PMID- 37146227 OWN - NLM STAT- MEDLINE DCOM- 20230508 LR - 20240103 IS - 1469-493X (Electronic) IS - 1361-6137 (Linking) VI - 5 IP - 5 DP - 2023 May 4 TI - First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis. PG - CD013798 LID - 10.1002/14651858.CD013798.pub2 [doi] LID - CD013798 AB - BACKGROUND: Since the approval of tyrosine kinase inhibitors, angiogenesis inhibitors and immune checkpoint inhibitors, the treatment landscape for advanced renal cell carcinoma (RCC) has changed fundamentally. Today, combined therapies from different drug categories have a firm place in a complex first-line therapy. Due to the large number of drugs available, it is necessary to identify the most effective therapies, whilst considering their side effects and impact on quality of life (QoL). OBJECTIVES: To evaluate and compare the benefits and harms of first-line therapies for adults with advanced RCC, and to produce a clinically relevant ranking of therapies. Secondary objectives were to maintain the currency of the evidence by conducting continuous update searches, using a living systematic review approach, and to incorporate data from clinical study reports (CSRs). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings and relevant trial registries up until 9 February 2022. We searched several data platforms to identify CSRs. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating at least one targeted therapy or immunotherapy for first-line treatment of adults with advanced RCC. We excluded trials evaluating only interleukin-2 versus interferon-alpha as well as trials with an adjuvant treatment setting. We also excluded trials with adults who received prior systemic anticancer therapy if more than 10% of participants were previously treated, or if data for untreated participants were not separately extractable. DATA COLLECTION AND ANALYSIS: All necessary review steps (i.e. screening and study selection, data extraction, risk of bias and certainty assessments) were conducted independently by at least two review authors. Our outcomes were overall survival (OS), QoL, serious adverse events (SAEs), progression-free survival (PFS), adverse events (AEs), the number of participants who discontinued study treatment due to an AE, and the time to initiation of first subsequent therapy. Where possible, analyses were conducted for the different risk groups (favourable, intermediate, poor) according to the International Metastatic Renal-Cell Carcinoma Database Consortium Score (IMDC) or the Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Our main comparator was sunitinib (SUN). A hazard ratio (HR) or risk ratio (RR) lower than 1.0 is in favour of the experimental arm. MAIN RESULTS: We included 36 RCTs and 15,177 participants (11,061 males and 4116 females). Risk of bias was predominantly judged as being 'high' or 'some concerns' across most trials and outcomes. This was mainly due to a lack of information about the randomisation process, the blinding of outcome assessors, and methods for outcome measurements and analyses. Additionally, study protocols and statistical analysis plans were rarely available. Here we present the results for our primary outcomes OS, QoL, and SAEs, and for all risk groups combined for contemporary treatments: pembrolizumab + axitinib (PEM+AXI), avelumab + axitinib (AVE+AXI), nivolumab + cabozantinib (NIV+CAB), lenvatinib + pembrolizumab (LEN+PEM), nivolumab + ipilimumab (NIV+IPI), CAB, and pazopanib (PAZ). Results per risk group and results for our secondary outcomes are reported in the summary of findings tables and in the full text of this review. The evidence on other treatments and comparisons can also be found in the full text. Overall survival (OS) Across risk groups, PEM+AXI (HR 0.73, 95% confidence interval (CI) 0.50 to 1.07, moderate certainty) and NIV+IPI (HR 0.69, 95% CI 0.69 to 1.00, moderate certainty) probably improve OS, compared to SUN, respectively. LEN+PEM may improve OS (HR 0.66, 95% CI 0.42 to 1.03, low certainty), compared to SUN. There is probably little or no difference in OS between PAZ and SUN (HR 0.91, 95% CI 0.64 to 1.32, moderate certainty), and we are uncertain whether CAB improves OS when compared to SUN (HR 0.84, 95% CI 0.43 to 1.64, very low certainty). The median survival is 28 months when treated with SUN. Survival may improve to 43 months with LEN+PEM, and probably improves to: 41 months with NIV+IPI, 39 months with PEM+AXI, and 31 months with PAZ. We are uncertain whether survival improves to 34 months with CAB. Comparison data were not available for AVE+AXI and NIV+CAB. Quality of life (QoL) One RCT measured QoL using FACIT-F (score range 0 to 52; higher scores mean better QoL) and reported that the mean post-score was 9.00 points higher (9.86 lower to 27.86 higher, very low certainty) with PAZ than with SUN. Comparison data were not available for PEM+AXI, AVE+AXI, NIV+CAB, LEN+PEM, NIV+IPI, and CAB. Serious adverse events (SAEs) Across risk groups, PEM+AXI probably increases slightly the risk for SAEs (RR 1.29, 95% CI 0.90 to 1.85, moderate certainty) compared to SUN. LEN+PEM (RR 1.52, 95% CI 1.06 to 2.19, moderate certainty) and NIV+IPI (RR 1.40, 95% CI 1.00 to 1.97, moderate certainty) probably increase the risk for SAEs, compared to SUN, respectively. There is probably little or no difference in the risk for SAEs between PAZ and SUN (RR 0.99, 95% CI 0.75 to 1.31, moderate certainty). We are uncertain whether CAB reduces or increases the risk for SAEs (RR 0.92, 95% CI 0.60 to 1.43, very low certainty) when compared to SUN. People have a mean risk of 40% for experiencing SAEs when treated with SUN. The risk increases probably to: 61% with LEN+PEM, 57% with NIV+IPI, and 52% with PEM+AXI. It probably remains at 40% with PAZ. We are uncertain whether the risk reduces to 37% with CAB. Comparison data were not available for AVE+AXI and NIV+CAB. AUTHORS' CONCLUSIONS: Findings concerning the main treatments of interest comes from direct evidence of one trial only, thus results should be interpreted with caution. More trials are needed where these interventions and combinations are compared head-to-head, rather than just to SUN. Moreover, assessing the effect of immunotherapies and targeted therapies on different subgroups is essential and studies should focus on assessing and reporting relevant subgroup data. The evidence in this review mostly applies to advanced clear cell RCC. CI - Copyright (c) 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. FAU - Aldin, Angela AU - Aldin A AD - Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Besiroglu, Burcu AU - Besiroglu B AD - Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Adams, Anne AU - Adams A AD - Institute of Medical Statistics and Computational Biology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Monsef, Ina AU - Monsef I AD - Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Piechotta, Vanessa AU - Piechotta V AD - Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Tomlinson, Eve AU - Tomlinson E AD - Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. FAU - Hornbach, Carolin AU - Hornbach C AD - Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Dressen, Nadine AU - Dressen N AD - Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Goldkuhle, Marius AU - Goldkuhle M AD - Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Maisch, Philipp AU - Maisch P AD - Department of Urology, University of Ulm, Ulm, Germany. FAU - Dahm, Philipp AU - Dahm P AD - Urology Section, Minneapolis VA Health Care System, Minneapolis, Minnesota, USA. FAU - Heidenreich, Axel AU - Heidenreich A AD - Department of Urology, Uro-oncology, Special Urological and Robot-assisted Surgery, University Hospital of Cologne, Cologne, Germany. FAU - Skoetz, Nicole AU - Skoetz N AD - Cochrane Haematology, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. LA - eng SI - ClinicalTrials.gov/NCT00065468 SI - ClinicalTrials.gov/NCT00072046 SI - ClinicalTrials.gov/NCT00081614 SI - ClinicalTrials.gov/NCT00098657/NCT00083889 SI - ClinicalTrials.gov/NCT00117637 SI - ClinicalTrials.gov/NCT00126594 SI - ClinicalTrials.gov/NCT00334282 SI - ClinicalTrials.gov/NCT00420888 SI - ClinicalTrials.gov/NCT00609401 SI - ClinicalTrials.gov/NCT00619268 SI - ClinicalTrials.gov/NCT00631371 SI - ClinicalTrials.gov/NCT00719264 SI - ClinicalTrials.gov/NCT00720941 SI - ClinicalTrials.gov/NCT00732914 SI - ClinicalTrials.gov/NCT00738530 SI - ClinicalTrials.gov/NCT00903175 SI - ClinicalTrials.gov/NCT00920816 SI - ClinicalTrials.gov/NCT00979966 SI - ClinicalTrials.gov/NCT01024920 SI - ClinicalTrials.gov/NCT01030783 SI - ClinicalTrials.gov/NCT01064310 SI - ClinicalTrials.gov/NCT01108445 SI - ClinicalTrials.gov/NCT01274273 SI - ClinicalTrials.gov/NCT01392183 SI - ClinicalTrials.gov/NCT01481870 SI - ClinicalTrials.gov/NCT01613846 SI - ClinicalTrials.gov/NCT01835158 SI - ClinicalTrials.gov/NCT01984242 SI - ClinicalTrials.gov/NCT02231749 SI - ClinicalTrials.gov/NCT02420821 SI - ClinicalTrials.gov/NCT02684006 SI - ClinicalTrials.gov/NCT02761057 SI - ClinicalTrials.gov/NCT02811861 SI - ClinicalTrials.gov/NCT02853331 SI - ClinicalTrials.gov/NCT03141177 PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't PT - Review PT - Systematic Review DEP - 20230504 PL - England TA - Cochrane Database Syst Rev JT - The Cochrane database of systematic reviews JID - 100909747 RN - C9LVQ0YUXG (Axitinib) RN - 31YO63LBSN (Nivolumab) RN - V99T50803M (Sunitinib) SB - IM UOF - doi: 10.1002/14651858.CD013798 MH - Male MH - Female MH - Adult MH - Humans MH - *Carcinoma, Renal Cell/drug therapy MH - Axitinib MH - Nivolumab MH - Network Meta-Analysis MH - Sunitinib PMC - PMC10158799 COIS- AAa: The grant by the German Federal Ministry of Education and Research does not lead to a conflict of interest. She is editor at Cochrane, but was not involved in the editorial process for this review. BB: none known. AAb: The grant by the German Federal Ministry of Education and Research does not lead to a conflict of interest. She is editor at Cochrane, but was not involved in the editorial process for this review. IM: none known. She is information specialist for Cochrane Haematology, but was not involved in the editorial process for this review. VP: none known. ET: none known. CH: none known. ND: none known. PM: none known. PD: none known; he is Co-ordinating Editor of Cochrane Urology, but was not involved in the editorial process for this review. MG: none known. AH: speaker honorary and research grant for renal cell carcinoma by BMS; however, this does not lead to a conflict of interest. NS: none known; she is Co-ordinating Editor of Cochrane Haematology, but was not involved in the editorial process for this review. EDAT- 2023/05/05 18:42 MHDA- 2023/05/08 06:42 PMCR- 2024/05/04 CRDT- 2023/05/05 15:03 PHST- 2024/05/04 00:00 [pmc-release] PHST- 2023/05/08 06:42 [medline] PHST- 2023/05/05 18:42 [pubmed] PHST- 2023/05/05 15:03 [entrez] AID - CD013798.pub2 [pii] AID - 10.1002/14651858.CD013798.pub2 [doi] PST - epublish SO - Cochrane Database Syst Rev. 2023 May 4;5(5):CD013798. doi: 10.1002/14651858.CD013798.pub2.