Medication-related jaw osteonecrosis in metastatic RCC treated with VEGFR-TKIs ± IO and bone agents: A real-world analysis

Despite Immune-Oncology (IO) combinations, bone metastases (BM) remain a clinical challenge, occurring in ~30% of metastatic renal cell carcinoma (mRCC) patients and leading to skeletal-related events (SREs). Bone-targeted therapies (BTT), denosumab (Dmab) and zoledronic acid (ZOL AC), reduce SREs but are associated with a risk of Medication-Related Osteonecrosis of the Jaw (MRONJ), especially when combined with Vascular Endothelial Growth Factor Receptor - Tyrosine Kinase Inhibitors (VEGFR-TKIs). We retrospectively collected data from mRCC patients with BM who received IO alone or in combinations and VEGFR-TKIs concurrent or sequential with BTT from January 2013 to January 2025. We identified 104 mRCC patients who received BTT (Dmab: 86/104; ZOL AC: 18/104; switch: 4/104). MRONJ occurred in 12/104 (11.5%) patients, with a median BTT exposure of 13.8 months vs. 11.6 months in the overall cohort. At ONJ diagnosis, 10/12 patients were on VEGFR-TKI, one on IO (previously on pazopanib), and one off therapy (previously on tivozanib). Notably, patients on IO-IO or IO-TKI combinations (10) did not develop MRONJ. This study represents one of the largest real-world cohorts assessing MRONJ incidence in mRCC patients treated with VEGFR-TKIs and IO-combo with concomitant BTT. Our findings confirm an MRONJ rate consistent with prior reports (10-17%) of patients treated with TKIs monotherapy and BTT.