Susanne Unverzagt, Ines Moldenhauer, Monika Nothacker, Dorothea Roßmeißl, Andreas V Hadjinicolaou, Frank Peinemann, Francesco Greco, Barbara Seliger

Since the mid-2000s, the field of metastatic renal cell carcinoma (mRCC) has experienced a paradigm shift from non-specific therapy with broad-acting cytokines to specific regimens, which directly target the cancer, the tumour microenvironment, or both.Current guidelines recommend targeted therapies with agents such as sunitinib, pazopanib or temsirolimus (for people with poor prognosis) as the standard of care for first-line treatment of people with mRCC and mention non-specific cytokines as an alternative option for selected patients.In November 2015, nivolumab, a checkpoint inhibitor directed against programmed death-1 (PD-1), was approved as the first specific immunotherapeutic agent as second-line therapy in previously treated mRCC patients. To assess the effects of immunotherapies either alone or in combination with standard targeted therapies for the treatment of metastatic renal cell carcinoma and their efficacy to maximize patient benefit. We searched the Cochrane Library, MEDLINE (Ovid), Embase (Ovid), ISI Web of Science and registers of ongoing clinical trials in November 2016 without language restrictions. We scanned reference lists and contacted experts in the field to obtain further information. We included randomized controlled trials (RCTs) and quasi-RCTs with or without blinding involving people with mRCC. We collected and analyzed studies according to the published protocol. Summary statistics for the primary endpoints were risk ratios (RRs) and mean differences (MD) with their 95% confidence intervals (CIs). We rated the quality of evidence using GRADE methodology and summarized the quality and magnitude of relative and absolute effects for each primary outcome in our 'Summary of findings' tables. We identified eight studies with 4732 eligible participants and an additional 13 ongoing studies. We categorized studies into comparisons, all against standard therapy accordingly as first-line (five comparisons) or second-line therapy (one comparison) for mRCC.Interferon (IFN)-α monotherapy probably increases one-year overall mortality compared to standard targeted therapies with temsirolimus or sunitinib (RR 1.30, 95% CI 1.13 to 1.51; 2 studies; 1166 participants; moderate-quality evidence), may lead to similar quality of life (QoL) (e.g. MD -5.58 points, 95% CI -7.25 to -3.91 for Functional Assessment of Cancer - General (FACT-G); 1 study; 730 participants; low-quality evidence) and may slightly increase the incidence of adverse events (AEs) grade 3 or greater (RR 1.17, 95% CI 1.03 to 1.32; 1 study; 408 participants; low-quality evidence).There is probably no difference between IFN-α plus temsirolimus and temsirolimus alone for one-year overall mortality (RR 1.13, 95% CI 0.95 to 1.34; 1 study; 419 participants; moderate-quality evidence), but the incidence of AEs of 3 or greater may be increased (RR 1.30, 95% CI 1.17 to 1.45; 1 study; 416 participants; low-quality evidence). There was no information on QoL.IFN-α alone may slightly increase one-year overall mortality compared to IFN-α plus bevacizumab (RR 1.17, 95% CI 1.00 to 1.36; 2 studies; 1381 participants; low-quality evidence). This effect is probably accompanied by a lower incidence of AEs of grade 3 or greater (RR 0.77, 95% CI 0.71 to 0.84; 2 studies; 1350 participants; moderate-quality evidence). QoL could not be evaluated due to insufficient data.Treatment with IFN-α plus bevacizumab or standard targeted therapy (sunitinib) may lead to similar one-year overall mortality (RR 0.37, 95% CI 0.13 to 1.08; 1 study; 83 participants; low-quality evidence) and AEs of grade 3 or greater (RR 1.18, 95% CI 0.85 to 1.62; 1 study; 82 participants; low-quality evidence). QoL could not be evaluated due to insufficient data.Treatment with vaccines (e.g. MVA-5T4 or IMA901) or standard therapy may lead to similar one-year overall mortality (RR 1.10, 95% CI 0.91 to 1.32; low-quality evidence) and AEs of grade 3 or greater (RR 1.16, 95% CI 0.97 to 1.39; 2 studies; 1065 participants; low-quality evidence). QoL could not be evaluated due to insufficient data.In previously treated patients, targeted immunotherapy (nivolumab) probably reduces one-year overall mortality compared to standard targeted therapy with everolimus (RR 0.70, 95% CI 0.56 to 0.87; 1 study; 821 participants; moderate-quality evidence), probably improves QoL (e.g. RR 1.51, 95% CI 1.28 to 1.78 for clinically relevant improvement of the FACT-Kidney Symptom Index Disease Related Symptoms (FKSI-DRS); 1 study, 704 participants; moderate-quality evidence) and probably reduces the incidence of AEs grade 3 or greater (RR 0.51, 95% CI 0.40 to 0.65; 1 study; 803 participants; moderate-quality evidence). Evidence of moderate quality demonstrates that IFN-α monotherapy increases mortality compared to standard targeted therapies alone, whereas there is no difference if IFN is combined with standard targeted therapies. Evidence of low quality demonstrates that QoL is worse with IFN alone and that severe AEs are increased with IFN alone or in combination. There is low-quality evidence that IFN-α alone increases mortality but moderate-quality evidence on decreased AEs compared to IFN-α plus bevacizumab. Low-quality evidence shows no difference for IFN-α plus bevacizumab compared to sunitinib with respect to mortality and severe AEs. Low-quality evidence demonstrates no difference of vaccine treatment compared to standard targeted therapies in mortality and AEs, whereas there is moderate-quality evidence that targeted immunotherapies reduce mortality and AEs and improve QoL.