Real-World Outcomes of First-Line Immune-Based Combination Therapies in Bone-Metastatic Clear Cell Renal Cell Carcinoma

Background Bone metastases occur in one third of patients with metastatic clear cell renal cell carcinoma (mccRCC) and are associated with poor prognosis. Optimal first-line treatment for this subgroup of patients remains undefined. Methods We conducted a multicenter retrospective study of patients with bone-metastatic (BM+) mccRCC treated with first-line immune checkpoint inhibitor (ICI)-based combinations between January 2015 and February 2024 across eight French centers. The primary endpoint was time to next treatment (TTNT). Secondary endpoints included overall survival (OS), bone progression-free survival (bPFS), incidence of skeletal-related events (SREs) and changes in bone pain. Results A total of 124 patients were included; 55% received ICI-ICI and 45% an ICI plus a tyrosine kinase inhibitor (TKI). Median follow-up was 36.8 months. Median TTNT was 11.7 months (95% CI: 8.38-20.0), OS 28.8 months (95% CI: 23.7-40.2) and bPFS 11.7 months (95% CI: 7.69-21.7). Median TTNT was numerically longer with ICI-TKI compared to ICI-ICI (17.9 vs 8.5 months; p=0.40), with no significant difference in OS or bPFS between treatment groups. SREs occurred in 32% of patients. Bone progression was observed in 48%, with a concomitant SRE in 54% mostly involving preexisting lesions (78%). Bone pain improved in 45% of evaluable patients. No significant differences were observed between treatment groups for SRE incidence or bone pain improvement. Hypercalcemia was associated with shorter OS and bPFS, while bone-only disease correlated with improved OS. Use of bone-targeting agents (BTAs) was independently associated with longer bPFS. Conclusion ICI-CI and ICI-TKI combinations showed comparable outcomes in BM+ mccRCC. Bone progression and SREs remained frequent and often involved preexisting bone lesions. These findings support early integration of local treatments as well as BTAs, which were independently associated with longer bPFS. Micro-Abstract Bone metastases affect one-third of patients with metastatic clear cell renal cell carcinoma and remain a major cause of morbidity. In this multicenter real-world study of 124 patients treated with first-line ICI–ICI or ICI–TKI combinations, both strategies showed comparable outcomes. Bone progression and skeletal events remained frequent, with bone-targeting agents independently associated with improved bone progression-free survival.