Single-agent versus combination paradigms: A systematic review and meta-analysis of the immunotherapy clinical profile in metastatic renal cell carcinoma.

Abstract

e16549 Background: Immunotherapy-based combinations are established as the first-line standard of care for metastatic renal cell carcinoma (mRCC) across major NCCN Guidelines and ESMO Guidelines. While these intensified regimens offer superior efficacy compared to historical monotherapies, they are associated with increased treatment-related toxicities and significant financial burden. The role of single-agent immunotherapy in patients with comorbidities or favorable-risk mRCC remains clinically controversial. This systematic review and meta-analysis evaluate the comparative safety and efficacy profiles of single-agent versus double-agent regimens in patients with mRCC. Methods: Following PRISMA guidelines, a systematic search was conducted across PubMed, Cochrane, Scopus, and ClinicalTrials.gov through October 2025 to retrieve 1,015 articles. Eight studies (including RCTs and cohorts) were selected. Data synthesis was performed using RevMan 5.4.1, employing a random-effects model to calculate Risk Ratios (RR) and Hazard Ratios (HR). Statistical significance was set at p < 0.05. Results: A total of 3,018 patients were included (n = 1,546 receiving single-agent immunotherapy; n = 1,472 receiving doublet-regimens). Across the 8 included studies, nivolumab (n = 3) and bevacizumab (n = 4) were the primary intervention arms. The median age was 60 (55–65) years, with a male predominance and clear cell carcinoma as the primary histological subtype. Regarding safety, single-agent immunotherapy was associated with a significantly higher risk of ALT elevation (RR 2.48; 95% CI: 1.08–5.71; p = 0.03; I² = 0%) and proteinuria (RR 1.46; 95% CI: 1.04–2.05; p = 0.03; I² = 0%). Conversely, single-agent therapy was associated with a significantly lower risk of Grade 3–4 fatigue (RR 0.17; 95% CI: 0.05–0.60; p = 0.006; I² = 0%) and anemia (RR 0.33; 95% CI: 0.14–0.77; p = 0.01). No statistically significant differences were observed for overall adverse events, nausea, hyponatremia, hypertension, hematuria, fever, or diarrhea. In terms of efficacy, overall survival, objective response rate, and progression-free survival were comparable between the two groups. While heterogeneity for specific toxicities was low, overall heterogeneity across the included studies remained moderate to high. Conclusions: Single-agent immunotherapy demonstrates a comparable clinical profile to doublet regimens in mRCC. Despite increased risks of ALT elevation and proteinuria, monotherapy significantly mitigates Grade 3–4 fatigue and anemia. These findings suggest that monotherapy is a tailored strategy for patients prioritizing quality of life and the avoidance of hematological toxicities. However, high-quality RCTs are warranted to provide robust evidence for personalized treatment sequencing.