A randomized phase 2 trial of nivolumab, relatlimab plus ipilimumab vs. nivolumab plus ipilimumab in first-line advanced renal cell carcinoma.

Abstract

TPS580 Background: Ipilimumab plus nivolumab (ipi/nivo) is a standard of care for treatment-naïve, metastatic clear cell renal cell carcinoma (ccRCC). While durability of response may be superior to combination therapy with PD-1 inhibitors and agent tyrosine kinase inhibitors, ipi/nivo has a relatively low objective response rate (ORR) and relatively high progressive disease (PD) as best response. Building on the benefits of ipi/nivo through additional immune manipulation has biologic rationale and could expand the efficacy of this regimen. Lymphocyte-associated gene 3 (LAG3) is an inhibitory receptor on activated immune cells that plays a role in T cell exhaustion. LAG3 is expressed on T cells and is co-expressed with other inhibitory receptors such as PD-1. This co-expression induces the disfunction of T cells and thus limits the anti-tumor T cell response. Relatlimab is a human LAG-3-specific antibody that binds to the LAG-3 receptor with high affinity and blocks LAG-3 interactions with its canonical ligand, major histocompatibility complex (MHC) Class II, which is the peptide antigen presentation molecule recognized by CD4+ T cells. Relatlimab binding inhibits the negative regulatory function of LAG-3 in vitro. Relatlimab restores effector function of exhausted T cells. Combined LAG3 inhibition with relatlimab and PD-1 inhibition with nivolumab was recently demonstrated in the RELATIVITY-047 melanoma study. These compelling preclinical and clinical data have led to the hypothesis that adding relatlimab to ipilimumab plus nivolumab will increase objective response rate in patients with metastatic ccRCC. Methods: This is a phase 2 randomized, multicenter, study investigating the efficacy of nivolumab 480 mg every 4 weeks (Q4W), relatlimab 160 mg Q4W and ipilimumab 1 mg/kg every 8 weeks (Q8W) intravenous (IV) versus a doublet arm treating with nivolumab 480 mg Q3W and ipilimumab 1mg/kg Q3W IV followed by maintenance nivolumab in first-line advanced ccRCC. Co-primary endpoints include safety and ORR. Up to 60 patients with treatment naive, biopsy-proven ccRCC with adequate organ/marrow function with at least one evaluable lesion by RECIST 1.1 will be enrolled and randomized 2:1 to the experimental arm versus ipi/nivo. Ongoing safety and futility monitoring will employ a 2-arm Bayesian optimal phase 2 (BOP2) design. Sample size provides 64% power at a one-sided 0.15 significance level to detect a difference between the arms assuming the overall response rates are 40% vs. 60% for nivo/ipi vs. experimental arm, respectively. Secondary endpoints include progression free survival and OS. To explore the effects of the treatment on inducing activated T cell infiltration, biopsies and circulating immune cell subsets will be obtained for single cell analysis and spatial transcriptomic studies. Over 10 patients are enrolled at the time of submission. Clinical trial information: NCT06708949 .