ZAMBONI: A phase II study of zanzalintinib for metastatic clear cell renal cell carcinoma with bone metastases previously treated with immune checkpoint inhibitors.

TPS4634 Background: Bone metastases (BM) in metastatic renal cell carcinoma (mRCC) are associated with aggressive disease behavior and poor prognosis, particularly following progression on immunotherapy (IO)-based treatment regimens. Oral vascular endothelial growth factor receptor (VEGFR)-targeting tyrosine kinase inhibitors (TKIs) have demonstrated efficacy in mRCC with BM and have been shown to modulate production of osteoclastogenic factors in the tumor microenvironment. Zanzalintinib is a novel oral VEGFR-targeting TKI that has demonstrated a tolerable safety profile in phase I studies; its broad multikinase targeting profile and short half-life of 16-22 hours may enhance efficacy and tolerability compared with other VEGFR-targeting TKIs. However, the efficacy of zanzalintinib in patients with BM is unknown. Methods: This is a single-institution, phase II trial of zanzalintinib plus investigator-choice bone modifying agent (BMA) in patients with metastatic clear cell RCC with BM that has been previously treated with immunotherapy (IO). Eligible patients will have primarily clear cell histology, at least three BM including at least one BM not previously treated with radiation therapy (RT), and prior disease progression on 1-3 prior lines of therapy including at least one IO-based therapy administered in either the adjuvant or metastatic setting. Measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 is not required. Patients will receive zanzalintinib 60mg by mouth daily in 28-day cycles; treatment will be continued until disease progression or unacceptable toxicity occurs. Dose reduction, re-escalation, or interruption of up to 6 weeks is allowed for patients experiencing adverse events. Investigator-choice BMA may include zoledronic acid, pamidronate, ibandronate, or denosumab, will be administered at a standard dose/interval starting within 30 days of cycle 1, day 1 (C1D1), and continued until criteria for discontinuation of BMA or removal from study are met. RT and/or steroid therapy for symptomatic metastases, including BM, is allowed per investigator discretion. Patients will be radiologically evaluated starting 8 weeks after C1D1 and every 12 weeks thereafter. Adverse events will be monitored throughout the study and for 30 days following cessation of study treatment. Enrollment will continue until 20 patients evaluable for primary endpoint are enrolled, or up to a maximum of 24 patients. The primary endpoint is 12-month landmark progression-free survival and will be evaluated in patients with RECIST-measurable disease at baseline; key secondary endpoints include overall survival, rate of skeletal-related events, and rate of osteonecrosis of the jaw and will be measured in all patients. Clinical trial information: NCT07043608 .