PMID- 33058158 OWN - NLM STAT- MEDLINE DCOM- 20201113 LR - 20240227 IS - 1469-493X (Electronic) IS - 1361-6137 (Linking) VI - 10 IP - 10 DP - 2020 Oct 14 TI - Targeted therapy for metastatic renal cell carcinoma. PG - CD012796 LID - 10.1002/14651858.CD012796.pub2 [doi] LID - CD012796 AB - 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 naive 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 naive 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. CI - Copyright (c) 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. FAU - Hofmann, Fabian AU - Hofmann F AD - Department of Urology, Sunderby Sjukhus, Umea University, Lulea, Sweden. FAU - Hwang, Eu Chang AU - Hwang EC AD - Department of Urology, Chonnam National University Medical School, Chonnam National University Hwasun Hospital, Hwasun, Korea, South. FAU - Lam, Thomas Bl AU - Lam TB AD - Academic Urology Unit, University of Aberdeen, Aberdeen, UK. FAU - Bex, Axel AU - Bex A AD - Department of Urology and UCL Division of Surgery and Interventional Science, Royal Free London NHS Foundation Trust, London, UK. FAU - Yuan, Yuhong AU - Yuan Y AD - Department of Medicine, Division of Gastroenterology, McMaster University, Hamilton, Canada. FAU - Marconi, Lorenzo So AU - Marconi LS AD - Department of Urology and Renal Transplantation, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal. FAU - Ljungberg, Borje AU - Ljungberg B AD - Department of Surgical and Perioperative Sciences, Umea University, Umea, Sweden. LA - eng SI - ClinicalTrials.gov/NCT03141177 SI - ClinicalTrials.gov/NCT03937219 SI - ClinicalTrials.gov/NCT02959554 SI - ClinicalTrials.gov/NCT02811861 PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Systematic Review DEP - 20201014 PL - England TA - Cochrane Database Syst Rev JT - The Cochrane database of systematic reviews JID - 100909747 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 0 (Antineoplastic Agents, Immunological) RN - 0 (Indazoles) RN - 0 (Ipilimumab) RN - 0 (Phenylurea Compounds) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrimidines) RN - 0 (Quinolines) RN - 0 (Sulfonamides) RN - 172030934T (tivozanib) RN - 2S9ZZM9Q9V (Bevacizumab) RN - 624KN6GM2T (temsirolimus) RN - 7RN5DR86CK (pazopanib) RN - 9HW64Q8G6G (Everolimus) RN - 9ZOQ3TZI87 (Sorafenib) RN - C9LVQ0YUXG (Axitinib) RN - DPT0O3T46P (pembrolizumab) RN - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor) RN - KXG2PJ551I (avelumab) RN - V99T50803M (Sunitinib) RN - W36ZG6FT64 (Sirolimus) RN - Clear-cell metastatic renal cell carcinoma SB - IM UOF - doi: 10.1002/14651858.CD012796 MH - Adult MH - Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use MH - Antineoplastic Agents/adverse effects/*therapeutic use MH - Antineoplastic Agents, Immunological/therapeutic use MH - Axitinib/adverse effects/therapeutic use MH - Bevacizumab/adverse effects/therapeutic use MH - Bias MH - Carcinoma, Renal Cell/*drug therapy/mortality MH - Everolimus/adverse effects/therapeutic use MH - Humans MH - Indazoles MH - Ipilimumab/adverse effects/therapeutic use MH - Kidney Neoplasms/*drug therapy/mortality/pathology MH - Phenylurea Compounds/adverse effects/therapeutic use MH - Progression-Free Survival MH - Protein Kinase Inhibitors/adverse effects/*therapeutic use MH - Pyrimidines/adverse effects/therapeutic use MH - Quality of Life MH - Quinolines/adverse effects/therapeutic use MH - Randomized Controlled Trials as Topic MH - Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors MH - Sirolimus/adverse effects/analogs & derivatives/therapeutic use MH - Sorafenib/adverse effects/therapeutic use MH - Sulfonamides/adverse effects/therapeutic use MH - Sunitinib/adverse effects/therapeutic use PMC - PMC8094280 COIS- 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. EDAT- 2020/10/16 06:00 MHDA- 2020/11/18 06:00 PMCR- 2021/10/14 CRDT- 2020/10/15 17:40 PHST- 2020/10/15 17:40 [entrez] PHST- 2020/10/16 06:00 [pubmed] PHST- 2020/11/18 06:00 [medline] PHST- 2021/10/14 00:00 [pmc-release] AID - CD012796.pub2 [pii] AID - 10.1002/14651858.CD012796.pub2 [doi] PST - epublish SO - Cochrane Database Syst Rev. 2020 Oct 14;10(10):CD012796. doi: 10.1002/14651858.CD012796.pub2.