Immune checkpoint inhibitor combinations across clinically distinct metastatic renal cell carcinoma populations with limited or heterogeneous trial evidence: A systematic review, evidence map, and meta-analysis.

Immune checkpoint inhibitor (ICI) combinations are standard for metastatic renal cell carcinoma (mRCC), but evidence is uneven across distinct populations. We searched PubMed, Embase and Cochrane CENTRAL through June 3, 2026, and synthesized original studies reporting efficacy or safety in non-clear cell RCC, brain, bone or liver metastases, adults aged 75 years or older, poor performance status, trial ineligibility, frailty, renal impairment or hemodialysis, and sarcomatoid differentiation. Independent studies were the analytical unit. Proportions were pooled only when at least three studies were available, using logit random effects models with Paule-Mandel heterogeneity and modified Hartung-Knapp confidence intervals. Forty-nine studies were included, 13 prospective and 36 retrospective. The pooled objective response rate (ORR) was 37.1% (95% confidence interval [CI]: 28.8-46.2) in non-clear cell RCC, 34.9% (CI: 17.4-57.6) for systemic response in brain metastases, and 41.8% (CI: 31.8-52.5) in adults aged 75 years or older. Study-level ORRs were 30.0-35.3% in poor performance status cohorts, 41.7% in one trial-ineligible cohort, and 24.1% in one hemodialysis cohort. In sarcomatoid differentiation, ICI combinations versus sunitinib improved progression-free survival (PFS; hazard ratio 0.48, CI: 0.34-0.66) and overall survival (OS; hazard ratio 0.55, CI: 0.38-0.80). Safety was described without pooling because definitions and regimens differed. These results quantify response signals, distinguish evidence that can inform routine care, and identify settings requiring individualized judgment and prospective confirmation.