Phase 1b/2 study of combination ¹⁷⁷ Lu girentuximab plus cabozantinib and nivolumab in treatment naive patients with advanced clear cell RCC.

TPS614 Background: Complete response (CR) is a rare event in advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab plus cabozantinib was recently approved for first-line treatment of ccRCC, demonstrating improved progression-free survival (PFS) and objective response rate (ORR) in comparison to sunitinib. However, CR is only 9%. Drugs that could synergize with T cell anti-tumor activity can improve CR rates. Radiation-induced DNA damage to activate the cGAS-STING pathway is a promising mechanism. 177 Lu-girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase 9, expressed in >90% ccRCC, to deliver targeted radiation to cancer with minimal damage to surrounding healthy cells. As a single agent in metastatic ccRCC, 177 Lu-girentuximab was safe and effective in stabilizing disease in 57% of patients. We hypothesize 177 Lu-girentuximab-induced DNA damage will potentiate the STING pathway, synergizing with nivolumab and cabozantinib to promote trafficking and infiltration of activated T cells and achieve higher CR rates. Methods: Up to 100 patients with treatment naive, biopsy-proven ccRCC with adequate organ/marrow function with 1 evaluable lesion by RECIST 1.1 will be enrolled. A 5-patient safety lead-in will evaluate myelosuppression. Ongoing safety and futility monitoring will employ a Bayesian approach. The sample size was chosen for reasonable operating characteristics to distinguish a CR rate (primary endpoint) of 18% as better than 9% using a beta (0.09, 0.91) prior. Secondary endpoints are ORR, PFS by RECIST 1.1, and overall survival. 177 Lu-girentuximab 1480 MBq/m 2 (61% of single agent MTD) will be administered every 12 weeks for up to 3 cycles. Starting with the second cycle, nivolumab and cabozantinib will be added at standard dose. To explore the effects of the treatment on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET scan with 18 F-AraG radiotracer as well as biopsies for single cell, spatial transcriptomics, and proteomics studies. Clinical trial information: NCT05663710 .