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Meta-Analysis
. 2020 Oct 14;10(10):CD012796.
doi: 10.1002/14651858.CD012796.pub2.

Targeted therapy for metastatic renal cell carcinoma

Fabian Hofmann  1 , Eu Chang Hwang  2 , Thomas Bl Lam  3 , Axel Bex  4 , Yuhong Yuan  5 , Lorenzo So Marconi  6 , Börje Ljungberg  7
Affiliations
Meta-Analysis

Targeted therapy for metastatic renal cell carcinoma

Fabian Hofmann et al. Cochrane Database Syst Rev. .

Abstract

Background: Several comparative randomised controlled trials (RCTs) have been performed including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors since the publication of a Cochrane Review on targeted therapy for metastatic renal cell carcinoma (mRCC) in 2008. This review represents an update of that original review.

Objectives: To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy.

Search methods: We performed a comprehensive search with no restrictions on language or publication status. The date of the latest search was 18 June 2020.

Selection criteria: We included randomised controlled trials, recruiting patients with clear cell mRCC naïve to previous systemic treatment. The index intervention was any TKI-based targeted therapy.

Data collection and analysis: Two review authors independently assessed the included studies and extracted data for the primary outcomes: progression-free survival (PFS), overall survival (OS) and serious adverse events (SAEs); and the secondary outcomes: health-related quality of life (QoL), response rate and minor adverse events (AEs). We performed statistical analyses using a random-effects model and rated the certainty of evidence according to the GRADE approach.

Main results: We included 18 RCTs reporting on 11,590 participants randomised across 18 comparisons. This abstract focuses on the primary outcomes of select comparisons. 1. Pazopanib versus sunitinib Pazopanib may result in little to no difference in PFS as compared to sunitinib (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.90 to 1.23; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more OSs (95% CI 19 fewer to 70 more) per 1000 participants. Pazopanib may result in little to no difference in SAEs as compared to sunitinib (risk ratio (RR) 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low-certainty evidence). Based on the control event risk of 734 per 1000 in this trial, this corresponds to 7 more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants. 2. Sunitinib versus avelumab and axitinib Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. Sunitinib may result in little to no difference in OS (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low-certainty evidence). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. Sunitinib may result in little to no difference in SAEs (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low-certainty evidence). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants. 3. Sunitinib versus pembrolizumab and axitinib Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 590 per 1000 in this trial at 12 months, this corresponds to 125 fewer participants experiencing PFS (95% CI 195 fewer to 56 fewer) per 1000 participants. Sunitinib probably reduces OS (HR 1.90, 95% CI 1.36 to 2.65; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 880 per 1000 in this trial at 12 months, this would result in 96 fewer OSs (95% CI 167 fewer to 40 fewer) per 1000 participants. Sunitinib may reduce SAEs as compared to pembrolizumab plus axitinib (RR 0.90, 95% CI 0.81 to 1.02; 1 study, 854 participants; low-certainty evidence) although the CI includes the possibility of no effect. Based on the control event risk of 604 per 1000 in this trial, this corresponds to 60 fewer SAEs (95% CI 115 fewer to 12 more) per 1000 participants. 4. Sunitinib versus nivolumab and ipilimumab Sunitinib may reduce PFS as compared to nivolumab plus ipilimumab (HR 1.30, 95% CI 1.11 to 1.52; 1 study, 847 participants; low-certainty evidence). Based on the control event risk of 280 per 1000 in this trial at 30 months' follow-up, this corresponds to 89 fewer PFSs (95% CI 136 fewer to 37 fewer) per 1000 participants. Sunitinib reduces OS (HR 1.52, 95% CI 1.23 to 1.89; 1 study, 847 participants; high-certainty evidence). Based on the control event risk 600 per 1000 in this trial at 30 months, this would result in 140 fewer OSs (95% CI 219 fewer to 67 fewer) per 1000 participants. Sunitinib probably increases SAEs (RR 1.37, 95% CI 1.22 to 1.53; 1 study, 1082 participants; moderate-certainty evidence). Based on the control event risk of 457 per 1000 in this trial, this corresponds to 169 more SAEs (95% CI 101 more to 242 more) per 1000 participants.

Authors' conclusions: Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single-agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single-agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.

Trial registration: ClinicalTrials.gov NCT03141177 NCT03937219 NCT02959554 NCT02811861.

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Conflict of interest statement

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.

Figures

1
1
Study flow diagram.
2
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.
3
3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
1.1
1.1. Analysis
Comparison 1: Sorafenib versus Sunitinib, Outcome 1: Progression‐free survival
1.2
1.2. Analysis
Comparison 1: Sorafenib versus Sunitinib, Outcome 2: Overall survival
1.3
1.3. Analysis
Comparison 1: Sorafenib versus Sunitinib, Outcome 3: Serious adverse events (Grade 3 or 4)
1.4
1.4. Analysis
Comparison 1: Sorafenib versus Sunitinib, Outcome 4: Response rate
1.5
1.5. Analysis
Comparison 1: Sorafenib versus Sunitinib, Outcome 5: Minor adverse events (Grade 1 or 2)
2.1
2.1. Analysis
Comparison 2: Pazopanib versus Sunitinib, Outcome 1: Progression‐free survival
2.2
2.2. Analysis
Comparison 2: Pazopanib versus Sunitinib, Outcome 2: Overall survival
2.3
2.3. Analysis
Comparison 2: Pazopanib versus Sunitinib, Outcome 3: Serious adverse events (Grade 3 or 4)
2.4
2.4. Analysis
Comparison 2: Pazopanib versus Sunitinib, Outcome 4: Health‐related quality of life
2.5
2.5. Analysis
Comparison 2: Pazopanib versus Sunitinib, Outcome 5: Response rate
2.6
2.6. Analysis
Comparison 2: Pazopanib versus Sunitinib, Outcome 6: Minor adverse events (Grade 1 or 2)
3.1
3.1. Analysis
Comparison 3: Tivozanib versus Sorafenib, Outcome 1: Progression‐free survival
3.2
3.2. Analysis
Comparison 3: Tivozanib versus Sorafenib, Outcome 2: Overall survival
3.3
3.3. Analysis
Comparison 3: Tivozanib versus Sorafenib, Outcome 3: Serious adverse events (Grade 3 or 4)
3.4
3.4. Analysis
Comparison 3: Tivozanib versus Sorafenib, Outcome 4: Health‐related quality of life
3.5
3.5. Analysis
Comparison 3: Tivozanib versus Sorafenib, Outcome 5: Response rate
3.6
3.6. Analysis
Comparison 3: Tivozanib versus Sorafenib, Outcome 6: Minor adverse events (Grade 1 or 2)
4.1
4.1. Analysis
Comparison 4: Sorafenib versus Pazopanib, Outcome 1: Progression‐free survival
4.2
4.2. Analysis
Comparison 4: Sorafenib versus Pazopanib, Outcome 2: Overall survival
4.3
4.3. Analysis
Comparison 4: Sorafenib versus Pazopanib, Outcome 3: Serious adverse events (Grade 3 or 4)
4.4
4.4. Analysis
Comparison 4: Sorafenib versus Pazopanib, Outcome 4: Health‐related quality of life
4.5
4.5. Analysis
Comparison 4: Sorafenib versus Pazopanib, Outcome 5: Response rate
4.6
4.6. Analysis
Comparison 4: Sorafenib versus Pazopanib, Outcome 6: Minor adverse events (Grade 1 or 2)
5.1
5.1. Analysis
Comparison 5: Sunitinib versus Everolimus, Outcome 1: Progression‐free survival
5.2
5.2. Analysis
Comparison 5: Sunitinib versus Everolimus, Outcome 2: Overall survival
5.3
5.3. Analysis
Comparison 5: Sunitinib versus Everolimus, Outcome 3: Serious adverse events (Grade 3 or 4)
5.4
5.4. Analysis
Comparison 5: Sunitinib versus Everolimus, Outcome 4: Health‐related quality of life
5.5
5.5. Analysis
Comparison 5: Sunitinib versus Everolimus, Outcome 5: Response rate
5.6
5.6. Analysis
Comparison 5: Sunitinib versus Everolimus, Outcome 6: Minor adverse events (Grade 1 or 2)
6.1
6.1. Analysis
Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 1: Progression‐free survival
6.2
6.2. Analysis
Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 2: Overall survival
6.3
6.3. Analysis
Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 3: Serious adverse events (Grade 3 or 4)
6.4
6.4. Analysis
Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 4: Response rate
6.5
6.5. Analysis
Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 5: Minor adverse events (Grade 1 or 2)
7.1
7.1. Analysis
Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 1: Progression‐free survival
7.2
7.2. Analysis
Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 2: Overall survival
7.3
7.3. Analysis
Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 3: Serious adverse events (Grade 3 or 4)
7.4
7.4. Analysis
Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 4: Response rate
7.5
7.5. Analysis
Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 5: Minor adverse events (Grade 1 or 2)
8.1
8.1. Analysis
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 1: Progression‐free survival
8.2
8.2. Analysis
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 2: Overall survival
8.3
8.3. Analysis
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 3: Serious adverse events (Grade 3 or 4)
8.4
8.4. Analysis
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 4: Health‐related quality of life
8.5
8.5. Analysis
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 5: Response rate
8.6
8.6. Analysis
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 6: Minor adverse events (Grade 1 or 2)
9.1
9.1. Analysis
Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 1: Progression‐free survival
9.2
9.2. Analysis
Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 2: Overall survival
9.3
9.3. Analysis
Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 3: Serious adverse events (Grade 3 or 4)
9.4
9.4. Analysis
Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 4: Response rate
9.5
9.5. Analysis
Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 5: Minor adverse events (Grade 1 or 2)
10.1
10.1. Analysis
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 1: Progression‐free survival
10.2
10.2. Analysis
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 2: Overall survival
10.3
10.3. Analysis
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 3: Serious adverse events (Grade 3 or 4)
10.4
10.4. Analysis
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 4: Health‐related quality of life
10.5
10.5. Analysis
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 5: Response rate
10.6
10.6. Analysis
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 6: Minor adverse events (Grade 1 or 2)
11.1
11.1. Analysis
Comparison 11: Temsirolimus versus IFN‐α, Outcome 1: Progression‐free survival
11.2
11.2. Analysis
Comparison 11: Temsirolimus versus IFN‐α, Outcome 2: Overall survival
11.3
11.3. Analysis
Comparison 11: Temsirolimus versus IFN‐α, Outcome 3: Serious adverse events (Grade 3 or 4)
11.4
11.4. Analysis
Comparison 11: Temsirolimus versus IFN‐α, Outcome 4: Health‐related quality of life
11.5
11.5. Analysis
Comparison 11: Temsirolimus versus IFN‐α, Outcome 5: Response rate
11.6
11.6. Analysis
Comparison 11: Temsirolimus versus IFN‐α, Outcome 6: Minor adverse events (Grade 1 or 2)
12.1
12.1. Analysis
Comparison 12: Sunitinib versus Atezolizumab, Outcome 1: Progression‐free survival
12.2
12.2. Analysis
Comparison 12: Sunitinib versus Atezolizumab, Outcome 2: Overall survival
12.3
12.3. Analysis
Comparison 12: Sunitinib versus Atezolizumab, Outcome 3: Serious adverse events (Grade 3 or 4)
12.4
12.4. Analysis
Comparison 12: Sunitinib versus Atezolizumab, Outcome 4: Health‐related quality of life
12.5
12.5. Analysis
Comparison 12: Sunitinib versus Atezolizumab, Outcome 5: Response rate
12.6
12.6. Analysis
Comparison 12: Sunitinib versus Atezolizumab, Outcome 6: Minor adverse events (Grade 1 or 2)
13.1
13.1. Analysis
Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 1: Progression‐free survival
13.2
13.2. Analysis
Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 2: Overall survival
13.3
13.3. Analysis
Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 3: Serious adverse events (Grade 3 or 4)
13.4
13.4. Analysis
Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 4: Response rate
13.5
13.5. Analysis
Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 5: Minor adverse events (Grade 1 or 2)
14.1
14.1. Analysis
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 1: Progression‐free survival
14.2
14.2. Analysis
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 2: Overall survival
14.3
14.3. Analysis
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 3: Serious adverse events (Grade 3 or 4)
14.4
14.4. Analysis
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 4: Health‐related quality of life
14.5
14.5. Analysis
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 5: Response rate
14.6
14.6. Analysis
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 6: Minor adverse events (Grade 1 or 2)
15.1
15.1. Analysis
Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 1: Progression‐free survival
15.2
15.2. Analysis
Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 2: Overall survival
15.3
15.3. Analysis
Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 3: Serious adverse events (Grade 3 or 4)
15.4
15.4. Analysis
Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 4: Response rate
15.5
15.5. Analysis
Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 5: Minor adverse events (Grade 1 or 2)
16.1
16.1. Analysis
Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 1: Progression‐free survival
16.2
16.2. Analysis
Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 2: Overall survival
16.3
16.3. Analysis
Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 3: Serious adverse events (Grade 3 or 4)
16.4
16.4. Analysis
Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 4: Response rate
16.5
16.5. Analysis
Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 5: Minor adverse events (Grade 1 or 2)
17.1
17.1. Analysis
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 1: Progression‐free survival
17.2
17.2. Analysis
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 2: Overall survival
17.3
17.3. Analysis
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 3: Serious adverse events (Grade 3 or 4)
17.4
17.4. Analysis
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 4: Health‐related quality of life
17.5
17.5. Analysis
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 5: Response rate
17.6
17.6. Analysis
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 6: Minor adverse events (Grade 1 or 2)
18.1
18.1. Analysis
Comparison 18: Pazopanib versus Placebo, Outcome 1: Progression‐free survival
18.2
18.2. Analysis
Comparison 18: Pazopanib versus Placebo, Outcome 2: Overall survival
18.3
18.3. Analysis
Comparison 18: Pazopanib versus Placebo, Outcome 3: Serious adverse events (Grade 3 or 4)
18.4
18.4. Analysis
Comparison 18: Pazopanib versus Placebo, Outcome 4: Health‐related quality of life
18.5
18.5. Analysis
Comparison 18: Pazopanib versus Placebo, Outcome 5: Response rate
18.6
18.6. Analysis
Comparison 18: Pazopanib versus Placebo, Outcome 6: Minor adverse events (Grade 1 or 2)
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Update of

References

References to studies included in this review

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Escudier 2017 {published data only}
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    1. Motzer RJ, Rini BI, McDermott DF, Aren Frontera O, Hammers HJ, Carducci MA, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncology 2019;S1470-2045(19):30413-9. [PMID: ] - PMC - PubMed
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Hudes 2007 {published data only}
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    1. Armstrong AJ, George DJ, Halabi S. Serum lactate dehydrogenase as a biomarker for survival with mTOR inhibition in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology 2010;28(15 suppl):4361. [DOI: 10.1200/jco.2010.28.15_suppl.4631] - DOI - PubMed
    1. Dutcher JP, Szczylik C, Tannir N, Benedetto P, Ruff P, Hsu A, et al. Correlation of survival with tumor histology, age, and prognostic risk group for previously untreated patients with advanced renal cell carcinoma receiving temsirolimus or interferon-alpha. Journal of Clinical Oncology 2007;25(18 suppl):5033. [DOI: 10.1200/jco.2007.25.18_suppl.5033] - DOI
    1. Dutcher JP, Souza P, Figlin R, et al. Effect of temsirolimus versus interferon- on survival of patients with advanced renal cell carcinoma of different histologies. In: Genitourinary Cancers Symposium, ASCO, abstr 384. 2008.
    1. Dutcher JP, Souza P, McDermott D, Figlin RA, Berkenblit A, Thiele A, et al. Effect of temsirolimus versus interferon- on outcome of patients with advanced renal cell carcinoma of different histologies. Medical Oncology 2009;26(2):202–9. [PMID: ] - PubMed
McDermott 2018 {published data only}
    1. Atkins MB, McDermott DF, Powles T, Motzer RJ, Rini BI, Fong L, et al. IMmotion150: A phase II trial in untreated metastatic renal cell carcinoma (mRCC) patients (pts) of atezolizumab (atezo) and bevacizumab (bev) vs and following atezo or sunitinib (sun). Journal of Clinical Oncology 2017;35(15 suppl):4505. [DOI: 10.1200/JCO.2017.35.15_suppl.4505] - DOI
    1. McDermott DF, Atkins MB, Motzer RJ, Rini BI, Escudier BJ, Fong L, et al. A phase II study of atezolizumab (atezo) with or without bevacizumab (bev) versus sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC) patients (pts). Journal of Clinical Oncology 2017;35(6 suppl):431. [DOI: 10.1200/JCO.2017.35.6_suppl.431] - DOI
    1. McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI, Escudier B, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nature Medicine 2018;24(6):749-57. [PMID: ] - PMC - PubMed
    1. NCT01984242. A study of atezolizumab (an engineered anti-programmed death-ligand 1 [PD-L1] antibody) as monotherapy or in combination with bevacizumab (avastin®) compared to sunitinib (Sutent®) in participants with untreated advanced renal cell carcinoma (IMmotion150) [A phase II, randomized study of atezolizumab (anti-PD-L1 antibody) administered as monotherapy or in combination with bevacizumab versus sunitinib in patients with untreated advanced renal cell carcinoma]. clinicaltrials.gov/ct2/show/NCT01984242 (first received 14 November 2013). [NCT01984242]
    1. Pal SK, McDermott DF, Atkins MB, Escudier B, Rini BI, Motzer RJ, et al. Patient-reported outcomes in a phase 2 study comparing atezolizumab alone or with bevacizumab vs sunitinib in previously untreated metastatic renal cell carcinoma. BJU Int 2020;126:73-82. [DOI: 10.1111/bju.15058] - DOI - PMC - PubMed
Motzer 2010 {published data only}
    1. Castellano D, Muro XG, Pérez-Gracia JL, González-Larriba JL, Abrio MV, Ruiz MA, et al. Patient-reported outcomes in a phase III, randomized study of sunitinib versus interferon-{alpha} as first-line systemic therapy for patients with metastatic renal cell carcinoma in a European population. Annals of Oncology 2009;20(11):1803-12. [PMID: ] - PMC - PubMed
    1. Cella D, Cappelleri JC, Bushmakin A, Charbonneau C, Li JZ, Kim ST, et al. Quality of life predicts progression-free survival in patients with renal cell carcinoma treated with sunitinib versus interferon alfa. Journal of Oncology Practice 2009;5(2):66-70. [PMID: ] - PMC - PubMed
    1. Cella D, Li JZ, Cappelari JC, Bushmakin A, Charbonneau C, Kim ST, et al. Quality of life in patients with metastatic renal cell carcinoma treated with sunitinib or interferon alfa: results from a phase III randomized trial. Journal of Clinical Oncology 2008;26(22):3763-9. [PMID: ] - PubMed
    1. Cella D, Li JZ, Cappelleri JC, Bushmakin A, Charbonneau C, Kim ST, Chen I, et al. Quality of life (QOL) predicts for progression-free survival (PFS) in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib compared to interferon-alpha (IFN-α). Journal of Clinical Oncology 2007;25(18 suppl):6594. [DOI: 10.1200/jco.2007.25.18_suppl.6594] - DOI
    1. Cella D, Michaelson MD, Bushmakin AG, Cappelleri JC, Charbonneau C, Kim ST, et al. Health-related quality of life in patients with metastatic renal cell carcinoma treated with sunitinib vs interferon-a in a phase III trial: final results and geographical analysis. British Journal of Cancer 2010;102(4):658-64. [PMID: ] - PMC - PubMed
Motzer 2013a {published data only}
    1. Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. New England Journal of Medicine 2013;369(8):722-1. [PMID: ] - PubMed
    1. Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. New England Journal of Medicine 2014;370(18):1769-70. [PMID: ] - PubMed
    1. NCT00720941. Pazopanib versus sunitinib in the treatment of locally advanced and/or metastatic renal cell carcinoma (COMPARZ) [Study VEG108844, A study of pazopanib versus sunitinib in the treatment of subjects with locally advanced and/or metastatic renal cell carcinoma]. clinicaltrials.gov/ct2/show/NCT00720941 (first received 23 July 2008). [NCT00720941]
Motzer 2013b {published data only}
    1. Hutson T, Nosov D, Tomczak P, Bondarenko I, Lipatov ON, Sternberg CN, et al. Tivozanib vs sorafenib targeted therapy for advanced renal cell carcinoma: Final results of a phase III trial (901) and efficacy results of a 2nd line tivozanib extension study (902). Journal of Clinical Oncology 2015;33(15 suppl):4557. [DOI: 10.1200/jco.2015.33.15_suppl.4557] - DOI
    1. Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. Journal of Clinical Oncology 2013;31(30):3791-9. [PMID: ] - PMC - PubMed
    1. NCT01030783. A study to compare tivozanib (AV-951) to sorafenib in subjects with advanced renal cell carcinoma (TIVO-1) [A phase 3, randomized, controlled, multi-center, open-label study to compare tivozanib (AV-951) to sorafenib in subjects with advanced renal cell carcinoma (TIVO-1)]. clinicaltrials.gov/ct2/show/NCT01030783 (first received 11 December 2009). [NCT01030783]
Motzer 2014 {published data only}
    1. Knox JJ, Barrios CH, Kim TM, Cosgriff T, Srimuninnimit V, Pittman K, et al. Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC. Annals of Oncology 2017;28(6):1339-45. [PMID: ] - PMC - PubMed
    1. Knox JJ, Barrios CH, Kim TM, Cosgriff T, Srimuninnimit V, Pittman KB, et al. Final overall survival analysis for the RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC (mRCC). Journal of Clinical Oncology 2015;33(15 suppl):4554. [DOI: 10.1200/jco.2015.33.15_suppl.4554] - DOI
    1. Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology 2014;32(25):2765-72. [PMID: ] - PMC - PubMed
    1. NCT00903175. Efficacy and safety comparison of RAD001 versus sunitinib in the first-line and second-line treatment of patients with metastatic renal cell carcinoma (RECORD-3) [An open-label, multicenter phase II study to compare the efficacy and safety of RAD001 as first-line followed by second-line sunitinib versus sunitinib as First-line followed by second-line RAD001 in the treatment of patients with metastatic renal cell carcinoma.]. clinicaltrials.gov/ct2/show/NCT00903175 (first received 18 May 2009). [NCT00903175]
Motzer 2019 {published data only}
    1. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus axitinib versus sunitinib for advanced renal cell carcinoma. New England Journal of Medicine 2019;380(12):1103-5. [PMID: ] - PMC - PubMed
    1. NCT02684006. A study of avelumab with axitinib versus sunitinib in advanced renal cell cancer (JAVELIN Renal 101) [A phase 3, multinational, randomized, open-label, parallel-arm study of avelumab (MSB0010718C) in combination with axitinib (Inlyta(registered)) versus sunitinib (Sutent(registered)) monotherapy in the first-line treatment of patients with advanced renal cell carcinoma]. clinicaltrials.gov/ct2/show/NCT02684006 (first received 17 February 2016). [NCT02684006]
Ravaud 2015 {published data only}
    1. NCT00719264. Safety and efficacy of bevacizumab plus RAD001 versus interferon alfa-2a and bevacizumab for the first-line treatment in adult patients with kidney cancer [A randomized, open-label, multi-center phase II study to compare bevacizumab plus RAD001 versus interferon alfa-2a plus bevacizumab for the first-line treatment of patients with metastatic clear cell carcinoma of the kidney]. clinicaltrials.gov/ct2/show/study/NCT00719264 (first received 21 July 2008). [NCT00719264]
    1. Ravaud A, Barrios CH, Alekseev B, Tay MH, Agarwala SS, Yalcin S, et al. RECORD-2: phase II randomized study of everolimus and bevacizumab versus interferon α-2a and bevacizumab as first-line therapy in patients with metastatic renal cell carcinoma. Annals of Oncology 2015;26(7):1378-84. [PMID: ] - PubMed
Retz 2019 {published data only}
    1. NCT01613846. Phase III sequential open-label study to evaluate the efficacy and safety of sorafenib followed by pazopanib versus pazopanib followed by sorafenib in the treatment of advanced / metastatic renal cell carcinoma (SWITCH-II) [Phase III randomized sequential open-label study to evaluate the efficacy and safety of sorafenib followed by pazopanib versus pazopanib followed by sorafenib in the treatment of advanced / metastatic renal cell carcinoma]. clinicaltrials.gov/ct2/show/study/NCT01613846 (first received 7 June 2012). [NCT01613846]
    1. Retz M, Bedke J, Bögemann M, Grimm MO, Zimmermann U, Müller L, et al. SWITCH II: Phase III randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-pazopanib versus pazopanib-sorafenib in the treatment of advanced or metastatic renal cell carcinoma (AUO AN 33/11). European Journal of Cancer 2019;107:37-45. [PMID: ] - PubMed
    1. Retz M, BedkeJ, Herrmann E, Grimm M, Zimmermann U, Müller L, et al. Phase III randomized, sequential, open-label study to evaluate the efficacy and safety of sorafenib-pazopanib versus pazopanib sorafenib in the treatment of metastatic renal cell carcinoma(SWITCH-II). Annals of Oncology 2017;28(suppl 5):295. [DOI: 10.1093/annonc/mdx371] - DOI - PubMed
Rini 2008 {published data only}
    1. Halabi S, Rini BI, Stadler WM, Small EJ. Use of progression-free survival (PFS) to predict overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC). Journal of Clinical Oncology 2010;28(15 suppl):4525. [DOI: 10.1200/jco.2010.28.15_suppl.4525] - DOI
    1. Harzstark AL, Halabi S, Stadler WM, et al. Hypertensionis associated with clinical outcome for patients with metastatic renal cell carcinoma treated with interferon and bevacizumab on CALGB 90206. In: Genitourinary Cancers Symposium, ASCO, abstr 351. 2010.
    1. NCT00072046. Interferon alfa-2b with or without bevacizumab in treating patients with advanced renal cell carcinoma (Kidney Cancer) [A randomized phase III trial of interferon alfa-2B or interferon alfa-2B plus bevacizumab in patients with advanced renal carcinoma]. clinicaltrials.gov/ct2/show/study/NCT00072046 (first received 6 November 2003). [NCT00072046]
    1. Rini BI, Halabi S, Rosenberg J, Stadler WM, Vaena DA, Atkins JN, et al. Bevacizumab plus interferon-alfa versus interferon-alfa monotherapy in patients with metastatic renal cell carcinoma: results of overall survival for CALGB 90206. Journal of Clinical Oncology 2009;27(18 suppl):LBA5019. [DOI: 10.1200/jco.2009.27.18_suppl.lba5019 ] - PMC - PubMed
    1. Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB90206. Journal of Clinical Oncology 2008;26(33):5422-8. [PMID: ] - PMC - PubMed
Rini 2014 {published data only}
    1. NCT00631371. Study Comparing Bevacizumab + Temsirolimus vs. Bevacizumab + Interferon-Alfa In Advanced Renal Cell Carcinoma Subjects (INTORACT). linicaltrials.gov/ct2/show/NCT00631371 (first received 20 May 2019). [NCT00631371]
    1. Rini BI, Bellmunt J, Clancy J, Wang K, Niethammer AG, Hariharan S, et al. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. Journal of Clinical Oncology 2014;32(8):752-9. [PMID: ] - PubMed
Rini 2016 {published data only}
    1. NCT01265901. IMA901 in patients receiving sunitinib for advanced/metastatic renal cell carcinoma [A randomized, controlled phase III study investigating IMA901 multipeptide cancer vaccine in patients receiving sunitinib as first-line therapy for advanced/metastatic renal cell carcinoma]. clinicaltrials.gov/ct2/show/study/NCT01265901 (first received 23 December 2010). [NCT01265901]
    1. Rini BI, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M, Oudard S, et al. IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncology 2016;17(11):1599-611. [PMID: ] - PubMed
Rini 2019a {published data only}
    1. NCT02853331. Study to evaluate the efficacy and safety of pembrolizumab (MK-3475) in combination with axitinib versus sunitinib monotherapy in participants with renal cell carcinoma (MK-3475-426/KEYNOTE-426) [A phase III randomized, open-label study to evaluate efficacy and safety of pembrolizumab (MK-3475) in combination with axitinib versus sunitinib monotherapy as a first-line treatment for locally advanced or metastatic renal cell carcinoma (mRCC) (KEYNOTE-426)]. clinicaltrials.gov/ct2/show/NCT02853331 (first received 2 August 2016). [NCT02853331]
    1. Powles T, Plimack ER, Stus V, Gafanov RA, Hawkins RE, Nosov D. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study. Journal of Clinical Oncology 2019;37(7 suppl):543-543.
    1. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. New England Journal of Medicine 2019;380(12):1116-27. [PMID: ] - PubMed
Rini 2019b {published data only}
    1. Atkins MB, Rini BI, Motzer RJ, Powles T, McDermott DF, Suarez C, et al. Patient-reported outcomes from the phase 3 randomized IMmotion151 trial: atezolizumab + bevacizumab vs sunitinib in treatment-naive metastatic renal cell carcinoma. Clinical Cancer Research 2020;26(11):2506-2514. - PMC - PubMed
    1. Escudier B, Motzer RJ, Rini BI, Powles T, McDermott DF, Suarez C, et al. Patient-reported outcomes (PROs) in IMmotion151: atezolizumab (atezo) + bevacizumab (bev) vs sunitinib (sun) in treatment (tx) naive metastatic renal cell carcinoma (mRCC). Journal of Clinical Oncology 2018;36(15_suppl):4511. [DOI: 10.1200/JCO.2018.36.15_suppl.4511] - DOI
    1. Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, et al. IMmotion151: a randomized phase III study of atezolizumab plus bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma (mRCC). Journal of Clinical Oncology 2018;36(6 suppl):578. [DOI: 10.1200/JCO.2018.36.6_suppl.578] - DOI
    1. NCT02420821. A study of atezolizumab in combination with bevacizumab versus sunitinib in participants with untreated advanced renal cell carcinoma (RCC) (IMmotion151) [A phase III, open-label, randomized study of atezolizumab (Anti-PD-L1 Antibody) in combination with bevacizumab versus sunitinib in patients with untreated advanced renal cell carcinoma]. clinicaltrials.gov/ct2/show/NCT02420821 (first received 20 April 2015). [NCT02420821]
    1. Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet 2019;393(10189):2404-15. [PMID: ] - PubMed
Sternberg 2010 {published data only}
    1. Cella D, Pickard AS, Duh MS, Guerin A, Mishagina N, Antràs L, et al. Health-related quality of life in patients with advanced renal cell carcinoma receiving pazopanib or placebo in a randomised phase III trial. European Journal of Cancer 2012;48(3):311-23. [PMID: ] - PubMed
    1. Hutson TE, Bukowski RM. A phase II study of GW786034 using a randomized discontinuation design in patients with locally recurrent or metastatic clear-cell renal cell carcinoma. Clinical Genitourinary Cancer 2006;4(4):296-8. [PMID: ] - PubMed
    1. Hutson TE, Davis ID, Machiels JP, Souza PL, Hong BF, Rottey S, et al. Pazopanib (GW786034) is active in metastatic renal cell carcinoma (RCC): Interim results of a phase II randomized discontinuation trial (RDT). Journal of Clinical Oncology 2007;25(18 suppl):5031. [DOI: 10.1200/jco.2007.25.18_suppl.5031] - DOI
    1. NCT00334282. Safety and efficacy of GW786034 (pazopanib) In metastatic renal cell carcinoma [A randomised, double-blind, placebo controlled, multi-center phase III study to evaluate the efficacy and safety of pazopanib (GW786034) compared to placebo in patients with locally advanced and/or metastatic renal cell carcinoma]. clinicaltrials.gov/ct2/show/study/NCT00334282 (first received 7 June 2006). [NCT00334282]
    1. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. Journal of Clinical Oncology 2010;28(6):1061-8. [PMID: ] - PubMed

References to studies excluded from this review

Armstrong 2016 {published data only}
    1. Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncology 2016;17(3):378-88. [PMID: ] - PMC - PubMed
Atkins 2004 {published data only}
    1. Atkins MB, Hidalgo M, Stadler W, Logan TF, Dutcher JP, Hudes GR, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin inhibitor, in patients with advanced refractory renal cell carcinoma. Journal of Clinical Oncology 2004;22:909-18. [PMID: ] - PubMed
Bracarda 2010 {published data only}
    1. Bracarda S, Porta C, Boni C, Santoro A, Mucciarini C, Pazzola A, et al. Could interferon still play a role in metastatic renal cell carcinoma? A randomized study of two schedules of sorafenib plus interferon-alpha 2a (RAPSODY). European Urology 2013;63(2):254-61. [PMID: ] - PubMed
Broom 2015 {published data only}
    1. Broom RJ, Hinder V, Sharples K, Proctor J, Duffey S, Pollard S, et al. Everolimus and zoledronic acid in patients with renal cell carcinoma with bone metastases: A randomized first-line phase II trial. Clinical Genitourinary Cancer 2015;13(1):50-8. [PMID: 25163397] - PubMed
Bukowski 2007 {published data only}
    1. Bukowski RM, Kabbinavar F, Figlin RA, Flaherty K, Srinivas S, Vaishampayan UN, et al. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. Journal of Clinical Oncology 2007;25(29):4536–41. [PMID: ] - PubMed
Choueiri 2015 {published data only}
    1. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. New England Journal of Medicine 2015;373(19):1814–23. [PMID: ] - PMC - PubMed
Choueiri 2017 {published data only}
    1. Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: The Alliance A031203 CABOSUN Trial. Journal of Clinical Oncology 2017;35(6):591-7. [PMID: ] - PMC - PubMed
Cirkel 2016 {published data only}
    1. Cirkel GA, Hamberg P, Sleijfer S, Loosveld OJL, Dercksen MW, Los M, et al. Alternating treatment with pazopanib and everolimus vs continuous pazopanib to delay disease progressionin patients with metastatic clear cell renal cell cancer: The ROPETAR randomized clinical trial. JAMA Oncology 2017;3(4):501-8. [PMID: ] - PubMed
Dorff 2015 {published data only}
    1. Dorff TB, Longmate JA, Pal SK, Stadler WM, Fishman MN, Vaishampayan UN, et al. Bevacizumab alone or in combination with TRC105 for patients with refractory metastatic renal cell cancer. Cancer 2017;123(23):4566-73. [PMID: ] - PMC - PubMed
Ebbinghaus 2007 {published data only}
    1. Ebbinghaus S, Hussain M, Tannir N, Gordon M, Desai AA, Knight RA, et al. Phase 2 study of ABT-510 in patients with previously untreated advanced renal cell carcinoma. Clinical Cancer Research 2007;13(22 Pt 1):6689–95. [PMID: ] - PubMed
Eisen 2015 {published data only}
    1. Eisen T, Loembé A-B, Shparyk Y, MacLeod N, Jones RJ, Mazurkiewicz M, Temple G, et al. A randomised, phase II study of nintedanib or sunitinib in previously untreated patients with advanced renal cell cancer: 3-year results. British Journal of Cancer 2015;113(8):1140-7. [PMID: ] - PMC - PubMed
Escudier 2007 {published data only}
    1. Escudier B, Choueiri TK, Oudard S, Szczylik C, Négrier S, Ravaud A, et al. Prognostic factors of metastatic renal cell carcinoma after failure of immunotherapy: new paradigm from a large phase III trial with shark cartilage extract AE 941. Journal of Urology 2007;178:1901-5. [PMID: ] - PubMed
Escudier 2009 {published data only}
    1. Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology 2009;27:1280–9. [PMID: ] - PubMed
Escudier 2010a {published data only}
    1. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. New England Journal of Medicine 2007;356(2):125-34. [PMID: ] - PubMed
Flaherty 2015 {published data only}
    1. Flaherty KT, Manola JB, Pins M, McDermott DF, Atkins MB, Dutcher JJ, et al. BEST: A randomized phase II study of vascular endothelial growth factor, RAF Kinase, and mammalian target of rapamycin combination targeted therapy with bevacizumab, sorafenib, and temsirolimus in advanced renal cell carcinoma--A trial of the ECOG-ACRIN cancer research group (E2804). Journal of Clinical Oncology 2015;33(21):2384-91. [PMID: ] - PMC - PubMed
Gordon 2004 {published data only}
    1. Gordon MS, Manola J, Fairclough D, Cella D, Richardson R, Sosman J, et al. Low dose interferon-α2b + thalidomide in patients with previously untreated renal cell cancer. Improvement in progression-free survival but not quality of life or overall survival. A phase III study of the Eastern Cooperative Oncology Group(E2898). Journal of Clinical Oncology 2004;22(14 suppl):4516. [DOI: 10.1200/jco.2004.22.90140.4516] - DOI
Hainsworth 2015 {published data only}
    1. Hainsworth JD, Reeves JA, Mace JR, Crane EJ, Hamid O, Stille JR, et al. A randomized, open-Label phase 2 study of the CXCR4 Inhibitor LY2510924 in combination with sunitinib versus sunitinib alone in patients with metastatic renal cell carcinoma (RCC). Targeted Oncology 2016;11(5):643-53. [PMID: ] - PubMed
Hawkins 2016 {published data only}
    1. Hawkins R, Gore M, Shparyk Y, Bondar V, Gladkov O, Ganev T, et al. A randomized phase II/III study of naptumomab estafenatox þ IFNa versus IFNa in renal cell carcinoma: final analysis with baseline biomarker subgroup and trend analysis. Clinical Cancer Research 2016;22(13):3172-81. [PMID: ] - PubMed
Hutson 2013 {published data only}
    1. Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncology 2013;14(13):1287-94. [PMID: ] - PubMed
Hutson 2014 {published data only}
    1. Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology 2014;32(8):760-7. [PMID: ] - PMC - PubMed
Jonasch 2010 {published data only}
    1. Jonasch E, Corn P, Pagliaro LC, Warneke CL, Johnson MM, Tamboli P, et al. Upfront, randomized, phase 2 trial of sorafenib versus sorafenib and low-dose interferon alfa in patients with advanced renal cell carcinoma. Cancer 2010;116(1):57-65. [PMID: ] - PMC - PubMed
Jonasch 2017 {published data only}
    1. Jonasch E, Hasanov E, Corn PG, Moss T, Shaw KR, Stovall S, et al. A randomized phase 2 study of MK-2206 versus everolimus in refractory renal cell carcinoma. Annals of Oncology 2017;28(4):804-8. [PMID: ] - PMC - PubMed
Lee 2006 {published data only}
    1. Lee CP, Patel PM, Selby PJ, Hancock BW, Mak I, Pyle L, et al. Randomized phase II study comparing thalidomide with medroxyprogesterone acetate in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology 2006;24(6):898-903. [PMID: ] - PubMed
Lee 2015 {published data only}
    1. Lee JL, Kim MK, Park I, Ahn JH, Lee DH, Ryoo HM, et al. Randomized phase II trial of sunitinib four weeks on and two weeks off versus Two weeks on and One week off in metastatic clear-cell type Renal cell carcinoma: RESTORE trial. Annals of Oncology 2015;26(11):2300-5. [PMID: ] - PubMed
Madhusudan 2004 {published data only}
    1. Madhusudan S, Protheroe A, Vasey P, Patel P, Selby P, Altman D, et al. A randomized phase II study of interferon alpha alone or in combination with thalidomide in metastatic renal cancer. Journal of Clinical Oncology 2004;22(14_suppl):4742. [DOI: 10.1200/jco.2004.22.90140.4742] - DOI
Motzer 2008 {published data only}
    1. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomized, placebo-controlled phase III trial. Lancet 2008;372(9637):449-56. [PMID: ] - PubMed
Motzer 2012 {published data only}
    1. Motzer RJ, Hutson TE, Olsen MR, Hudes GR, Burke JM, Edenfield WJ, et al. Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. Journal of Clinical Oncology 2012;30(12):1371-7. [PMID: 22430274 ] - PubMed
Motzer 2014b {published data only}
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Mulders 2012 {published data only}
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Powles 2014 {published data only}
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Powles 2016a {published data only}
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Powles 2016b {published data only}
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Rini 2013 {published data only}
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Tannir 2016 {published data only}
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Tomita 2014 {published data only}
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References to ongoing studies

Choueiri 2018 {published and unpublished data}
    1. Choueiri TK, Apolo AB, Powles T, Escudier B, Aren OR, Shah A, et al. A phase 3, randomized, open-label study of nivolumab combined with cabozantinib vs sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC; CheckMate 9ER). Journal of Clinical Oncology 2018;36(15_suppl):TPS4598. [DOI: 10.1200/JCO.2018.36.15_suppl.TPS4598] - DOI
    1. NCT03141177. A study of nivolumab combined with cabozantinib compared to sunitinib in previously untreated advanced or metastatic renal cell carcinoma (CheckMate 9ER). clinicaltrials.gov/ct2/show/NCT03141177 (first received May 2019).
Choueiri 2019 {published and unpublished data}
    1. Choueiri TK, Albiges L, Powles T, Scheffold C, Wang F, Motzer RJ, et al. A phase III study (COSMIC-313) of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal cell carcinoma of intermediate or poor-risk. Journal of Clinical Oncology 2020;38(6_suppl):TPS767. [DOI: 10.1200/JCO.2020.38.6_suppl.TPS767] - DOI
    1. NCT03937219. Study of Cabozantinib in Combination With Nivolumab and Ipilimumab in Patients With Previously Untreated Advanced or Metastatic Renal Cell Carcinoma (COSMIC-313). https://clinicaltrials.gov/ct2/show/NCT03937219 (first received June 2020).
Grünwald 2018 {published and unpublished data}
    1. Grunwald V, Bergmann L, Steiner T, Grullich C, Muller L, Staib P, et al. A randomized phase II study with NIVOlumab or continuation of therapy as an early SWITCH approach in patients with advanced or metastatic renal cell carcinoma (RCC) and disease control after 3 months of treatment with a tyrosine kinase inhibitor (NIVOSWITCH). Oncology Research and Treatment 2018;41:75.
    1. NCT02959554. Study in Which Therapy is Either Switched to Nivolumab After 3 Months of Treatment or Therapy is Continued With a Tyrosine Kinase Inhibitor in Patients With Metastatic Renal Cell Carcinoma (RCC) and Disease Control (NIVOSWITCH) [A randomized phase II study with NIVOlumab or continuation of therapy as an early SWITCH approach in patients with advanced or metastatic renal cell carcinoma (RCC) and disease control after 3 months of treatment with a tyrosine kinase inhibitor (NIVOSWITCH)]. https://clinicaltrials.gov/ct2/show/NCT02959554.
Motzer 2018 {published and unpublished data}
    1. Motzer RJ, Grünwald V, Hutson TE, Porta C, Powles T, Eto M, et al. A phase 3 trial to compare efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab versus sunitinib alone in first-line treatment of patients with metastatic renal cell carcinoma. Journal of Clinical Oncology 2018;36(6 suppl):TPS706. [DOI: 10.1200/JCO.2018.36.6_suppl.TPS706] - DOI
    1. NCT02811861. Lenvatinib/everolimus or Lenvatinib/pembrolizumab versus sunitinib alone as treatment of advanced renal cell carcinoma (CLEAR) [A multicenter, open-label, randomized, phase 3 trial to compare the efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab versus sunitinib alone in first-line treatment of subjects with advanced renal cell carcinoma]. clinicaltrials.gov/ct2/show/study/NCT02811861 (first received 23 June 2016).

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References to other published versions of this review

Coppin 2006
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