pazopanib

Sorafenib

Sunitinib

Temsirolimus

Tivozanib

Other agents identified during search

Table 1. Individual targeted agents to be searched

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Table 2. Participants disposition

Studies	Intervention(s)/ Comparator(s)	Randomised (N)	Received treatment (N)	Discontinued treatment (N)	Efficacy analysis (N)	Safety analysis (N)
Eichelberg 2015	Soreafenib/ Sunitinib	182	177	161	182	177
Eichelberg 2015	Sunitinib/ Sorafenib	183	176	156	183	176
Escudier 2010	Bevacizumab + IFN‐a2a	327	325	206	327	337
Escudier 2010	IFN‐a2a + Placebo	322	316	274	322	304
Escudier 2017 ¹	Sunitinib	546	535	438	546	535
Escudier 2017 ¹	Nivolumab + Ipilimumab	550	547	419	550	547
Hudes 2007	Temsirolimus	209	208	199	209	208
	Temsirolimus + Interferon	210	208	193	210	208
	Interferon	207	200	194	207	200
McDermott 2017	Sunitinib	101	100	83	101	100
	Atezolizumab + Bevacizumab	101	101	69	101	101
	Atezolizumab	103	103	80	103	103
Motzer 2010	Sunitinib	375	375	127	375	375
Motzer 2010	IFN‐a2a	375	360	234	375	360
Motzer 2013a	Pazopanib	557	554	486	557	554
Motzer 2013a	Sunitinib	553	548	483	553	548
Motzer 2013b	Tivozanib	260	259	154	260	259
Motzer 2013b	Sorafenib	257	257	192	257	257
Motzer 2014	Sunitinib/ Everolimus	233	231	192	233	231
Motzer 2014	Everolimus/ Sunitinib	238	238	201	238	238
Motzer 2019	Sunitinib	444	439	227	444	439
Motzer 2019	Avelumab + Axitinib	442	434	187	442	434
Ravaud 2015	Everolimus + Bevacizumab	182	180	175	182	180
Ravaud 2015	Interferon + Bevacizumab	183	181	175	183	181
Retz 2019	Sorafenib/ Pazopanib	189	183	115	189	183
Retz 2019	Pazopanib/ Sorafenib	188	183	110	188	183
Rini 2008	Bevacizumab + IFN‐a2b	369	366	355	369	366
Rini 2008	IFN‐a2b	363	350	355	363	349
Rini 2014	Temsirolimus + Bevacizumab	400	393	372	400	393
Rini 2014	Temsirolimus + Interferon	391	391	354	391	391
Rini 2016	Sunitinib	135	130	23	135	132
Rini 2016	IMA901 + Sunitinib	204	185	28	204	202
Rini 2019a	Sunitinib	429	425	242	429	425
Rini 2019a	Pembrolizumab + Axitinib	432	429	176	432	429
Rini 2019b	Sunitinib	461	446	308	461	446
Rini 2019b	Atezolizumab + Bevacizumab	454	451	265	454	451
Sternberg 2010	Pazopanib	290	290	227	290	290
Sternberg 2010	Placebo	145	145	131	145	145
Total		11590	11419	8366	11590	11437
¹ Included overall population; but in the data and analyses section and summary of findings table, we used IMDC intermediate and poor risk patients for efficacy analysis.

Table 2. Participants disposition

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Table 3. Baseline characteristics

Studies	Phase of study	Accrual	Blinding	RCC subtype	Prior therapy	Intervention
Studies	Phase of study	Accrual	Blinding	RCC subtype	Prior therapy	Comparator
Eichelberg 2015	3	Feb 2009 to Dec 2011	open label study	any, 87% clear cell	naïve	Soreafenib/Sunitinib
Eichelberg 2015	3	Feb 2009 to Dec 2011	open label study	any, 87% clear cell	naïve	Sunitinib/Sorafenib
Escudier 2010	3	Jun 2004 to Oct 2005	double‐blind study	clear cell	naïve	Bevacizumab + IFN‐a2a
Escudier 2010	3	Jun 2004 to Oct 2005	double‐blind study	clear cell	naïve	IFN‐a2a + Placebo
Escudier 2017	3	Oct 2014 to Feb 2016	open label study	clear cell	naïve	Sunitinib
Escudier 2017	3	Oct 2014 to Feb 2016	open label study	clear cell	naïve	Nivolumab + Ipilimumab
Hudes 2007	3	Jul 2003 to Apr 2005	open label study	any, 80% clear cell	naïve	Temsirolimus
						Temsirolimus + Interferon
						Inferferon
McDermott 2017	2	Jan 2014 to Mar 2015	open label study	clear cell	naïve	Sunitinib
						Atezolizumab + Bevacizumab
						Atezolizumab
Motzer 2010	3	Aug 2004 to Oct 2005	radiologic assessment	clear cell	naïve	Sunitinib
Motzer 2010	3	Aug 2004 to Oct 2005	radiologic assessment	clear cell	naïve	IFN‐a2a
Motzer 2013a	3	Aug 2008 to Sep 2011	open label study	clear cell	naïve	Pazopanib
Motzer 2013a	3	Aug 2008 to Sep 2011	open label study	clear cell	naïve	Sunitinib
Motzer 2013b	2	Feb 2010 to Aug 2010	open label study	clear cell	naïve	Tivozanib
Motzer 2013b	2	Feb 2010 to Aug 2010	open label study	clear cell	naïve	Sorafenib
Motzer 2014	2	Sep 2009 to Jun 2012	open label study	any, 85% clear cell	naïve	Sunitinib/ Everolimus
Motzer 2014	2	Sep 2009 to Jun 2012	open label study	any, 85% clear cell	naïve	Everolimus/ Sunitinib
Motzer 2019	3	Mar 2016 to Dec 2017	open label study	clear cell	naïve	Sunitinib
Motzer 2019	3	Mar 2016 to Dec 2017	open label study	clear cell	naïve	Avelumab + Axitinib
Ravaud 2015	2	‐	open label study	any 96% clear cell	naïve	Everolimus + Bevacizumab
Ravaud 2015	2	‐	open label study	any 96% clear cell	naïve	Interferon + Bevacizumab
Retz 2019	3	Jun 2012 to Nov 2016	open label study	any, 87% clear cell	naïve	Sorafenib/ Pazopanib
Retz 2019	3	Jun 2012 to Nov 2016	open label study	any, 87% clear cell	naïve	Pazopanib/ Sorafenib
Rini 2008	3	Oct 2003 to Jul 2005	open label study	clear cell	naïve	Bevacizumab + IFN‐a2b
Rini 2008	3	Oct 2003 to Jul 2005	open label study	clear cell	naïve	IFN‐a2b
Rini 2014	3	Apr 2008 to Oct 2010	open label study	any, 80% clear cell	naïve	Temsirolimus + Bevacizumab
Rini 2014	3	Apr 2008 to Oct 2010	open label study	any, 80% clear cell	naïve	Bevacizumab + Inferferon
Rini 2016	3	Dec 2010 to Dec 2012	open label study	clear cell	naïve	Sunitinib
Rini 2016	3	Dec 2010 to Dec 2012	open label study	clear cell	naïve	IMA901 + Sunitinib
Rini 2019a	3	Oct 2016 to Jan 2018	open label study	clear cell	naïve	Sunitinib
Rini 2019a	3	Oct 2016 to Jan 2018	open label study	clear cell	naïve	Pembrolizumab + Axitinib
Rini 2019b	3	May 2015 to Oct 2016	open label study	clear cell	naïve	Sunitinib
Rini 2019b	3	May 2015 to Oct 2016	open label study	clear cell	naïve	Atezolizumab + Bevacizumab
Sternberg 2010	3	Apr 2006 to Apr 2007	double‐blind study	clear cell	54% naive	Pazopanib
Sternberg 2010	3	Apr 2006 to Apr 2007	double‐blind study	clear cell	54% naive	Placebo
‐ denotes not reported
IFN: interferon; RCC: renal cell carcinoma

Table 3. Baseline characteristics

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Comparison 1. Sorafenib versus Sunitinib

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

1.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

1.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.4 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

1.5 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 1. Sorafenib versus Sunitinib

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Comparison 2. Pazopanib versus Sunitinib

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

2.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

2.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.4 Health‐related quality of life Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

2.5 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2.6 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 2. Pazopanib versus Sunitinib

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Comparison 3. Tivozanib versus Sorafenib

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

3.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

3.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.4 Health‐related quality of life Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

3.5 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

3.6 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 3. Tivozanib versus Sorafenib

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Comparison 4. Sorafenib versus Pazopanib

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

4.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

4.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.4 Health‐related quality of life Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

4.5 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

4.6 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 4. Sorafenib versus Pazopanib

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Comparison 5. Sunitinib versus Everolimus

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

5.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

5.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.4 Health‐related quality of life Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

5.5 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

5.6 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 5. Sunitinib versus Everolimus

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Comparison 6. Sunitinib versus Avelumab + Axitinib

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

6.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

6.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

6.4 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

6.5 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 6. Sunitinib versus Avelumab + Axitinib

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Comparison 7. Sunitinib versus Pembrolizumab + Axitinib

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

7.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

7.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

7.4 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

7.5 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 7. Sunitinib versus Pembrolizumab + Axitinib

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Comparison 8. Sunitinib versus Atezolizumab + Bevacizumab

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Progression‐free survival Show forest plot	2	1117	Hazard Ratio (IV, Random, 95% CI)	1.18 [1.02, 1.36]

8.2 Overall survival Show forest plot	2	1117	Hazard Ratio (IV, Random, 95% CI)	0.99 [0.73, 1.33]

8.3 Serious adverse events (Grade 3 or 4) Show forest plot	2	1098	Risk Ratio (M‐H, Random, 95% CI)	1.22 [1.00, 1.49]

8.4 Health‐related quality of life Show forest plot	2	691	Mean Difference (IV, Random, 95% CI)	1.00 [0.68, 1.32]

8.5 Response rate Show forest plot	2	1117	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.77, 1.07]

8.6 Minor adverse events (Grade 1 or 2) Show forest plot	2	1098	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.74, 0.97]

Comparison 8. Sunitinib versus Atezolizumab + Bevacizumab

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Comparison 9. Sunitinib versus IMA901 + Sunitinib

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

9.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

9.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

9.4 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

9.5 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 9. Sunitinib versus IMA901 + Sunitinib

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Comparison 10. Sunitinib versus Interferon‐α (IFN‐α)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

10.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

10.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

10.4 Health‐related quality of life Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

10.5 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

10.6 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 10. Sunitinib versus Interferon‐α (IFN‐α)

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Comparison 11. Temsirolimus versus IFN‐α

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

11.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

11.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

11.4 Health‐related quality of life Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

11.5 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

11.6 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 11. Temsirolimus versus IFN‐α

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Comparison 12. Sunitinib versus Atezolizumab

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

12.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

12.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

12.4 Health‐related quality of life Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

12.5 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

12.6 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 12. Sunitinib versus Atezolizumab

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Comparison 13. Bevacizumab + IFN versus IFN (+ placebo)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
13.1 Progression‐free survival Show forest plot	2	1381	Hazard Ratio (IV, Random, 95% CI)	0.68 [0.60, 0.77]

13.2 Overall survival Show forest plot	2	1381	Hazard Ratio (IV, Random, 95% CI)	0.88 [0.79, 0.99]

13.3 Serious adverse events (Grade 3 or 4) Show forest plot	2	1356	Risk Ratio (M‐H, Random, 95% CI)	1.31 [1.20, 1.42]

13.4 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

13.5 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 13. Bevacizumab + IFN versus IFN (+ placebo)

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Comparison 14. Temsirolimus + IFN‐α versus IFN‐α

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
14.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

14.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

14.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

14.4 Health‐related quality of life Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

14.5 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

14.6 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 14. Temsirolimus + IFN‐α versus IFN‐α

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Comparison 15. Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
15.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

15.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

15.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

15.4 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

15.5 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 15. Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α

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Comparison 16. Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
16.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

16.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

16.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

16.4 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

16.5 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 16. Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab

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Comparison 17. Sunitinib versus Nivolumab + Ipilimumab

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
17.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

17.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

17.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

17.4 Health‐related quality of life Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

17.5 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

17.6 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 17. Sunitinib versus Nivolumab + Ipilimumab

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Comparison 18. Pazopanib versus Placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
18.1 Progression‐free survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

18.2 Overall survival Show forest plot	1		Hazard Ratio (IV, Random, 95% CI)	Totals not selected

18.3 Serious adverse events (Grade 3 or 4) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

18.4 Health‐related quality of life Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

18.5 Response rate Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

18.6 Minor adverse events (Grade 1 or 2) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Comparison 18. Pazopanib versus Placebo

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Tratamiento dirigido para el carcinoma metastásico de células renales

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