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

Abstract

TPS582 Background: Complete response (CR) remains a rare outcome in advanced clear cell renal cell carcinoma (ccRCC). The combination of nivolumab and cabozantinib was approved for first-line treatment of ccRCC, demonstrating an improved progression-free survival (PFS) and objective response rate (ORR) in comparison to sunitinib. However, CR remains low, at only 12%. Strategies to enhance T cell anti-tumor activity may improve CR rates. Radiation-induced DNA damage to activate the cGAS-STING pathway is a promising immunomodulatory mechanism. 177 Lu-girentuximab is the first antibody-radioisotope designed for ccRCC, targeting carbonic anhydrase 9-expressing cells expressed in >90% ccRCC to deliver targeted beta radiation to cancer with minimal off-target toxicity. As monotherapy in metastatic ccRCC, 177 Lu-girentuximab was safe and effective and stabilized disease in 57% of patients. We hypothesize 177 Lu-girentuximab-induced DNA damage will potentiate the STING pathway, synergizing with nivolumab and cabozantinib to enhance activated T cell trafficking and infiltration, thereby increasingCR rates. Methods: Up to 100 treatment naive, biopsy-confirmed ccRCC patients with adequate organ/marrow function and at least one 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 to provide reasonable operating characteristics to distinguish a clinically meaningful CR rate of 18%(primary endpoint) from 9%, using a beta (0.09, 0.91) prior distribution. Secondary endpoints are ORR, PFS by RECIST 1.1, and overall survival. 177 Lu-girentuximab will be administered at 1480 MBq/m 2 (61% of single agent MTD)every 12 weeks for up to 3 cycles with 24-hour post treatment SPECT/CT imaging. Starting with cycle 2, patients will also receive standard-dose nivolumab and cabozantinib. To explore the effects of the treatment on inducing activated T cell infiltration, patients will undergo pre/post-treatment PET/CT with 18 F-FAraG radiotracer as along with tumor biopsies for single cell, spatial transcriptomics and proteomics studies. Clinical trial information: NCT05663710 .