First-Line Therapy For Advanced Non–Clear Cell Renal Cell Carcinoma

Importance Non–clear cell renal cell carcinomas (nccRCCs) present considerable challenges owing to their heterogeneity and limited clinical trial representation. Understanding the benefits of combining immunotherapy and targeted therapy for these subtypes is crucial for improving patient outcomes. Objective To evaluate the efficacy of various first-line immunotherapy combinations and targeted therapy in treating metastatic nccRCC. Data Sources A systematic literature search was conducted across PubMed, Embase, and Cochrane Library databases from inception until December 31, 2024, using relevant keywords and medical subject headings terms. Study Selection Studies were included if they involved patients with nccRCC, reported on immune checkpoint inhibitor (ICI)–based therapies, and provided data on objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and disease control rate (DCR). Data extraction and Synthesis Two independent reviewers extracted data, with discrepancies resolved by a third expert. Observational study quality was assessed using the Newcastle-Ottawa Scale. A random-effects meta-analysis was performed, and heterogeneity was evaluated using the I 2 statistic. Main Outcome and Measures The primary outcomes of interest were ORR, PFS, OS, and DCR. Results The analysis included 23 studies encompassing various subtypes of nccRCC. Pooled results indicated an ORR of 26.6% and a DCR of 57.8% for nccRCC treatments. Median PFS was 6.59 months, and the median OS was 21.11 months. ICIs demonstrated significant efficacy in nccRCC, exhibiting marked clinical activity across different subtypes. Although monotherapy with ICIs showed effectiveness, combination therapies yielded superior clinical outcomes. Conclusions and Relevance This systematic review and meta-analysis found that ICIs, particularly when combined with targeted therapies, showed promising efficacy in treating metastatic nccRCC. These findings support their integration into treatment guidelines and emphasize the importance of personalized treatment strategies. Future research should focus on long-term outcomes, safety profiles, and the identification of biomarkers to optimize patient selection and improve outcomes.