STARLITE 2: Phase 2 study of nivolumab plus ¹⁷⁷ lutetium-labeled anti–carbonic anhydrase IX (CAIX) monoclonal antibody girentuximab ( ¹⁷⁷ Lu-girentuximab) in patients with advanced clear cell renal cell carcinoma (ccRCC).

TPS608 Background: CAIX is a cell surface glycoprotein expressed in >90% of ccRCC but rarely in normal tissues, providing a target for imaging and therapeutic application. Radiolabeling the anti-CAIX monoclonal antibody girentuximab with 89 Zr has shown promise as a novel PET tracer and labeling with 177 Lu promise as a therapeutic agent in ccRCC. Targeted delivery of radiation to ccRCC cells may prime the immune response by enhancing tumor antigen presentation, providing rationale for combining 177 Lu-girentuximab with nivolumab. This phase 2, open-label, single arm study evaluates 177 Lu-girentuximab in combination with nivolumab in patients (pts) with previously treated ccRCC. Methods: Pts with biopsy-proven RCC of clear cell type or with CAIX expression, progressive disease (PD) after ≥1 immunotherapy (IO) agent, adequate organ/marrow function, and ≥1 evaluable lesion by RECIST 1.1 that is also avid on 89 Zr-girentuximab PET will be enrolled. There is no limit on number of prior lines of systemic therapy, but pts who stopped IO for immune toxicity are excluded. Treatment consists of 177 Lu- girentuximab q12-14 weeks for a maximum of 3 doses plus nivolumab 240mg q2 weeks until PD or unacceptable toxicity. Due to expected cumulative myelosuppression, each subsequent 177 Lu-girentuximab dose given to the same patient is reduced by 25% (dose 2 = 75% of dose 1; dose 3 = 75% of dose 2). Tumor imaging is performed q12 weeks. Pts will be evaluated in a safety lead-in phase followed by an expansion phase. In the safety lead-in phase, the MTD of 177 Lu-girentuximab in combination with nivolumab will be determined with a 3+3 design using a starting dose of 1804 MBq/m 2 (75% of single agent MTD). Based on DLTs, the 177 Lu-girentuximab dose will either be escalated to 2405 MBq/m 2 (cohort 2; single agent MTD) or de-escalated to 1353 MBq/m 2 (cohort -1) for the next cohort. In the expansion phase, a Simon 2-stage optimal design is used to evaluate the primary endpoint of response rate by RECIST 1.1 within 24 weeks. With ≥1 response in the first Simon stage (n = 10; includes pts treated at MTD during safety lead-in), a second stage will open (n = 19) for a total of 29 pts with ≥4 responses indicating the regimen worthy of further study. Secondary endpoints include PFS, OS, and toxicity including a continuous safety monitoring rule during expansion. Exploratory imaging with 89 Zr-girentuximab PET is performed at baseline and before each 177 Lu-girentuximab dose with results correlated with RECIST response on conventional imaging. In addition, whole body planar and SPECT imaging are performed after each 177 Lu-girentuximab dose to evaluate distribution, lesion uptake and dosimetry. The pre-specified number of DLTs was exceeded in cohort 2 such that dosing reverted back to cohort 1, in which accrual is ongoing. Clinical trial information: NCT05239533 .