Efficacy of immune-oncology combinations versus sunitinib in patients with bone metastases from renal cell carcinoma: A systematic review and meta-analysis of phase iii trials with long-term follow-up

Background Bone metastases occur in approximately one-third of patients with metastatic clear-cell renal cell carcinoma (ccRCC) and are associated with poor prognosis. Although immune-oncology (IO)-based combinations are the standard first-line treatment, the relative efficacy of IO plus tyrosine kinase inhibitor (IO+TKI) versus dual immunotherapy (IO+IO) in this subgroup remains uncertain. Methods We performed a systematic review and meta-analysis of phase III randomized trials comparing first-line IO-based combinations with sunitinib in treatment-naïve metastatic ccRCC. Eligible studies reported hazard ratios (HRs) for progression-free survival (PFS) and/or overall survival (OS) in patients with baseline bone metastases and had a median follow-up of at least 36 months. The primary analysis pooled IO+TKI trials, whereas the single eligible IO+IO study was analyzed separately. Fixed- and random-effects inverse-variance models were applied. Results Three phase III trials were included: CLEAR (lenvatinib plus pembrolizumab versus sunitinib), CheckMate 9ER (nivolumab plus cabozantinib versus sunitinib), and CheckMate 214 (nivolumab plus ipilimumab versus sunitinib). IO+TKI significantly improved PFS versus sunitinib (HR 0.46, 95% CI 0.35–0.61; p < 0.0001), with no heterogeneity (I 2 = 0%). In contrast, IO+IO showed no PFS benefit (HR 1.07, 95% CI 0.76–1.51). Pooling all trials introduced substantial heterogeneity (I 2 = 85.9%), and subgroup analysis confirmed a significant interaction between treatment class and PFS ( p = 0.0002). IO+TKI also improved OS (HR 0.66, 95% CI 0.50–0.88; p = 0.0041), again without heterogeneity (I 2 = 0%). IO+IO showed a non-significant trend toward improved OS (HR 0.82, 95% CI 0.61–1.11), with no significant difference between treatment classes for OS ( p = 0.314). Conclusions In patients with metastatic ccRCC and bone metastases, IO+TKI combinations were associated with significant improvements in PFS and OS compared with sunitinib, whereas IO+IO did not improve PFS. These findings suggest that treatment strategy may influence outcomes in this high-risk subgroup.