Tratamiento dirigido para el carcinoma metastásico de células renales
Referencias
Referencias de los estudios incluidos en esta revisión
Referencias de los estudios excluidos de esta revisión
Referencias de los estudios en curso
Referencias adicionales
Referencias de otras versiones publicadas de esta revisión
Characteristics of studies
Characteristics of included studies [ordered by study ID]
| Study characteristics | ||
| Methods | Study type: multicentre RCT Phase: 3 Accrual period: February 2009 to December 2011 Blinding: open label study Strata: MSKCC risk category IMC: data not found Crossover: from first to second line after disease progression | |
| Participants | Histology: all histologies Prior systemic therapy: treatment‐naïve Measurable disease: required Non‐metastatic %: combined data not found M/F: 274/91 Eligible PS: ECOG PS 1 or better Age median (range): 65 (39 to 84) Prior nephrectomy: 335 Prognostic strata: system, good/intermediate/poor risk: MSKCC; 153/202/2 | |
| Interventions | sorafenib 400 mg po twice daily followed, on progression or toxicity, by sunitinib 50 mg po daily 4 wks on, 2 wks off or vice versa | |
| Outcomes | PFS: primary outcome (time from randomisation to confirmed progression or death during second‐line therapy); secondary outcome (time from randomisation to confirmed progression or death during first‐line therapy) OS: secondary endpoint AE: reported in toxicity table QoL: not analysed RR: secondary outcome Other: disease control rate, total time to progression, time to first‐line treatment failure, cardiotoxicity | |
| Funding Sources | German Cancer Society (DKG), Austrian Social Security Institutions, grants from industry study sponsor | |
| Declarations of interest | Reported | |
| Notes | Planned as a non‐inferiority study, amended to a superiority design; power reduced from 90% to 85% due to slower rate of events than expected | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Central randomisation via fax" |
| Allocation concealment (selection bias) | Low risk | "the person who generated the randomisation list was not involved in the study project management, monitoring, or data management." |
| Blinding of participants and personnel (performance bias) | Low risk | Open label study design, participants and personnel not blinded to treatment; no effect on OS expected |
| Blinding of participants and personnel (performance bias) | High risk | Open label study design, participants and personnel not blinded to treatment; both arms treated with same drugs in different sequence |
| Blinding of outcome assessment (detection bias) | Low risk | Assessed by investigator; no effect on OS expected |
| Blinding of outcome assessment (detection bias) | High risk | PFS assessed by investigator |
| Incomplete outcome data (attrition bias) | Low risk | All patients reported, 5/7 did not receive treatment in first line |
| Incomplete outcome data (attrition bias) | Low risk | All patients reported, 5/7 did not receive treatment in first line |
| Incomplete outcome data (attrition bias) | Low risk | All treated patients in first and second line reported |
| Selective reporting (reporting bias) | Low risk | All planned outcomes reported |
| Other bias | Unclear risk | Study design changed from non‐inferiority design to superiority design after randomisation of 138 participants |
| Study characteristics | ||
| Methods | Study type: multicentre RCT Phase: 3 Accrual period: June 2006 to October 2005 Blinding: double‐blind study Strata: country, risk group IMC: data safety monitoring board used Crossover: not planned but at preplanned interim OS analysis, difference in PFS clinically and statistically significant and DSMB recommended that patients in the control group who had not experienced progression should cross over to receive bevacizumab | |
| Participants | Histology: clear cell Prior systemic therapy: treatment‐naïve Measurable disease: required Non metastatic %: data not found M/F: 457/192 Eligible PS: Karnofsky > 60 Age median (range): 61 (18 to 82) Prior nephrectomy: required Prognostic strata: system, good/intermediate/poor risk %: MSKCC 30/61/9 | |
| Interventions | Interferon‐a2a 9 MU sc tiw (subcutaneous thrice weekly) plus either (1) BEVACIZUMAB 10 mg/kg IV q2w, or (2) placebo [crossed over at final PFS analysis if not progressed] | |
| Outcomes | PFS: reported [protocol modified to permit final PFS analysis before mature OS data] OS: primary endpoint AE: reported in toxicity table QoL: not assessed RR: secondary outcome Other: ‐ | |
| Funding Sources | Industry sponsored | |
| Declarations of interest | Reported | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | “randomization was done centrally” |
| Allocation concealment (selection bias) | Low risk | Clearly described; interactive voice recognition system |
| Blinding of participants and personnel (performance bias) | Low risk | "Double blind placebo controlled trial". Participants and personnel were blinded to treatment |
| Blinding of participants and personnel (performance bias) | Low risk | "Double blind placebo controlled trial". Participants and personnel were blinded to treatment |
| Blinding of outcome assessment (detection bias) | Low risk | Investigator assessed, no effect on OS expected |
| Blinding of outcome assessment (detection bias) | Low risk | PFS assessed by investigator who were blinded to treatment |
| Incomplete outcome data (attrition bias) | Low risk | 4% in each arm lost or withdrew consent; intention to treat population analysed |
| Incomplete outcome data (attrition bias) | Low risk | 4% in each arm lost or withdrew consent; intention to treat population analysed |
| Incomplete outcome data (attrition bias) | Low risk | All treated participants analysed |
| Selective reporting (reporting bias) | Low risk | All protocol endpoints reported |
| Other bias | Unclear risk | Early unblinding and addition of bevacizumab; recommended for unprogressed placebo‐assigned patients by independent monitoring committee based on unplanned final PFS and preplanned interim survival analysis |
| Study characteristics | ||
| Methods | Study design: multicentre RCT Phase: 3 Accrual period: October 2014 to February 2016 Blinding: open label study design Strata: IMDC score, region IMC (independent monitoring committee): a data and safety monitoring committee reviewed efficacy and safety Crossover: not planned | |
| Participants | Histology: clear cell Prior systemic therapy: treatment‐naïve Measurable disease: required Non metastatic %: data not found; at least 78% of participants had 2 or more target or non‐target lesions M/F: 808/288 Eligible PS: Karnofsky PS 70% or better Age median: 62 (21 to 85) Prior nephrectomy: 890 Prognostic strata: system, % good/intermediate/poor/NA risk: IMDC risk score (0 vs. 1 or 2 vs. 3 to 6) and geographic region | |
| Interventions | nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 wk for 4 doses followed by nivolumab 3 mg/kg every 2 wk vs sunitinib 50 mg daily orally for 4 wk (6‐wk cycles) | |
| Outcomes | PFS: primary endpoint OS: primary endpoint AE: toxicity table reported QoL: reported RR: primary endpoint Other: ‐ | |
| Funding Sources | Industry sponsored | |
| Declarations of interest | Published online | |
| Notes | Stopped early | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Begins with the randomization call to the Interactive Voice Response System (IVRS)" (from protocol) |
| Allocation concealment (selection bias) | Low risk | "Begins with the randomization call to the Interactive Voice Response System (IVRS)" (from protocol) |
| Blinding of participants and personnel (performance bias) | Low risk | "Open‐label, phase 3 trial" participants and personnel were not blinded to treatment; no effect on OS expected |
| Blinding of participants and personnel (performance bias) | High risk | "Open‐label, phase 3 trial" participants and personnel were not blinded to treatment |
| Blinding of outcome assessment (detection bias) | Low risk | No effect on OS expected |
| Blinding of outcome assessment (detection bias) | High risk | (from protocol) Progression free survival; Tumor assessments for ongoing study treatment decisions will be completed by the investigator using RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria Health related quality of life, Minor adverse events; Open label trial |
| Incomplete outcome data (attrition bias) | Low risk | All IMDC intermediate and poor risk patients analysed for efficacy as predefined outcome |
| Incomplete outcome data (attrition bias) | Low risk | All IMDC intermediate and poor risk patients analysed for efficacy as predefined outcome |
| Incomplete outcome data (attrition bias) | Low risk | All treated participants analysed |
| Incomplete outcome data (attrition bias) | Unclear risk | More than 80% completion rate in both groups but final analysed participants were 44/425 (10.3%) in Nivolumab + Ipilimumab arm and 26/422 (6.1%) in sunitinib arm. |
| Selective reporting (reporting bias) | Low risk | All planned outcomes reported |
| Other bias | Low risk | Completed planned accrual |
| Study characteristics | ||
| Methods | Study type: multicentre RCT Phase: 3 Accrual period: June 2003 to April 2005 Blinding: imaging Strata: according to the geographic location of the centre and nephrectomy status IMC: an independent data and safety monitoring committee reviewed the study at 6‐month intervals Crossover: not allowed | |
| Participants | Histology: all histologies Prior therapy: naïve Measurable disease: required (RECIST)Non metastatic %: <20M/F: 432/194 Eligible PS: Karnofsky > 50; actual KPS( > 70) = 17% Age median (range): 59 (23 to 86) Prior nephrectomy: 419 Prognostic strata: system, % good/intermediate/poor risk: MSKCC, ‐/26/74% | |
| Interventions | TEMSIROLIMUS 25mg IV weekly, Interferon‐a2a 3‐18MU sc tiw, or both | |
| Outcomes | PFS: secondary endpoint OS: primary endpoint AE: reported in toxicity table QoL: reported Other: ‐ | |
| Funding Sources | Industry sponsored | |
| Declarations of interest | Reported in main publication | |
| Notes | Only poor risk (76%) and intermediate risk (26%) patients included in trial | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Patients were randomly assigned in equal proportions, with the use of permuted blocks of three, to one of three treatment groups." Central randomisation presumed |
| Allocation concealment (selection bias) | Low risk | "Patients were randomly assigned in equal proportions, with the use of permuted blocks of three, to one of three treatment groups." Central randomisation presumed |
| Blinding of participants and personnel (performance bias) | Low risk | Participants and personnel were not blinded to treatment, no effects on OS expected |
| Blinding of participants and personnel (performance bias) | High risk | Participants and personnel were not blinded to treatment, active treatment in all 3 groups |
| Blinding of outcome assessment (detection bias) | Low risk | Unblinded clinical investigator assessment, no effects on OS expected |
| Blinding of outcome assessment (detection bias) | High risk | Shorter investigator assessed PFS in comparison to independent radiologic assessment; which is explained by different inclusion criteria |
| Incomplete outcome data (attrition bias) | Low risk | Intention‐to‐treat population reported |
| Incomplete outcome data (attrition bias) | High risk | 82% of ITT population reported; only selected participants included in analysis which underwent tumour assessment after the baseline |
| Incomplete outcome data (attrition bias) | Low risk | All treated participants reported |
| Incomplete outcome data (attrition bias) | High risk | 65% of participants were evaluable for QoL analysis |
| Selective reporting (reporting bias) | Low risk | All planned outcomes reported |
| Other bias | Low risk | Completed planned accrual; stopped early at the second interim analysis |
| Study characteristics | ||
| Methods | Study type: multicentre RCT Phase: 2 Accrual period: January 2014 to March 2015 Blinding: open label design Strata: MSKCC risk category, prior nephrectomy status, and PD‐L1 status IMC: "Independent review facility‐assessed efficacy endpoints" Crossover: allowed | |
| Participants | Histology: clear cell Prior systemic therapy: treatment‐naïve Eligible PS: Karnowsky PS 70% or better Measurable disease: required Non metastatic %: not specified M/F: 230/75 Age median (range): 61 Prior nephrectomy: 184 Prognostic strata: system, good/intermediate/poor risk: MSKCC, 77/201/27 | |
| Interventions | atezolizumab 1200 mg IV q3w + bevacizumab 15 mg/kg IV q3w, atezolizumab alone or sunitinib 50 mg PO QD 4 wk on/2 wk off | |
| Outcomes | PFS: co‐primary endpoint OS: secondary endpoint AE: reported QoL: exploratory outcome RR: secondary endpoint Other: primary endpoint: percentage of participants with disease progression per response evaluation | |
| Funding Sources | Industry sponsored | |
| Declarations of interest | Published online | |
| Notes | Crossover to atezolizumab + bevacizumab arm allowed on progression | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "interactive voice/web response system (IxRS)" used; "Stratified permuted block randomization was used to assign patients in a 1:1:1 ratio to one of three treatment arms" |
| Allocation concealment (selection bias) | High risk | "allocation was unmasked" |
| Blinding of participants and personnel (performance bias) | Low risk | "The study was open‐label"; participants and personnel were not blinded to treatment; no effect on OS expected |
| Blinding of participants and personnel (performance bias) | High risk | "The study was open‐label"; participants and personnel were not blinded to treatment, all participants received an active treatment with different administration forms |
| Blinding of outcome assessment (detection bias) | Low risk | Independent review facility (IRF)‐assessed efficacy |
| Blinding of outcome assessment (detection bias) | High risk | Independent review facility (IRF)‐assessed efficacy, no blinding used |
| Incomplete outcome data (attrition bias) | Low risk | ITT population reported, 1 patient did not receive treatment |
| Incomplete outcome data (attrition bias) | Low risk | ITT population reported, 1 patient did not receive treatment |
| Incomplete outcome data (attrition bias) | Low risk | All treated participants included in safety analysis |
| Incomplete outcome data (attrition bias) | Low risk | "96 (95%) of 101 patients in the atezolizumab plus bevacizumab group and 93 (92%) of 101 patients in the sunitinib |
| Selective reporting (reporting bias) | Low risk | All planned outcomes except for quality of life reported |
| Other bias | Unclear risk | Industry sponsored |
| Study characteristics | ||
| Methods | Study type: multicentre RCT Phase: 3 Accrual period: August 2004 to October 2005 Blinding: imaging Strata: LDH, PS, nephrectomy status IMC: used for data and safety Crossover: study amended when sunitinib approved in January 2006 to allow cross‐over of patients on IFN on documented disease progression as primary endpoint of PFS had been met ‒ agreed with IMC | |
| Participants | Histology: clear cell Prior systemic therapy: treatment‐naïve Measurable disease: required Non metastatic %: metastatic disease required M/F %: 536/214 Eligible PS: ECOG 0 to 1 Age median (range): 61 (27 to 87) Prior nephrectomy: 675 Prognostic strata: system, good/intermediate/poor risk %: MSKCC, 37/56/7% | |
| Interventions | (1) SUNITINIB 50 mg oral daily for 4 weeks of 6‐week cycle; (2) Interferon‐alfa2a | |
| Outcomes | PFS: primary endpoint OS: secondary endpoint AE: toxicity table, secondary endpoint QoL: secondary endpoint (FACT‐G, FKSI) RR: secondary endpoint Other: cross‐over post study | |
| Funding Sources | Industry sponsored | |
| Declarations of interest | Reported | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | “patients were randomly assigned”, presumed central randomisation |
| Allocation concealment (selection bias) | Unclear risk | Data not found |
| Blinding of participants and personnel (performance bias) | Low risk | Open label study design, participants and personnel were not blinded to treatment, no effect on OS expected |
| Blinding of participants and personnel (performance bias) | High risk | Open label study design, participants and personnel were not blinded to treatment, 2 active treatments used with different administration forms |
| Blinding of outcome assessment (detection bias) | Low risk | Assessed by investigator, no effect on OS expected |
| Blinding of outcome assessment (detection bias) | Low risk | "A blinded central review of radiologic images was used to assess the primary end point and the objective response rate" |
| Incomplete outcome data (attrition bias) | Low risk | 8% of patients withdrew consent on the control arm (vs 1%, P < 0.001) but primary end‐ point was analysed by allocation |
| Incomplete outcome data (attrition bias) | Low risk | All randomised participants analysed |
| Incomplete outcome data (attrition bias) | Low risk | All treated participants analysed |
| Incomplete outcome data (attrition bias) | Unclear risk | No information on how many participants completed questionnaire found |
| Selective reporting (reporting bias) | Low risk | All planned outcomes reported |
| Other bias | High risk | Cross‐over permitted after second interim analysis but planned accrual had been completed, OS analysis secondary endpoint |
| Study characteristics | ||
| Methods | Study type: multicentre RCT Phase: 3 Accrual period: Aug 2008 to Sep 2011 Blinding: open label design Strata: Karnofsky PS, LDH, nephrectomy status IMC: safety reviewed Crossover: not allowed | |
| Participants | Histology: clear cell component Prior systemic therapy: treatment‐naïve Eligible PS: Karnofsky 70% or more Measurable disease: required Non metastatic %: < 20 M/F: 813/297 Age median (range): 61 (18 to 88) Prior nephrectomy: 924 Prognostic strata: system, good/intermediate/poor risk: MSKCC, 303/650/119 | |
| Interventions | pazopanib 800 mg po vs sunitinib 50 mg po 4 wks on, 2 wks off | |
| Outcomes | PFS: primary outcome as non‐inferiority measure OS: secondary outcome AE: reported in toxicity table, secondary outcome QoL: secondary outcome RR: secondary outcome Other: medical resource utilization | |
| Funding Sources | Industry sponsored | |
| Declarations of interest | Published online | |
| Notes | Non‐inferiority design | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | “GSK interactive voice response system called RAMOS (Registration And Medication Ordering System), by the investigator or authorized site staff for stratification and central randomization.” from protocol |
| Allocation concealment (selection bias) | Low risk | “GSK interactive voice response system called RAMOS (Registration And Medication Ordering System), by the investigator or authorized site staff for stratification and central randomization.” from protocol |
| Blinding of participants and personnel (performance bias) | Low risk | Open label study design, participants and personnel were not blinded to treatment, OS reported as secondary outcome |
| Blinding of participants and personnel (performance bias) | High risk | Open label study design, participants and personnel were not blinded to treatment, oral administered, active drugs used in both arms |
| Blinding of outcome assessment (detection bias) | Low risk | Not specifically reported but no effect on OS expected |
| Blinding of outcome assessment (detection bias) | High risk | "The primary end point was progression‐free survival as assessed by independent review"; tumour response and PFS assessed independently, lack of blinding |
| Incomplete outcome data (attrition bias) | Low risk | ITT population assessed, 8 patients not treated |
| Incomplete outcome data (attrition bias) | Low risk | ITT population assessed, 8 patients not treated |
| Incomplete outcome data (attrition bias) | Low risk | All treated participants assessed |
| Incomplete outcome data (attrition bias) | High risk | High losses in questionnaire completion rates |
| Selective reporting (reporting bias) | Low risk | All planned outcomes reported |
| Other bias | Unclear risk | Protocol amended to increase sample size for planned events, non‐inferiority design |
| Study characteristics | ||
| Methods | Study design: multicentre RCT Phase: 3 Accrual period: February 2010 to August 2010 Blinding: open label design Strata: region, number of prior treatments, number of metastatic sites and organs involved IMC: data monitored not specified Crossover: at progression | |
| Participants | Histology: clear cell component Prior systemic therapy: treatment‐naïve; except for immunotherapy, chemotherapy, or hormonal therapy Eligible PS: ECOG PS 1 or better Measurable disease: required Non metastatic %: ≤ 21 M/F: 374/143 Age median (range): 59 (23 to 85) Prior nephrectomy: required Prognostic strata: system, good/intermediate/poor risk: MSKCC 157/333/27 | |
| Interventions | tivozanib 1.5 mg, 3 wks on/1 wks off vs sorafenib 400 mg bid | |
| Outcomes | PFS: primary outcome OS: secondary outcome AE: secondary outcome QoL: secondary outcome RR: secondary outcome Other: tolerability, kidney specific symptoms | |
| Funding Sources | Industry sponsored | |
| Declarations of interest | Reported | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | “An Interactive Voice Response / Interactive Web Response (IVR/IWR) system will be used for enrolment, randomization and drug management” from protocol |
| Allocation concealment (selection bias) | Low risk | “An Interactive Voice Response / Interactive Web Response (IVR/IWR) system will be used for enrolment, randomization and drug management” from protocol; central randomization |
| Blinding of participants and personnel (performance bias) | Low risk | "This was an open‐label, randomized phase III trial"; participants and personnel were not blinded to treatment, no effect on OS expected |
| Blinding of participants and personnel (performance bias) | High risk | "This was an open‐label, randomized phase III trial"; participants and personnel were not blinded to treatment; oral administered, active drugs used in both arms |
| Blinding of outcome assessment (detection bias) | Low risk | Assessment not specified; no effect on OS expected |
| Blinding of outcome assessment (detection bias) | High risk | "The primary end point was progression‐free survival (PFS) by independent review", open label trial design |
| Incomplete outcome data (attrition bias) | Low risk | ITT population analysed, 1 patient not treated in experimental arm |
| Incomplete outcome data (attrition bias) | Low risk | ITT population analysed, 1 patient not treated in experimental arm |
| Incomplete outcome data (attrition bias) | Low risk | All treated participants assessed for safety |
| Incomplete outcome data (attrition bias) | Low risk | "HRQoL questionnaires were completed by more than 99% of patients in both arms at baseline. Completion rates decreased over time, in line with study dropout, falling below 50% after cycle 13" |
| Selective reporting (reporting bias) | Low risk | All planned outcomes reported |
| Other bias | High risk | Possible confounding of OS data by cross‐over design |
| Study characteristics | ||
| Methods | Study design: multicentre RCT Phase: 2 Accrual period: October 2009 to June 2011 Blinding: open label design Strata: MSKCC risk category IMC: data not found Crossover: within treatment arms from first to second line | |
| Participants | Histology: any Prior systemic therapy: treatment‐naïve Eligible PS: Karnofsky PS 70% or better Measurable disease: required Non metastatic %: not specified M/F: 342/129 Age median (range): 62 (20 to 89) Prior nephrectomy: 315 Prognostic strata: system, good/intermediate/poor risk: MSKCC, 139/263/67 | |
| Interventions | first line: everolimus 10 mg po; second line: sunitinib 50 mg po 4 wks on, 2 wks off vs first line: sunitinib 50 mg po 4 wks on, 2 wks off; second line everolimus 10 mg po | |
| Outcomes | PFS: primary outcome for first line treatment OS: secondary outcome AE: reported in toxicity table QoL: reported RR: assessed as secondary outcome Other: tolerability, PFS after second line treatment | |
| Funding Sources | Industry sponsored | |
| Declarations of interest | Reported | |
| Notes | Non‐inferiority design | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Patients were randomly assigned in a 1:1 manner; Interactive Voice Response System (IVRS) to randomize the patient" |
| Allocation concealment (selection bias) | Low risk | Patient randomisation list used; described in detail |
| Blinding of participants and personnel (performance bias) | Low risk | "RECORD‐3 [...] was an open‐label, randomized, multicenter, phase II study...", no effects on OS expected |
| Blinding of participants and personnel (performance bias) | High risk | "RECORD‐3 [...] was an open‐label, randomized, multicenter, phase II study..."; same drugs with different sequence used in both arms but participants and personnel were not blinded to treatment |
| Blinding of outcome assessment (detection bias) | Low risk | Assessment not specified, no effect on OS expected |
| Blinding of outcome assessment (detection bias) | High risk | "The primary end point was to assess progression‐free survival (PFS) non‐inferiority of first‐line everolimus compared with sunitinib by investigator assessment" |
| Incomplete outcome data (attrition bias) | Low risk | ITT population reported, 2 patients in control arm did not receive treatment |
| Incomplete outcome data (attrition bias) | Low risk | ITT population reported, 2 patients in control arm did not receive treatment |
| Incomplete outcome data (attrition bias) | Low risk | All treated participants reported |
| Incomplete outcome data (attrition bias) | Low risk | High initial questionnaire completion rate, decreased in both arms over time |
| Selective reporting (reporting bias) | Low risk | All planned outcomes reported |
| Other bias | High risk | Difference in baseline performance status, non‐inferiority design |
| Study characteristics | ||
| Methods | Study design: multicentre RCT Phase: 3 Accrual period: March 2016 to December 2017 Blinding: open label design Strata: ECOG PS (0 or 1), geographic region IMC: external data monitoring committee used for efficacy and safety Crossover: not planned | |
| Participants | Histology: clear cell renal cell carcinoma Prior systemic therapy: treatment‐naïve Eligible PS: Karnofsky PS 70% or better Measurable disease: required Non metastatic %: not specified M/F: 660/226 Age median (range): 61 (27 to 88) Prior nephrectomy: 707 Prognostic strata: system, good/intermediate/poor risk: MSKCC, 196/576/96 | |
| Interventions | Avelumab administered at 10 mg/kg IV every 2 weeks in combination with Axitinib, 5 mg PO BID versus Sunitinib given at 50 mg PO QD on schedule 4/2 | |
| Outcomes | PFS: primary outcome among patients with PD‐L1–positive tumours, secondary endpoint for overall population OS: primary outcome among patients with PD‐L1–positive tumours, secondary endpoint for overall population AE: reported in toxicity table QoL: not assessed RR: assessed as secondary outcome Other: pharmacokinetic measures, tumour‐tissue biomarker | |
| Funding Sources | Industry sponsored | |
| Declarations of interest | Reported online | |
| Notes | Primary endpoints changed after protocol amendment in June 2017 to evaluate PFS or OS for PD‐L1 positive participants | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "the study treatment assignment using the Interactive Response Technology (IRT) system (interactive web‐based response [IWR]/interactive voice response [IVR] system)" from protocol |
| Allocation concealment (selection bias) | Low risk | "the study treatment assignment using the Interactive Response Technology (IRT) system (interactive web‐based response [IWR]/interactive voice response [IVR] system)" from protocol |
| Blinding of participants and personnel (performance bias) | Low risk | "This was a multicenter, randomized, open‐label, phase‐3 trial..."; open label trial design, no effects on OS expected |
| Blinding of participants and personnel (performance bias) | High risk | "This was a multicenter, randomized, open‐label, phase‐3 trial..."; different drugs and administration form, participants and personnel were not blinded to treatment |
| Blinding of outcome assessment (detection bias) | Low risk | OS assessment of PD‐L1 positive population. The evaluation of PD‐L1 status a priori to assessment of OS is not considered as objective. Trial design is open‐label. However, we extracted OS result from overall population. |
| Blinding of outcome assessment (detection bias) | Low risk | Primary and main secondary endpoints determined by blinded independent central review |
| Incomplete outcome data (attrition bias) | Low risk | ITT and PD‐L1 population reported separately for PFS, 8 and 5 participants did not receive treatment |
| Incomplete outcome data (attrition bias) | Low risk | ITT and PD‐L1 population reported separately, 8 and 5 participants did not receive treatment |
| Incomplete outcome data (attrition bias) | Low risk | All treated participants reported in toxicity table |
| Selective reporting (reporting bias) | Unclear risk | OS data not mature at time of publication, protocol amended after study start but initially planned outcomes reported |
| Other bias | Low risk | Planned accrual completed, protocol changes after study start. |
| Study characteristics | ||
| Methods | Study type: multicentre RCT Phase: 2 Accrual period: data not found Blinding: open label design Strata: MSKCC risk category IMC: used to analyse tumour responses Crossover: not allowed | |
| Participants | Histology: predominantly clear‐cell mRCC Prior systemic therapy: treatment‐naïve Eligible PS: Karnofsky PS 70% or better Measurable disease: required Non metastatic %: 0, metastatic disease mandatory M/F: 269/96 Age median (range): 60 (20 to 84) Prior nephrectomy: partial or radical nephrectomy mandatory Prognostic strata: system, good/intermediate/poor risk: MSKCC, 131/208/26 | |
| Interventions | Everolimus 10 mg po and bevacizumab 10mg/kg iv every 2 wks vs IFN 9 MIU 3 times per wk plus bevacizumab 10 mg/kg every 2 weeks | |
| Outcomes | PFS: primary endpoint OS: secondary outcome AE: secondary outcome, reported in toxicity table QoL: not assessed RR: secondary outcome Other: duration of response | |
| Funding Sources | Industry sponsored | |
| Declarations of interest | Reported | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | "randomized 1:1" |
| Allocation concealment (selection bias) | Unclear risk | Data not found |
| Blinding of participants and personnel (performance bias) | Low risk | "open‐label, phase II RECORD‐2 trial"; personnel and participants were not blinded to treatment, different drug administration forms used, no effect on OS expected |
| Blinding of participants and personnel (performance bias) | Unclear risk | "open‐label, phase II RECORD‐2 trial"; personnel and participants were not blinded to treatment, different drug administration forms used |
| Blinding of outcome assessment (detection bias) | Low risk | Tumor response and progression were evaluated by the local radiologist and independent central review |
| Blinding of outcome assessment (detection bias) | High risk | Tumor response and progression were evaluated by the local radiologist and independent central review; trial design is open‐label |
| Incomplete outcome data (attrition bias) | Low risk | ITT population reported, 3 patients did not receive treatment |
| Incomplete outcome data (attrition bias) | Low risk | ITT population reported, 3 patients did not receive treatment |
| Incomplete outcome data (attrition bias) | Low risk | All but 1 participant who received treatment were included in safety analysis |
| Incomplete outcome data (attrition bias) | Unclear risk | No available data |
| Selective reporting (reporting bias) | Low risk | All outcomes reported |
| Other bias | Unclear risk | Study not powered to show significant treatment effect |
| Study characteristics | ||
| Methods | Study type: multicentre RCT Phase: 3 Accrual period: June 2012 to November 2016 Blinding: open label design Strata: low versus intermediate MSKCC risk score, clear cell versus non‐clear cell histology IMC: data not found Crossover: from first to second‐line after disease progression | |
| Participants | Histology: any Prior systemic therapy: treatment‐naïve Eligible PS: Karnofsky PS 70% or better Measurable disease: required Non metastatic %: data not found M/F: 189/188 Age median (range): 68 (26 to 86) Prior nephrectomy: 328 Prognostic strata: system, good/intermediate/poor risk: MSKCC, 186/179/9 | |
| Interventions | Sorafenib 400 mg bid orally until progression or intolerable toxicity, followed by pazopanib 800 mg once daily orally until progression or intolerable toxicity or vice versa | |
| Outcomes | PFS: primary outcome OS: reported AE: reported QoL: planned RR: planned Other: time to first‐line treatment failure, biomarker | |
| Funding Sources | Technische Universität München | |
| Declarations of interest | Reported online | |
| Notes | MSKCC PS low or intermediate patients only, non‐inferiority study | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | "377 patients were randomised" |
| Allocation concealment (selection bias) | Unclear risk | Data not found |
| Blinding of participants and personnel (performance bias) | Low risk | "Phase III randomized, sequential, open‐label study"; participants and personnel were not masked to treatment; no effect on OS expected |
| Blinding of participants and personnel (performance bias) | High risk | "Phase III randomized, sequential, open‐label study"; participants and personnel were not masked to treatment; same drugs used in both arms |
| Blinding of outcome assessment (detection bias) | Low risk | Open label study design but no effect on OS expected |
| Blinding of outcome assessment (detection bias) | Unclear risk | Data not found |
| Incomplete outcome data (attrition bias) | Low risk | Intention to treat population analysed |
| Incomplete outcome data (attrition bias) | Low risk | Intention to treat population analysed |
| Incomplete outcome data (attrition bias) | Low risk | 83/189 (96.8%) and 183/188 (97.3%) population analysed in each arm |
| Incomplete outcome data (attrition bias) | High risk | 136/189 (71.9%) and 131/188 (69.6%) population analysed in each arm |
| Selective reporting (reporting bias) | Unclear risk | Quality of life outcome not published in conference abstract |
| Other bias | Low risk | Not detected |
| Study characteristics | ||
| Methods | Study type: multicentre RCT Phase: 3 Accrual period: October 2003 to July 2005 Blinding: open label design Strata: nephrectomy status; prognostic risk IMC: Data Safety Monitoring Board Crossover: data not found | |
| Participants | Histology: clear cell Prior systemic therapy: naïve Measurable disease: measurable or non‐measurable disease Non metastatic %: not specified M/F %: 508/224 Eligible PS: Karnofsky; 100 to 70% Age median: 62 Prior nephrectomy: 620 Prognostic strata: system, good/intermediate/poor risk %: MSKCC, 26/64/10 | |
| Interventions | INTERFERON alfa‐2b (Intron, Schering‐Plough) 9 MU SC TIW (1) with, or (2) | |
| Outcomes | PFS: secondary endpoint OS: primary endpoint AE: secondary endpoint, reported in toxicity table QoL: not assessed RR: secondary endpoint Other: ‐ | |
| Funding Sources | Independent sponsoring | |
| Declarations of interest | Reported | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "A stratified random block design was used"; Central randomisation by cooperative groups (CALGB and NCI‐Canada) |
| Allocation concealment (selection bias) | Low risk | Central randomisation |
| Blinding of participants and personnel (performance bias) | Low risk | "There was no placebo infusion in this non blinded trial", participants and personnel were not blinded to treatment, no effect on OS expected |
| Blinding of participants and personnel (performance bias) | High risk | "There was no placebo infusion in this non blinded trial", participants and personnel were not blinded to treatment |
| Blinding of outcome assessment (detection bias) | Low risk | "no independent review of radiographs"; Investigator assessment of total population, overall survival primary outcome assumed reliable |
| Blinding of outcome assessment (detection bias) | High risk | "no independent review of radiographs", assessed by investigator |
| Incomplete outcome data (attrition bias) | Low risk | All patients accounted for with small symmetric losses |
| Incomplete outcome data (attrition bias) | Low risk | All patients accounted for with small symmetric losses |
| Incomplete outcome data (attrition bias) | Low risk | On treated participant not reported |
| Selective reporting (reporting bias) | Low risk | All protocol outcomes reported |
| Other bias | Low risk | Planned accrual completed; independently sponsored and conducted |
| Study characteristics | ||
| Methods | Study design: multicentre RCT | |
| Participants | Histology: clear cell component | |
| Interventions | Temsirolimus 25 mg iv weekly plus Bevacizumab 10 mg/kg iv every 2 weeks or IFN 9 million U[MIU] subcutaneously thrice weekly plus Bevacizumab 10 mg/kg IV every 2 weeks | |
| Outcomes | PFS: independent assessment as primary endpoint | |
| Funding Sources | Industry sponsored | |
| Declarations of interest | Reported in main publication | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "A computerized centrally located randomization system was used" |
| Allocation concealment (selection bias) | Low risk | "A computerized centrally located randomization system was used" |
| Blinding of participants and personnel (performance bias) | Low risk | "randomized, open‐label, multicenter, phase III study"; participants and personnel were not blinded to treatment, no effect on OS expected |
| Blinding of participants and personnel (performance bias) | High risk | "randomized, open‐label, multicenter, phase III study"; participants and personnel were not blinded to treatment |
| Blinding of outcome assessment (detection bias) | Low risk | "Secondary end points were investigator‐assessed PFS, independently assessed ORR, OS, and safety" no effect on OS expected |
| Blinding of outcome assessment (detection bias) | Low risk | "Radiographic evaluations were conducted at screening and every 8 weeks, and tumor progression was assessed both by investigators and by an independent blinded assessment" |
| Incomplete outcome data (attrition bias) | Low risk | ITT population reported, 7 patients in 1 arm did not receive treatment |
| Incomplete outcome data (attrition bias) | Low risk | ITT population reported, 7 patients in 1 arm did not receive treatment |
| Incomplete outcome data (attrition bias) | Low risk | All treated participants reported in toxicity table |
| Incomplete outcome data (attrition bias) | Low risk | "Completion rate for each questionnaire was uniformly high in both treatment arms, with rates above 90% among patients on treatment up to the end of treatment visit" assessed as exploratory outcome only |
| Selective reporting (reporting bias) | Low risk | All planned outcomes reported |
| Other bias | Unclear risk | Planned accrual almost completed (791 versus 800) |
| Study characteristics | ||
| Methods | Study design: multicentre RCT Phase: 3 Accrual period: December 2010 to December 2012 Blinding: open label design Strata: IMDC risk group, region, nephrectomy status IMC: data and safety monitored Crossover: not allowed | |
| Participants | Histology: clear cell component Prior systemic therapy: treatment‐naïve Eligible PS: Karnowsky PS 80% or better Measurable disease: required Non metastatic %: ≤ 28 M/F: 230/109 Age median (range): 61 (54 to 69) Prior nephrectomy: 306 Prognostic strata: system, good/intermediate/poor risk %: IMDC, 91/241/7 | |
| Interventions | Sunitinib 50 mg po 4 wks on, 2 wks off vs sunitinib 50 mg po 4 wks on, 2 wks off and Cyclophosphamide (1 dose of 300 mg/m² iv) at visit D (3 days before the first vaccination at visit 1) and the vaccination schedule (GM‐CSF 75 μg and IMA901 4.13 mg intradermally at each vaccination) included 6 vaccinations within the first 3 weeks (visits 1 to 6 on days 1, 2, 3, 8, 15, and 22, respectively) and a further 4 vaccinations at 3‐week intervals (visits 7 to 10 on days 43, 64, 85, and 106, respectively) | |
| Outcomes | PFS: secondary outcome OS: primary endpoint AE: reported in toxicity table, secondary outcome QoL: not assessed RR: secondary outcome Other: biomarker related OS | |
| Funding Sources | Industry sponsored | |
| Declarations of interest | Reported | |
| Notes | Only favourable or intermediate risk according to the International Metastatic Database Consortium (IMDC) risk criteria patients included, all patients treated with sunitinib and evaluated for efficacy before randomisation. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "...randomised centrally with an interactive web response system..." |
| Allocation concealment (selection bias) | Low risk | "...randomised centrally with an interactive web response system..." |
| Blinding of participants and personnel (performance bias) | Low risk | "patients and investigators were not masked to treatment allocation", open label study design, no effect on OS expected |
| Blinding of participants and personnel (performance bias) | High risk | "patients and investigators were not masked to treatment allocation", open label study design |
| Blinding of outcome assessment (detection bias) | Low risk | "The primary outcome was overall survival from randomisation until death of any cause as determined by local investigators"; no effect on OS expected |
| Blinding of outcome assessment (detection bias) | Low risk | "progression‐free survival from randomisation according to blinded, independent central review", "Best tumour response was assessed according to RECIST 1.1 and was based on centrally reviewed tumour images" |
| Incomplete outcome data (attrition bias) | Low risk | ITT population reported, 8 patients did not receive treatment |
| Incomplete outcome data (attrition bias) | Low risk | All randomised participants analysed |
| Incomplete outcome data (attrition bias) | Low risk | All treated participants analysed |
| Selective reporting (reporting bias) | Low risk | All planned outcomes reported |
| Other bias | High risk | All participants treated with 1 of the study drugs in run in phase, only responders randomised |
| Study characteristics | ||
| Methods | Study design: multicentre RCT Phase: 3 Accrual period: October 2016 to January 2018 Blinding: open label design Strata: IMDC risk group (favourable, intermediate, or poor risk) and geographic region IMC: an independent data and safety monitoring committee oversaw the trial Crossover: not planned | |
| Participants | Histology: clear‐cell renal‐cell carcinoma Prior systemic therapy: treatment‐naïve Eligible PS: Karnowsky PS 70% or better Measurable disease: required Non metastatic %: < 99 M/F: 628/233 Age median (range): 62 (26 to 90) Prior nephrectomy: 715 Prognostic strata: system, good/intermediate/poor risk %: IMDC, 269/484/108 | |
| Interventions | Pembrolizumab 200 mg intravenously every 3 weeks plus Axitinib 5 mg orally twice daily versus Sunitinib 50 mg orally once daily for 4 weeks and then are off treatment for 2 weeks | |
| Outcomes | PFS: co‐primary outcome assessed by blinded, independent central review OS: co‐primary outcome assessed by blinded, independent central review AE: reported in toxicity table, secondary outcome QoL: not assessed RR: secondary outcome assessed by blinded, independent central review Other: duration of response | |
| Funding Sources | Industry sponsored | |
| Declarations of interest | Reported online | |
| Notes | Planned accrual completed, primary endpoint for OS not met because of short follow up | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Treatment randomization will occur centrally using an interactive voice response system / integrated web response system (IVRS/IWRS)" from protocol |
| Allocation concealment (selection bias) | Low risk | "Treatment randomization will occur centrally using an interactive voice response system / integrated web response system (IVRS/IWRS)" from protocol; central randomisation |
| Blinding of participants and personnel (performance bias) | Low risk | "In this open‐label, phase 3 trial..." participants and personnel were not blinded to treatment, no effect on OS expected |
| Blinding of participants and personnel (performance bias) | High risk | "In this open‐label, phase 3 trial..." different drugs and administration form, participants and personnel were not blinded to treatment |
| Blinding of outcome assessment (detection bias) | Low risk | OS assessed by blinded, independent central review |
| Blinding of outcome assessment (detection bias) | Low risk | Subjective primary and secondary efficacy endpoints assessed by blinded, independent central review |
| Incomplete outcome data (attrition bias) | Low risk | Intention to treat population analysed; < 1% in both groups did not receive treatment |
| Incomplete outcome data (attrition bias) | Low risk | Intention to treat population analysed; < 1% in both groups did not receive treatment |
| Incomplete outcome data (attrition bias) | Low risk | All treated participants reported in toxicity table |
| Selective reporting (reporting bias) | Low risk | All planned outcomes reported, no mature OS data available |
| Other bias | Low risk | Not detected |
| Study characteristics | ||
| Methods | Study design: multicentre RCT Phase: 3 Accrual period: May 2015 to October 2016 Blinding: open label design Strata: PD‐L1 expression, presence of liver metastasis, MSKCC risk category IMC: "An independent data monitoring committee reviewed safety data during the study on a periodic basis" Crossover: "No prespecified crossover was planned per protocol" | |
| Participants | Histology: "clear‐cell histology and/or a component of sarcomatoid carcinoma" Prior systemic therapy: treatment‐naïve Eligible PS: Karnowsky PS 70% or better Measurable disease: required Non metastatic %: not specified M/F: 669/246 Age median (range): 61 (54 to 69) Prior nephrectomy: 664 Prognostic strata: system, good/intermediate/poor risk %: MSKCC, 179/629/107 | |
| Interventions | Atezolizumab administered at a fixed dose of 1200 milligrams (mg) via intravenous (IV) infusion on Days 1 and 22 of each 42‐day cycle in combination with Bevacizumab administered at a dose of 15 milligrams per kilogram (mg/kg) via IV infusion on Days 1 and 22 of each 42‐day cycle versus Sunitinib administered at a dose of 50 mg once daily, orally via capsule, on Day 1 through Day 28 of each 42‐day cycle. | |
| Outcomes | PFS: co‐primary outcome by investigator assessment in patients with PD‐L1 positive disease, secondary outcome in the ITT population OS: co‐primary outcome in the intention‐to‐treat population, secondary outcome in the PD‐L1 positive population AE: secondary outcome QoL: reported RR: secondary outcome Other: | |
| Funding Sources | Industry sponsored | |
| Declarations of interest | Reported in main publication | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Patients were randomly assigned (1:1) via an interactive voice and web response system to receive Atezolizumab plus Bevacizumab or Sunitinib." central randomisation presumed |
| Allocation concealment (selection bias) | Low risk | Central randomisation presumed |
| Blinding of participants and personnel (performance bias) | Low risk | "The study was open label, and investigators and participants were not masked to treatment allocation" No effect on OS expected |
| Blinding of participants and personnel (performance bias) | High risk | "The study was open label, and investigators and participants were not masked to treatment allocation", different drugs and forms of administration used in experimental and control arm |
| Blinding of outcome assessment (detection bias) | Low risk | Assessment not specified but not effect on OS expected |
| Blinding of outcome assessment (detection bias) | High risk | "Co‐primary endpoints were progression‐free survival (RECIST 1.1) by investigator assessment in patients with PD‐L1 positive disease" PFS results in PD‐L1 population differ from independent assessment |
| Incomplete outcome data (attrition bias) | Low risk | Intention to treat population reported, 3 participants in experimental and 15 participants in control arm did not receive treatment |
| Incomplete outcome data (attrition bias) | Low risk | Intention to treat population reported, 3 participants in experimental and 15 participants in control arm did not receive treatment |
| Incomplete outcome data (attrition bias) | Low risk | All treated participants reported |
| Incomplete outcome data (attrition bias) | Unclear risk | "386 (86%) of 451 patients in the atezolizumab plus bevacizumab group and 369 (83%) of 446 patients in the sunitinib |
| Selective reporting (reporting bias) | Low risk | All planned outcomes reported |
| Other bias | Low risk | Planned accrual completed |
| Study characteristics | ||
| Methods | Study type: multicentre RCT Phase: 3 Accrual period: April 2006 to April 2007 Blinding: double‐blind, placebo‐controlled Strata: ECOG PS 0vs1; nephrectomy status; prior cytokine IMC: responsible for safety monitoring and to review interim overall survival data Crossover: allowed from placebo to active treatment | |
| Participants | Histology: clear cell Prior systemic therapy: 1 line of cytokines permitted. Measurable disease: required Non metastatic %: < 18 M/F: 307/128 Eligible PS: ECOG 0 to 1 Age median(range): 59 (25 to 85) Prior nephrectomy: 385 Prognostic strata: system, good/intermediate/poor risk %: MSKCC; 39/54/3 | |
| Interventions | (1) PAZOPANIB 800 mg PO daily, vs (2) matched PLACEBO (2:1 randomization) Cross‐over 48% | |
| Outcomes | PFS: primary endpoint OS: principal secondary end point AE: toxicity table available, additional secondary end point QoL: reported RR: additional secondary end point Other: ‐ | |
| Funding Sources | Industry sponsored | |
| Declarations of interest | Reported | |
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | "Patients were centrally randomly assigned in a 2:1 ratio..."; central randomisation |
| Allocation concealment (selection bias) | Low risk | "Patients were centrally randomly assigned in a 2:1 ratio..."; central randomisation |
| Blinding of participants and personnel (performance bias) | Low risk | "was a placebo‐controlled, randomized, double‐blind, global, multicenter, phase III study"; participants and personnel were masked to treatment |
| Blinding of participants and personnel (performance bias) | Low risk | "was a placebo‐controlled, randomized, double‐blind, global, multicenter, phase III study"; participants and personnel were masked to treatment |
| Blinding of outcome assessment (detection bias) | Low risk | "All imaging scans were evaluated by an independent imaging‐review committee (IRC) blinded to study treatment" |
| Blinding of outcome assessment (detection bias) | Low risk | "All imaging scans were evaluated by an independent imaging‐review committee (IRC) blinded to study treatment" |
| Incomplete outcome data (attrition bias) | Low risk | All patients accounted for, losses 6% (investigational) and 3% (control) unlikely significant, “completion rates > 90% across most of the assessment time points” |
| Incomplete outcome data (attrition bias) | Low risk | All patients accounted for, losses 6% (investigational) and 3% (control) unlikely significant, “completion rates > 90% across most of the assessment time points” |
| Incomplete outcome data (attrition bias) | Low risk | All treated participants analysed |
| Incomplete outcome data (attrition bias) | Low risk | "Completion rates for QoL questionnaires were high across most of the assessment time points for each instrument" |
| Selective reporting (reporting bias) | Low risk | All protocol specified endpoints reported |
| Other bias | Low risk | Planned accrual completed |
AE: adverse event; ECOG: Eastern Cooperative Oncology Group; F: female; IMC: independent monitoring committee; IMDC: International Metastatic Renal Cell Carcinoma Database Consortium; ITT: intention to treat; M: male; MSKCC: Memorial Sloan Kettering Cancer Center; OS: overall survival; PFS: progression‐free survival; PS: performance status; QoL: quality of life; RCT: randomised controlled trial; RR: response rate; wks: weeks
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
| Non‐clear cell renal cell carcinoma participants only, less than 100 participants per treatment arm included | |
| Same targeted drug used in all treatment arms, less than 100 participants per treatment arm included, cytokine pretreatment required | |
| Same targeted treatment used in both arms, less than 100 participants per treatment arm included | |
| Less than 100 participants per treatment arm included | |
| Less than 100 participants per treatment arm included | |
| Participants were not treatment‐naïve | |
| Less than 100 participants per treatment arm included | |
| Less than 100 participants per treatment arm included | |
| Participants not treatment‐naïve, less than 100 participants per treatment arm included | |
| Same drug used in both treatment arms, less than 100 participants per treatment arm included | |
| Less than 100 participants per treatment arm included | |
| Treatment is not considered as targeted therapy | |
| Less than 100 participants per treatment arm included | |
| Participants were not treatment naïve | |
| Less than 100 participants per treatment arm included | |
| No treatment that is considered as targeted therapy was used in trial | |
| Less than 100 participants per treatment arm included | |
| Treatment not considered as targeted therapy, any renal cell carcinoma histologies included | |
| Participants were not treatment naïve | |
| Participants were not treatment naïve | |
| Less than 100 participants per treatment arm included | |
| Participants were not treatment naïve | |
| Treatment not considered as targeted therapy | |
| Same study drugs used in both arms, less than 100 participants per treatment arm included | |
| Treatment not considered as targeted therapy | |
| Participants were not treatment‐naïve | |
| Same study drug used in both arms | |
| Participants were not treatment‐naïve | |
| Participants were not treatment‐naïve | |
| Participants were not treatment‐naïve | |
| Participants were not treatment‐naïve | |
| Less than 100 participants per treatment arm included | |
| Less than 100 participants per treatment arm included | |
| Less than 100 participants per treatment arm included | |
| Less than 100 participants per treatment arm included, participants were not treatment‐naïve | |
| Less than 100 participants per treatment arm included, participants were not treatment‐naïve | |
| Less than 100 participants per treatment arm included, participants were not treatment‐naïve | |
| Less than 100 participants per treatment arm included, participants were not treatment‐naïve | |
| Less than 100 participants per treatment arm included, participants were not treatment‐naïve | |
| Less than 100 participants per treatment arm included | |
| Less than 100 participants per treatment arm included, 84% of participants pretreated | |
| Treatment in control arm not eligible for comparisons | |
| Participants were not treatment‐naïve | |
| Treatment in observational and control arm not eligible for comparison | |
| Less than 100 participants per treatment arm included | |
| Treatment not considered as targeted therapy | |
| Treatment is not considered as targeted therapy | |
| Less than 100 participants per treatment arm included, non‐clear cell renal cell carcinoma only | |
| Less than 100 participants per treatment arm included | |
| Less than 100 participants per treatment arm included | |
| Less than 100 participants per treatment arm included, participants were not treatment‐naïve | |
| Less than 100 participants per treatment arm included, participants were not treatment‐naïve |
Characteristics of ongoing studies [ordered by study ID]
| Study name | NCT03141177, CheckMate 9ER |
| Methods | Study type: multicentre RCT Phase: 3 Accrual period: data not found Blinding: open label study design Strata: IMDC risk score, PD‐1 ligand 1 (PD‐L1) tumour expression and geographic region IMC: data not found Crossover: data not found |
| Participants | Histology: clear cell component Prior systemic therapy: no prior systemic therapy for RCC Measurable disease: required Eligible PS: data not found Non metastatic %: data not found M/F %: data not found Age median(range): data not found Prior nephrectomy: data not found Prognostic strata: system, good/intermediate/poor risk %: data not found |
| Interventions | Nivolumab and cabozantinib versus sunitinib |
| Outcomes | PFS: primary endpoint OS: secondary end point AE: secondary end point QoL: not planned RR: secondary end point Other: ‐ |
| Starting date | July 2017 |
| Contact information | |
| Notes |
| Study name | NCT03937219, Cosmic‐313 |
| Methods | Study type: multicentre RCT Phase: 3 Accrual period: 25 June 2019 ‐ Blinding: double‐blind study design Strata: IMDC risk score and geographic region IMC: data not found Crossover: data not found |
| Participants | Histology: clear cell component Prior systemic therapy: no prior systemic therapy for RCC Measurable disease: required Eligible PS: Karnofsky PS 70% or better Non metastatic %: data not found M/F %: data not found Age median (range): data not found Prior nephrectomy: data not found Prognostic strata: system, good/intermediate/poor risk %: data not found |
| Interventions | Cabozantinib + nivolumab + ipilimumab (4 doses) followed by cabozantinib + nivolumab vs Cabozantinib‐matched placebo + nivolumab + ipilimumab (4 doses) followed by cabozantinib‐matched placebo + nivolumab |
| Outcomes | PFS: primary endpoint OS: secondary end point AE: ‐ QoL:‐ RR:‐ Other: ‐ |
| Starting date | June 2019 |
| Contact information | |
| Notes |
| Study name | NCT02959554, NIVOSWITCH |
| Methods | Study design: multicentre RCT Phase: 2 Accrual period: data not found Blinding: open label study design Strata: data not found IMC: data not found Crossover: data not found |
| Participants | Histology: clear cell component Prior systemic therapy: First‐line treatment with a TKI for 10‐12 weeks (limited to sunitinib or pazopanib) Eligible PS: ECOG‐PS 0‐2 Measurable disease: required Non metastatic %: data not found M/F %: data not found Age median, years: data not found Prior nephrectomy: data not found Prognostic strata: system, good/intermediate/poor risk %: data not found |
| Interventions | Nivolumab: 240 mg iv on D1 of every cycle (Q2W) for 16 weeks. After 16 weeks 480 mg iv on D1 of every cycle (Q4W) until disease progress, intolerable toxicity, withdrawal of consent or end of study versus Sunitinib: According to Standard of Care (SOC). Recommended dose is 50 mg PO once daily for 4 consecutive weeks followed by a 2‐week rest period (schedule 4/2) to comprise a complete cycle of 6 weeks (until disease progress, intolerable toxicity, withdrawal of consent or end of study) or Pazopanib: According to Standard of Care (SOC). Recommended dose is 800 mg PO daily continuously (until disease progress, intolerable toxicity, withdrawal of consent or end of study) |
| Outcomes | PFS: secondary endpoint OS: primary end point AE: secondary end point QoL: secondary endpoint RR: secondary end point Other: ‐ |
| Starting date | December 2016 |
| Contact information | Principal Investigator: Prof. Dr. Viktor Grünwald |
| Notes |
| Study name | NCT02811861 |
| Methods | Study design: multicentre RCT Phase: 3 Accrual period: data not found Blinding: open label design Strata: data not found IMC: data not found Crossover: data not found |
| Participants | Histology: clear cell carcinoma Prior systemic therapy: treatment‐naïve Eligible PS: Karnofsky PS 70% or better Measurable disease: required Non metastatic %: data not found M/F %: data not found Age median, years: data not found Prior nephrectomy: data not found Prognostic strata: system, good/intermediate/poor risk %: data not found |
| Interventions | lenvatinib 18 milligrams (mg) administered orally, once daily, plus everolimus 5 mg administered orally, once daily; Lenvatinib 20 mg administered orally, once daily, plus pembrolizumab 200 mg administered intravenously (IV), every 3 weeks; Sunitinib 50 mg administered orally, once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off treatment |
| Outcomes | PFS: primary endpoint OS: planned AE: planned QoL: planned RR: primary endpoint Other: ‐ |
| Starting date | Trial start date: 13 October 2016 Trial completion date: Estimated 15 January 2020 |
| Contact information | Responsible party/ principal investigator: Eisai Inc. |
| Notes | Study based on results of phase 2 study data |
AE: adverse event; ECOG: Eastern Cooperative Oncology Group; F: female; IMC: independent monitoring committee; IMDC: International Metastatic Renal Cell Carcinoma Database Consortium; IV; intravenous; M: male; OS: overall survival; PFS: progression‐free survival; PO; per oral; PS: performance status; QoL: quality of life; RCC: renal cell carcinoma; RR: response rate; TKI: tyrosine kinase inhibitor
Data and analyses
| 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 | |
| Analysis 1.1  Comparison 1: Sorafenib versus Sunitinib, Outcome 1: Progression‐free survival | ||||
| 1.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 1.2  Comparison 1: Sorafenib versus Sunitinib, Outcome 2: Overall survival | ||||
| 1.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 1.3  Comparison 1: Sorafenib versus Sunitinib, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 1.4 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 1.4  Comparison 1: Sorafenib versus Sunitinib, Outcome 4: Response rate | ||||
| 1.5 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 1.5  Comparison 1: Sorafenib versus Sunitinib, Outcome 5: Minor adverse events (Grade 1 or 2) | ||||
| 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 | |
| Analysis 2.1  Comparison 2: Pazopanib versus Sunitinib, Outcome 1: Progression‐free survival | ||||
| 2.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 2.2  Comparison 2: Pazopanib versus Sunitinib, Outcome 2: Overall survival | ||||
| 2.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 2.3  Comparison 2: Pazopanib versus Sunitinib, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 2.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Analysis 2.4  Comparison 2: Pazopanib versus Sunitinib, Outcome 4: Health‐related quality of life | ||||
| 2.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 2.5  Comparison 2: Pazopanib versus Sunitinib, Outcome 5: Response rate | ||||
| 2.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 2.6  Comparison 2: Pazopanib versus Sunitinib, Outcome 6: Minor adverse events (Grade 1 or 2) | ||||
| 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 | |
| Analysis 3.1  Comparison 3: Tivozanib versus Sorafenib, Outcome 1: Progression‐free survival | ||||
| 3.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 3.2  Comparison 3: Tivozanib versus Sorafenib, Outcome 2: Overall survival | ||||
| 3.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 3.3  Comparison 3: Tivozanib versus Sorafenib, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 3.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Analysis 3.4  Comparison 3: Tivozanib versus Sorafenib, Outcome 4: Health‐related quality of life | ||||
| 3.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 3.5  Comparison 3: Tivozanib versus Sorafenib, Outcome 5: Response rate | ||||
| 3.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 3.6  Comparison 3: Tivozanib versus Sorafenib, Outcome 6: Minor adverse events (Grade 1 or 2) | ||||
| 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 | |
| Analysis 4.1  Comparison 4: Sorafenib versus Pazopanib, Outcome 1: Progression‐free survival | ||||
| 4.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 4.2  Comparison 4: Sorafenib versus Pazopanib, Outcome 2: Overall survival | ||||
| 4.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 4.3  Comparison 4: Sorafenib versus Pazopanib, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 4.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Analysis 4.4  Comparison 4: Sorafenib versus Pazopanib, Outcome 4: Health‐related quality of life | ||||
| 4.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 4.5  Comparison 4: Sorafenib versus Pazopanib, Outcome 5: Response rate | ||||
| 4.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 4.6  Comparison 4: Sorafenib versus Pazopanib, Outcome 6: Minor adverse events (Grade 1 or 2) | ||||
| 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 | |
| Analysis 5.1  Comparison 5: Sunitinib versus Everolimus, Outcome 1: Progression‐free survival | ||||
| 5.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 5.2  Comparison 5: Sunitinib versus Everolimus, Outcome 2: Overall survival | ||||
| 5.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 5.3  Comparison 5: Sunitinib versus Everolimus, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 5.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Analysis 5.4  Comparison 5: Sunitinib versus Everolimus, Outcome 4: Health‐related quality of life | ||||
| 5.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 5.5  Comparison 5: Sunitinib versus Everolimus, Outcome 5: Response rate | ||||
| 5.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 5.6  Comparison 5: Sunitinib versus Everolimus, Outcome 6: Minor adverse events (Grade 1 or 2) | ||||
| 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 | |
| Analysis 6.1  Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 1: Progression‐free survival | ||||
| 6.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 6.2  Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 2: Overall survival | ||||
| 6.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 6.3  Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 6.4 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 6.4  Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 4: Response rate | ||||
| 6.5 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 6.5  Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 5: Minor adverse events (Grade 1 or 2) | ||||
| 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 | |
| Analysis 7.1  Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 1: Progression‐free survival | ||||
| 7.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 7.2  Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 2: Overall survival | ||||
| 7.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 7.3  Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 7.4 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 7.4  Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 4: Response rate | ||||
| 7.5 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 7.5  Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 5: Minor adverse events (Grade 1 or 2) | ||||
| 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] |
| Analysis 8.1  Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 1: Progression‐free survival | ||||
| 8.2 Overall survival Show forest plot | 2 | 1117 | Hazard Ratio (IV, Random, 95% CI) | 0.99 [0.73, 1.33] |
| Analysis 8.2  Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 2: Overall survival | ||||
| 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] |
| Analysis 8.3  Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 8.4 Health‐related quality of life Show forest plot | 2 | 691 | Mean Difference (IV, Random, 95% CI) | 1.00 [0.68, 1.32] |
| Analysis 8.4  Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 4: Health‐related quality of life | ||||
| 8.5 Response rate Show forest plot | 2 | 1117 | Risk Ratio (M‐H, Random, 95% CI) | 0.91 [0.77, 1.07] |
| Analysis 8.5  Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 5: Response rate | ||||
| 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] |
| Analysis 8.6  Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 6: Minor adverse events (Grade 1 or 2) | ||||
| 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 | |
| Analysis 9.1  Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 1: Progression‐free survival | ||||
| 9.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 9.2  Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 2: Overall survival | ||||
| 9.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 9.3  Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 9.4 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 9.4  Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 4: Response rate | ||||
| 9.5 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 9.5  Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 5: Minor adverse events (Grade 1 or 2) | ||||
| 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 | |
| Analysis 10.1  Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 1: Progression‐free survival | ||||
| 10.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 10.2  Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 2: Overall survival | ||||
| 10.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 10.3  Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 10.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Analysis 10.4  Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 4: Health‐related quality of life | ||||
| 10.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 10.5  Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 5: Response rate | ||||
| 10.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 10.6  Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 6: Minor adverse events (Grade 1 or 2) | ||||
| 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 | |
| Analysis 11.1  Comparison 11: Temsirolimus versus IFN‐α, Outcome 1: Progression‐free survival | ||||
| 11.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 11.2  Comparison 11: Temsirolimus versus IFN‐α, Outcome 2: Overall survival | ||||
| 11.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 11.3  Comparison 11: Temsirolimus versus IFN‐α, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 11.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Analysis 11.4  Comparison 11: Temsirolimus versus IFN‐α, Outcome 4: Health‐related quality of life | ||||
| 11.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 11.5  Comparison 11: Temsirolimus versus IFN‐α, Outcome 5: Response rate | ||||
| 11.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 11.6  Comparison 11: Temsirolimus versus IFN‐α, Outcome 6: Minor adverse events (Grade 1 or 2) | ||||
| 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 | |
| Analysis 12.1  Comparison 12: Sunitinib versus Atezolizumab, Outcome 1: Progression‐free survival | ||||
| 12.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 12.2  Comparison 12: Sunitinib versus Atezolizumab, Outcome 2: Overall survival | ||||
| 12.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 12.3  Comparison 12: Sunitinib versus Atezolizumab, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 12.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Analysis 12.4  Comparison 12: Sunitinib versus Atezolizumab, Outcome 4: Health‐related quality of life | ||||
| 12.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 12.5  Comparison 12: Sunitinib versus Atezolizumab, Outcome 5: Response rate | ||||
| 12.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 12.6  Comparison 12: Sunitinib versus Atezolizumab, Outcome 6: Minor adverse events (Grade 1 or 2) | ||||
| 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] |
| Analysis 13.1  Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 1: Progression‐free survival | ||||
| 13.2 Overall survival Show forest plot | 2 | 1381 | Hazard Ratio (IV, Random, 95% CI) | 0.88 [0.79, 0.99] |
| Analysis 13.2  Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 2: Overall survival | ||||
| 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] |
| Analysis 13.3  Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 13.4 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 13.4  Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 4: Response rate | ||||
| 13.5 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 13.5  Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 5: Minor adverse events (Grade 1 or 2) | ||||
| 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 | |
| Analysis 14.1  Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 1: Progression‐free survival | ||||
| 14.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 14.2  Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 2: Overall survival | ||||
| 14.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 14.3  Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 14.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Analysis 14.4  Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 4: Health‐related quality of life | ||||
| 14.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 14.5  Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 5: Response rate | ||||
| 14.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 14.6  Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 6: Minor adverse events (Grade 1 or 2) | ||||
| 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 | |
| Analysis 15.1  Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 1: Progression‐free survival | ||||
| 15.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 15.2  Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 2: Overall survival | ||||
| 15.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 15.3  Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 15.4 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 15.4  Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 4: Response rate | ||||
| 15.5 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 15.5  Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 5: Minor adverse events (Grade 1 or 2) | ||||
| 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 | |
| Analysis 16.1  Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 1: Progression‐free survival | ||||
| 16.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 16.2  Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 2: Overall survival | ||||
| 16.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 16.3  Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 16.4 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 16.4  Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 4: Response rate | ||||
| 16.5 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 16.5  Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 5: Minor adverse events (Grade 1 or 2) | ||||
| 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 | |
| Analysis 17.1  Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 1: Progression‐free survival | ||||
| 17.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 17.2  Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 2: Overall survival | ||||
| 17.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 17.3  Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 17.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Analysis 17.4  Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 4: Health‐related quality of life | ||||
| 17.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 17.5  Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 5: Response rate | ||||
| 17.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 17.6  Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 6: Minor adverse events (Grade 1 or 2) | ||||
| 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 | |
| Analysis 18.1  Comparison 18: Pazopanib versus Placebo, Outcome 1: Progression‐free survival | ||||
| 18.2 Overall survival Show forest plot | 1 | Hazard Ratio (IV, Random, 95% CI) | Totals not selected | |
| Analysis 18.2  Comparison 18: Pazopanib versus Placebo, Outcome 2: Overall survival | ||||
| 18.3 Serious adverse events (Grade 3 or 4) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 18.3  Comparison 18: Pazopanib versus Placebo, Outcome 3: Serious adverse events (Grade 3 or 4) | ||||
| 18.4 Health‐related quality of life Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Analysis 18.4  Comparison 18: Pazopanib versus Placebo, Outcome 4: Health‐related quality of life | ||||
| 18.5 Response rate Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 18.5  Comparison 18: Pazopanib versus Placebo, Outcome 5: Response rate | ||||
| 18.6 Minor adverse events (Grade 1 or 2) Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Analysis 18.6  Comparison 18: Pazopanib versus Placebo, Outcome 6: Minor adverse events (Grade 1 or 2) | ||||
Study flow diagram.
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.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Comparison 1: Sorafenib versus Sunitinib, Outcome 1: Progression‐free survival
Comparison 1: Sorafenib versus Sunitinib, Outcome 2: Overall survival
Comparison 1: Sorafenib versus Sunitinib, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 1: Sorafenib versus Sunitinib, Outcome 4: Response rate
Comparison 1: Sorafenib versus Sunitinib, Outcome 5: Minor adverse events (Grade 1 or 2)
Comparison 2: Pazopanib versus Sunitinib, Outcome 1: Progression‐free survival
Comparison 2: Pazopanib versus Sunitinib, Outcome 2: Overall survival
Comparison 2: Pazopanib versus Sunitinib, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 2: Pazopanib versus Sunitinib, Outcome 4: Health‐related quality of life
Comparison 2: Pazopanib versus Sunitinib, Outcome 5: Response rate
Comparison 2: Pazopanib versus Sunitinib, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 3: Tivozanib versus Sorafenib, Outcome 1: Progression‐free survival
Comparison 3: Tivozanib versus Sorafenib, Outcome 2: Overall survival
Comparison 3: Tivozanib versus Sorafenib, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 3: Tivozanib versus Sorafenib, Outcome 4: Health‐related quality of life
Comparison 3: Tivozanib versus Sorafenib, Outcome 5: Response rate
Comparison 3: Tivozanib versus Sorafenib, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 4: Sorafenib versus Pazopanib, Outcome 1: Progression‐free survival
Comparison 4: Sorafenib versus Pazopanib, Outcome 2: Overall survival
Comparison 4: Sorafenib versus Pazopanib, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 4: Sorafenib versus Pazopanib, Outcome 4: Health‐related quality of life
Comparison 4: Sorafenib versus Pazopanib, Outcome 5: Response rate
Comparison 4: Sorafenib versus Pazopanib, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 5: Sunitinib versus Everolimus, Outcome 1: Progression‐free survival
Comparison 5: Sunitinib versus Everolimus, Outcome 2: Overall survival
Comparison 5: Sunitinib versus Everolimus, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 5: Sunitinib versus Everolimus, Outcome 4: Health‐related quality of life
Comparison 5: Sunitinib versus Everolimus, Outcome 5: Response rate
Comparison 5: Sunitinib versus Everolimus, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 1: Progression‐free survival
Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 2: Overall survival
Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 4: Response rate
Comparison 6: Sunitinib versus Avelumab + Axitinib, Outcome 5: Minor adverse events (Grade 1 or 2)
Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 1: Progression‐free survival
Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 2: Overall survival
Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 4: Response rate
Comparison 7: Sunitinib versus Pembrolizumab + Axitinib, Outcome 5: Minor adverse events (Grade 1 or 2)
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 1: Progression‐free survival
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 2: Overall survival
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 4: Health‐related quality of life
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 5: Response rate
Comparison 8: Sunitinib versus Atezolizumab + Bevacizumab, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 1: Progression‐free survival
Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 2: Overall survival
Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 4: Response rate
Comparison 9: Sunitinib versus IMA901 + Sunitinib, Outcome 5: Minor adverse events (Grade 1 or 2)
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 1: Progression‐free survival
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 2: Overall survival
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 4: Health‐related quality of life
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 5: Response rate
Comparison 10: Sunitinib versus Interferon‐α (IFN‐α), Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 11: Temsirolimus versus IFN‐α, Outcome 1: Progression‐free survival
Comparison 11: Temsirolimus versus IFN‐α, Outcome 2: Overall survival
Comparison 11: Temsirolimus versus IFN‐α, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 11: Temsirolimus versus IFN‐α, Outcome 4: Health‐related quality of life
Comparison 11: Temsirolimus versus IFN‐α, Outcome 5: Response rate
Comparison 11: Temsirolimus versus IFN‐α, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 12: Sunitinib versus Atezolizumab, Outcome 1: Progression‐free survival
Comparison 12: Sunitinib versus Atezolizumab, Outcome 2: Overall survival
Comparison 12: Sunitinib versus Atezolizumab, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 12: Sunitinib versus Atezolizumab, Outcome 4: Health‐related quality of life
Comparison 12: Sunitinib versus Atezolizumab, Outcome 5: Response rate
Comparison 12: Sunitinib versus Atezolizumab, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 1: Progression‐free survival
Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 2: Overall survival
Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 4: Response rate
Comparison 13: Bevacizumab + IFN versus IFN (+ placebo), Outcome 5: Minor adverse events (Grade 1 or 2)
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 1: Progression‐free survival
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 2: Overall survival
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 4: Health‐related quality of life
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 5: Response rate
Comparison 14: Temsirolimus + IFN‐α versus IFN‐α, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 1: Progression‐free survival
Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 2: Overall survival
Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 4: Response rate
Comparison 15: Temsirolimus + Bevacizumab versus Bevacizumab + IFN‐α, Outcome 5: Minor adverse events (Grade 1 or 2)
Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 1: Progression‐free survival
Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 2: Overall survival
Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 4: Response rate
Comparison 16: Everolimus + Bevacizumab versus IFN α‐2a + Bevacizumab, Outcome 5: Minor adverse events (Grade 1 or 2)
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 1: Progression‐free survival
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 2: Overall survival
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 4: Health‐related quality of life
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 5: Response rate
Comparison 17: Sunitinib versus Nivolumab + Ipilimumab, Outcome 6: Minor adverse events (Grade 1 or 2)
Comparison 18: Pazopanib versus Placebo, Outcome 1: Progression‐free survival
Comparison 18: Pazopanib versus Placebo, Outcome 2: Overall survival
Comparison 18: Pazopanib versus Placebo, Outcome 3: Serious adverse events (Grade 3 or 4)
Comparison 18: Pazopanib versus Placebo, Outcome 4: Health‐related quality of life
Comparison 18: Pazopanib versus Placebo, Outcome 5: Response rate
Comparison 18: Pazopanib versus Placebo, Outcome 6: Minor adverse events (Grade 1 or 2)
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Sunitinib | Risk difference with Sorafenib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 10 months) | 365 | ⊕⊕⊝⊝ | HR 1.19 | Study population | |
| 340 per 1000 | 63 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) | 365 | ⊕⊝⊝⊝ | HR 0.99 | Study population | |
| 550 per 1000 | 3 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 353 | ⊕⊝⊝⊝ | RR 0.99 | Study population | |
| 670 per 1000 | 7 fewer per 1000 | ||||
| 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 | |||||
| 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 | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (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 | ⊕⊕⊝⊝ | HR 1.05 | Study population | |
| 420 per 1000 | 18 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 1110 | ⊕⊕⊝⊝ | HR 0.92 | Study population | |
| 550 per 1000 | 27 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 1102 | ⊕⊕⊝⊝ | RR 1.01 | Study population | |
| 734 per 1000 | 7 more per 1000 | ||||
| Health‐related quality of life (mean change value) follow‐up: after 4 cycle | 467 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life (mean change value) was ‐6.5 | MD 3.6 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 | |||||
| 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) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (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 | ⊕⊕⊝⊝ | HR 0.79 | Study population | |
| 360 per 1000 | 86 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 517 | ⊕⊕⊝⊝ | HR 1.25 | Study population | |
| 620 per 1000 | 70 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 516 | ⊕⊕⊝⊝ | RR 0.85 | Study population | |
| 689 per 1000 | 103 fewer per 1000 | ||||
| Health‐related quality of life | 506 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was ‐0.06 | MD 0.01 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 | |||||
| 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) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (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 | ⊕⊕⊕⊝ | HR 1.92 | Study population | |
| 380 per 1000 | 224 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 377 | ⊕⊕⊝⊝ | HR 1.22 | Study population | |
| 520 per 1000 | 70 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 366 | ⊕⊝⊝⊝ | RR 0.92 | Study population | |
| 639 per 1000 | 51 fewer per 1000 | ||||
| Health‐related quality of life follow‐up: not reported | 267 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was ‐9.9 | MD 3.1 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). | |||||
| GRADE Working Group grades of evidence | |||||
| 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) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (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 | ⊕⊕⊕⊝ | HR 0.71 | Study population | |
| 300 per 1000 | 125 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 471 | ⊕⊕⊝⊝ | HR 0.90 | Study population | |
| 470 per 1000 | 37 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 469 | ⊕⊕⊕⊝ | RR 1.34 | Study population | |
| 471 per 1000 | 160 more per 1000 | ||||
| Health‐related quality of life | 288 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was 65.5 | MD 5 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). | |||||
| GRADE Working Group grades of evidence | |||||
| 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) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Avelumab + Axitinib | Risk difference with Sunitinib | ||||
| Progression‐free survival follow‐up: median 10.8 months | 886 | ⊕⊕⊕⊝ | HR 1.45 | Study population | |
| 550 per 1000 | 130 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 12 months) | 886 | ⊕⊕⊝⊝ | HR 1.28 | Study population | |
| 890 per 1000 | 29 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 873 | ⊕⊕⊝⊝ | RR 1.01 | Study population | |
| 705 per 1000 | 7 more per 1000 | ||||
| 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 | |||||
| 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 | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Pembrolizumab + Axitinib | Risk difference with Sunitinib | ||||
| Progression‐free survival follow‐up: median 12.8 months | 861 | ⊕⊕⊕⊝ | HR 1.45 | Study population | |
| 590 per 1000 | 125 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 12 months) | 861 | ⊕⊕⊕⊝ | HR 1.90 | Study population | |
| 880 per 1000 | 96 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 854 | ⊕⊕⊝⊝ | RR 0.90 | Study population | |
| 604 per 1000 | 60 fewer per 1000 | ||||
| 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 | |||||
| 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 | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Atezolizumab + Bevacizumab | Risk difference with Sunitinib | ||||
| Progression‐free survival follow‐up: range 15 months to 20.7 months | 1117 | ⊕⊕⊝⊝ | HR 1.18 | Study population | |
| 480 per 1000 | 59 fewer per 1000 | ||||
| Overall survival follow‐up: range 20.7 months to 24 months | 1117 | ⊕⊝⊝⊝ | HR 0.99 | Study population | |
| 630 per 1000 | 3 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 1098 | ⊕⊝⊝⊝ | RR 1.22 | Study population | |
| 446 per 1000 | 98 more per 1000 | ||||
| Health‐related quality of life | 691 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life ranged from 0.56 to 1.57 | MD 1 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 | |||||
| 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) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with IMA901 + Sunitinib | Risk difference with Sunitinib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) | 339 | ⊕⊝⊝⊝ | HR 0.95 | Study population | |
| 590 per 1000 | 16 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 12 months) | 339 | ⊕⊕⊝⊝ | HR 0.75 | Study population | |
| 800 per 1000 | 46 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 334 | ⊕⊕⊝⊝ | RR 0.74 | Study population | |
| 550 per 1000 | 143 fewer per 1000 | ||||
| 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 | |||||
| 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 | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (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) | 750 | ⊕⊕⊕⊝ | HR 0.54 | Study population | |
| 400 per 1000 | 210 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) | 750 | ⊕⊕⊝⊝ | HR 0.82 | Study population | |
| 480 per 1000 | 68 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 735 | ⊕⊕⊕⊝ | RR 1.75 | Study population | |
| 258 per 1000 | 194 more per 1000 | ||||
| Health‐related quality of life follow‐up: after 2 cycle | 544 | ⊕⊕⊕⊝ | ‐ | The mean health‐related quality of life was 0.74 | MD 0.01 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). | |||||
| GRADE Working Group grades of evidence | |||||
| 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 | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type [80% clear cell]) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (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 | ⊕⊕⊝⊝ | HR 0.74 | Study population | |
| 100 per 1000 | 82 more per 1000 | ||||
| Overall survival survival (absolute effect size estimates based on survival rate at 12 months ) follow‐up: up to 80 months | 416 | ⊕⊕⊕⊝ | HR 0.78 | Study population | |
| 300 per 1000 | 91 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 408 | ⊕⊕⊝⊝ | RR 0.86 | Study population | |
| 780 per 1000 | 109 fewer per 1000 | ||||
| Health‐related quality of life follow‐up: not reported | 401 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was 0.66 | MD 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; 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 | |||||
| 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 | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Atezolizumab | Risk difference with Sunitinib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 12 months) | 204 | ⊕⊝⊝⊝ | HR 0.84 | Study population | |
| 420 per 1000 | 63 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) | 204 | ⊕⊝⊝⊝ | HR 0.94 | Moderate | |
| 630 per 1000 6 | 18 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 203 | ⊕⊕⊕⊝ | RR 1.73 | Study population | |
| 398 per 1000 | 291 more per 1000 | ||||
| Health‐related quality of life | 157 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was 1.04 | MD 1.46 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 | |||||
| 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 | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (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 | ⊕⊕⊕⊝ | HR 0.68 | Study population | |
| 200 per 1000 | 135 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: intervention: 23 months comparator: 21 months | 1381 | ⊕⊕⊝⊝ | HR 0.88 | Study population | |
| 500 per 1000 | 43 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 1356 | ⊕⊕⊕⊝ | RR 1.31 | Study population | |
| 536 per 1000 | 166 more per 1000 | ||||
| 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). | |||||
| GRADE Working Group grades of evidence | |||||
| 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 | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type [80% clear cell]) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (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 | ⊕⊕⊝⊝ | HR 0.76 | Study population | |
| 100 per 1000 | 74 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 12 months) follow‐up: up to 80 months | 417 | ⊕⊕⊝⊝ | HR 0.93 | Study population | |
| 300 per 1000 | 26 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 408 | ⊕⊕⊝⊝ | RR 1.12 | Study population | |
| 780 per 1000 | 94 more per 1000 | ||||
| Health‐related quality of life follow‐up: not reported | 394 | ⊕⊕⊝⊝ | ‐ | The mean health‐related quality of life was 0.66 | MD 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). | |||||
| GRADE Working Group grades of evidence | |||||
| 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) | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type [80% clear cell]) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (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 | ⊕⊕⊝⊝ | HR 1.10 | Study population | |
| 420 per 1000 | 35 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 791 | ⊕⊕⊕⊝ | HR 1.08 | Study population | |
| 550 per 1000 | 26 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 784 | ⊕⊕⊝⊝ | RR 1.05 | Study population | |
| 760 per 1000 | 38 more per 1000 | ||||
| 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). | |||||
| GRADE Working Group grades of evidence | |||||
| 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 | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (any cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (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 | ⊕⊝⊝⊝ | HR 0.91 | Study population | |
| 250 per 1000 | 33 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 365 | ⊕⊝⊝⊝ | HR 1.01 | Study population | |
| 533 per 1000 | 3 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 361 | ⊕⊕⊝⊝ | RR 1.06 | Study population | |
| 762 per 1000 | 46 more per 1000 | ||||
| Health‐related quality of life5 | 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). | |||||
| GRADE Working Group grades of evidence | |||||
| 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 | |||||
| Patient or population: Treatment‐naïve metastatic renal cell carcinoma (clear cell type); IMDC intermediate, poor risk patients only. | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (95% CI) | |
|---|---|---|---|---|---|
| Risk with Nivolumab + Ipilimumab | Risk difference with Sunitinib | ||||
| Progression‐free survival (absolute effect size estimates based on survival rate at 30 months) | 847 | ⊕⊕⊝⊝ | HR 1.30 | Study population | |
| 280 per 1000 | 89 fewer per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 30 months) | 847 | ⊕⊕⊕⊕ | HR 1.52 | Study population | |
| 600 per 1000 | 140 fewer per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 1082 | ⊕⊕⊕⊝ | RR 1.37 | Study population | |
| 457 per 1000 | 169 more per 1000 | ||||
| Health‐related quality of life Scale from: 0 to 76 | 460 | ⊕⊕⊕⊝ | ‐ | The mean health‐related quality of life was 2.6 | MD 4.1 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). | |||||
| GRADE Working Group grades of evidence | |||||
| 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 | |||||
| Patient or population: Previous treated and treatment‐naïve (54%) metastatic renal cell carcinoma (clear cell type) | |||||
| Outcomes | № of participants | Certainty of the evidence | Relative effect | Anticipated absolute effects* (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 | ⊕⊕⊕⊕ | HR 0.46 | Study population | |
| 180 per 1000 | 274 more per 1000 | ||||
| Overall survival (absolute effect size estimates based on survival rate at 24 months) follow‐up: not reported | 435 | ⊕⊕⊝⊝ | HR 0.91 | Study population | |
| 480 per 1000 | 33 more per 1000 | ||||
| Serious adverse events (Grade 3 or 4) | 435 | ⊕⊕⊕⊕ | RR 2.00 | Study population | |
| 200 per 1000 | 200 more per 1000 | ||||
| Health‐related quality of life | 300 | ⊕⊕⊕⊕ | ‐ | The mean health‐related quality of life was ‐0.5 | MD 3.1 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). | |||||
| GRADE Working Group grades of evidence | |||||
| 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) | |||||
| Axitinib |
| Bevacizumab |
| Dovitinib |
| Erlotinib |
| Everolimus |
| Lapatinib |
| Pazopanib |
| Sorafenib |
| Sunitinib |
| Temsirolimus |
| Tivozanib |
| Other agents identified during search |
| 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 |
| Sunitinib/ Sorafenib | 183 | 176 | 156 | 183 | 176 | |
| Escudier 2010 | Bevacizumab + IFN‐a2a | 327 | 325 | 206 | 327 | 337 |
| IFN‐a2a + Placebo | 322 | 316 | 274 | 322 | 304 | |
| Escudier 2017 1 | Sunitinib | 546 | 535 | 438 | 546 | 535 |
| 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 |
| IFN‐a2a | 375 | 360 | 234 | 375 | 360 | |
| Motzer 2013a | Pazopanib | 557 | 554 | 486 | 557 | 554 |
| Sunitinib | 553 | 548 | 483 | 553 | 548 | |
| Motzer 2013b | Tivozanib | 260 | 259 | 154 | 260 | 259 |
| Sorafenib | 257 | 257 | 192 | 257 | 257 | |
| Motzer 2014 | Sunitinib/ Everolimus | 233 | 231 | 192 | 233 | 231 |
| Everolimus/ Sunitinib | 238 | 238 | 201 | 238 | 238 | |
| Motzer 2019 | Sunitinib | 444 | 439 | 227 | 444 | 439 |
| Avelumab + Axitinib | 442 | 434 | 187 | 442 | 434 | |
| Ravaud 2015 | Everolimus + Bevacizumab | 182 | 180 | 175 | 182 | 180 |
| Interferon + Bevacizumab | 183 | 181 | 175 | 183 | 181 | |
| Retz 2019 | Sorafenib/ Pazopanib | 189 | 183 | 115 | 189 | 183 |
| Pazopanib/ Sorafenib | 188 | 183 | 110 | 188 | 183 | |
| Rini 2008 | Bevacizumab + IFN‐a2b | 369 | 366 | 355 | 369 | 366 |
| IFN‐a2b | 363 | 350 | 355 | 363 | 349 | |
| Rini 2014 | Temsirolimus + Bevacizumab | 400 | 393 | 372 | 400 | 393 |
| Temsirolimus + Interferon | 391 | 391 | 354 | 391 | 391 | |
| Rini 2016 | Sunitinib | 135 | 130 | 23 | 135 | 132 |
| IMA901 + Sunitinib | 204 | 185 | 28 | 204 | 202 | |
| Rini 2019a | Sunitinib | 429 | 425 | 242 | 429 | 425 |
| Pembrolizumab + Axitinib | 432 | 429 | 176 | 432 | 429 | |
| Rini 2019b | Sunitinib | 461 | 446 | 308 | 461 | 446 |
| Atezolizumab + Bevacizumab | 454 | 451 | 265 | 454 | 451 | |
| Sternberg 2010 | Pazopanib | 290 | 290 | 227 | 290 | 290 |
| 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. | ||||||
| Studies | Phase of study | Accrual | Blinding | RCC subtype | Prior therapy | Intervention |
|---|---|---|---|---|---|---|
| Comparator | ||||||
| Eichelberg 2015 | 3 | Feb 2009 to Dec 2011 | open label study | any, 87% clear cell | naïve | Soreafenib/Sunitinib |
| Sunitinib/Sorafenib | ||||||
| Escudier 2010 | 3 | Jun 2004 to Oct 2005 | double‐blind study | clear cell | naïve | Bevacizumab + IFN‐a2a |
| IFN‐a2a + Placebo | ||||||
| Escudier 2017 | 3 | Oct 2014 to Feb 2016 | open label study | clear cell | naïve | Sunitinib |
| 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 |
| IFN‐a2a | ||||||
| Motzer 2013a | 3 | Aug 2008 to Sep 2011 | open label study | clear cell | naïve | Pazopanib |
| Sunitinib | ||||||
| Motzer 2013b | 2 | Feb 2010 to Aug 2010 | open label study | clear cell | naïve | Tivozanib |
| Sorafenib | ||||||
| Motzer 2014 | 2 | Sep 2009 to Jun 2012 | open label study | any, 85% clear cell | naïve | Sunitinib/ Everolimus |
| Everolimus/ Sunitinib | ||||||
| Motzer 2019 | 3 | Mar 2016 to Dec 2017 | open label study | clear cell | naïve | Sunitinib |
| Avelumab + Axitinib | ||||||
| Ravaud 2015 | 2 | ‐ | open label study | any 96% clear cell | naïve | Everolimus + Bevacizumab |
| Interferon + Bevacizumab | ||||||
| Retz 2019 | 3 | Jun 2012 to Nov 2016 | open label study | any, 87% clear cell | naïve | Sorafenib/ Pazopanib |
| Pazopanib/ Sorafenib | ||||||
| Rini 2008 | 3 | Oct 2003 to Jul 2005 | open label study | clear cell | naïve | Bevacizumab + IFN‐a2b |
| IFN‐a2b | ||||||
| Rini 2014 | 3 | Apr 2008 to Oct 2010 | open label study | any, 80% clear cell | naïve | Temsirolimus + Bevacizumab |
| Bevacizumab + Inferferon | ||||||
| Rini 2016 | 3 | Dec 2010 to Dec 2012 | open label study | clear cell | naïve | Sunitinib |
| IMA901 + Sunitinib | ||||||
| Rini 2019a | 3 | Oct 2016 to Jan 2018 | open label study | clear cell | naïve | Sunitinib |
| Pembrolizumab + Axitinib | ||||||
| Rini 2019b | 3 | May 2015 to Oct 2016 | open label study | clear cell | naïve | Sunitinib |
| Atezolizumab + Bevacizumab | ||||||
| Sternberg 2010 | 3 | Apr 2006 to Apr 2007 | double‐blind study | clear cell | 54% naive | Pazopanib |
| Placebo | ||||||
| ‐ denotes not reported | ||||||
| IFN: interferon; RCC: renal cell carcinoma | ||||||
| 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 | |
| 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 | |
| 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 | |
| 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 | |
| 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 | |
| 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 | |
| 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 | |
| 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] |
| 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 | |
| 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 | |
| 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 | |
| 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 | |
| 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 | |
| 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 | |
| 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 | |
| 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 | |
| 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 | |
| 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 | |
