Ivonescimab in metastatic clear cell renal cell carcinoma (mccRCC) after immune checkpoint inhibitor therapy: The phase II IVORY trial.

TPS573 Background: ICI-based combinations, as dual ICIs or ICI plus a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI), constitute the first-line treatment for metastatic mccRCC. However, in the subsequent-line setting, adding ICIs to VEGF-TKIs did not demonstrate superior activity compared to VEGF-TKI monotherapy (CONTACT-03 Pal et al. Lancet 2023, TiNivo-2 Choueiri et al. Lancet 2024), highlighting the need for novel approaches to overcome ICI resistance. Ivonescimab is a first-in-class tetravalent bispecific antibody targeting PD1/PD-L1 and VEGF/VEGFR signaling, simultaneously inhibiting, two key mechanisms of mccRCC pathogenesis: immune escape and angiogenesis. In non-small cell lung cancer, ivonescimab has recently shown superiority over pembrolizumab (HARMONi-2). By spatially coordinated and simultaneous inhibition of PD-1 and VEGF pathways through a single molecule, we hypothesize that ivonescimab will enhance efficacy, address tumor heterogeneity, and reduce pharmacokinetic variability compared with separate agents. Methods: This phase II, single-arm, open-label, investigator-initiated study evaluates the activity of ivonescimab monotherapy in patients with mccRCC previously treated with ICIs. Cohort 1 (n=20) enrolls patients with no prior exposure to VEGF-directed agents, while Cohort 2 (n=20) enrolls patients had previously received VEGF-directed therapy. Ivonescimab is administered at 20 mg/kg IV dose every 3 weeks until disease progression or unacceptable toxicities. Each cohort follows a Time-to-event Bayesian Optimal Phase 2 (TOP) design, with simultaneous monitoring of two efficacy endpoints: objective response rate (ORR), defined as complete or partial response at any time, and disease control rate (DCR), defined as complete response, partial response or stable disease at 24 weeks, per RECIST 1.1. In cohort I, the null hypothesis is ORR= 10% or DCR= 30%, while the alternative hypothesis is ORR= 30% or DCR= 50%. The regimen will be deemed acceptable if more than 4 patients experience an objective response, or more than 9 patients experience disease control at 24 weeks, providing 96% power with 20% type I error rate. In cohort II, the null hypothesis is ORR= 5% or DCR= 20% and the alternative hypothesis is ORR= 20% or DCR= 40%. The regimen will be considered acceptable if more than 2 patients experience an objective response, or more than 6 patients experience disease control at 24 weeks, with 91% power and 12.5% type I error rate. Tissue, blood, and stool correlatives will be collected at baseline, during therapy and at the end of treatment to identify changes in specific immune-cell and gut microbiome subsets and elucidate the dynamic evolution of tumor and immune-cell compartments as well as their spatial relationships following ivonescimab. Clinical trial information: NCT06940518 .