20Phase II trial of ivonescimab in patients with advanced clear cell renal cell carcinoma previously treated with immune checkpoint blockade: IVORY trial (NCT06940518)

Abstract Background Immune checkpoint inhibitor (ICI)-based combinations, whether in the form of dual ICIs, or an ICI combined with a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI), constitute the first-line treatment for metastatic clear cell renal cell carcinoma (mccRCC). However, in the subsequent-line setting, the addition of ICIs to VEGF-TKIs did not demonstrate superior activity compared to VEGF-TKI monotherapy in two phase III clinical trials (CONTACT-03 Pal et al. Lancet 2023, TiNivo-2 Choueiri et al. Lancet 2024). This highlights the urgent need for novel approaches to overcome ICI resistance in further-line settings. Ivonescimab is a novel first-in-class tetravalent bispecific antibody blocking PD1/PD-L1 and VEGF/VEGFR signaling, thereby simultaneously inhibiting both immune escape and angiogenesis in the tumor microenvironment, two canonical mechanisms of mccRCC pathogenesis. In treatment-naïve non-small cell lung cancer, ivonescimab has recently shown superior clinical activity over pembrolizumab (HARMONi-2 Xiong et al. Lancet 2025). Ivonescimab may offer several advantages over the use of separate combination agents in mRCC: (1) enabling spatial proximity of concurrent PD-1 and VEGF inhibition within the tumor microenvironment, (2) providing integrated, synchronized inhibition of two key pathways potentially to address tumor heterogeneity, (3) avoiding pharmacokinetic variability and provide more predictable dosing and drug levels, improving efficacy and reducing the risk of suboptimal therapeutic exposure. Further, preclinical studies suggest that the cooperative inhibition of VEGF and PD-1, two key pathways implicated in mccRCC pathogenesis, may result in synergistic anti-tumor activity. Accordingly, we hypothesize that dual PD-1 and VEGF blockade via ivonescimab will restore treatment sensitivity in mccRCC following progression on prior VEGF and/or ICI therapies. Methods This is a phase II, single-arm, open-label, investigator-initiated study evaluating ivonescimab monotherapy in patients with previously treated mccRCC. All participants must have received prior ICI therapy. Cohort 1 will enroll patients with no prior exposure to VEGF-directed agents, while Cohort 2 will enroll patients who had disease progression on a prior VEGF-directed therapy. Participants will receive the recommended phase II dose of Ivonescimab (20 mg/kg IV every 3 weeks) and continue treatment until disease progression or unacceptable toxicities. Figure 1 presents the study schema. Each cohort will enroll 20 patients and follow a Bayesian Optimal Phase 2 (BOP2) 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, providing 87% power with a 10% 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, with 84% power and 10% 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. Trial Schema Significance & Vision This is the first clinical trial testing ivonescimab in RCC. Potential clinical activity signals and translational insights obtained will (1) shape the understanding of approaches to revert ICI-resistance and (2) open venues for further clinical testing of this agent in mccRCC. NCT: NCT06940518