Ivonescimab Shows Dual Inhibition of VEGF and PD-1 Pathways in ccRCC

In an interview with CancerNetwork®, Nazli Dizman, MD, a hematology/oncology fellow at MD Anderson Cancer Center, discussed the rationale and findings of her presentation of the phase 2 IVORY trial (NCT06940518) evaluating ivonescimab (SMT112) in patients with clear cell renal cell carcinoma (ccRCC) she gave during the 2025 Kidney Cancer Research Summit.

She contextualized the treatment landscape by highlighting 2 historical standards for patients with RCC: VEGF-directed therapies and immunotherapies. Although they display frontline efficacy, patients develop resistance to these therapies. Ivonescimab, according to Dizman, simultaneously targets the VEGF and PD-1, potentially offering an advantage over other therapies for this patient population.

Furthermore, she highlighted preclinical evidence that suggests that the dual inhibition of the VEGF and PD-1 pathways may synergize to bolster outcomes for this patient group, while mitigating resistance. Dizman concluded by highlighting the safety profile of the investigational agent, which displayed a short half-life and acceptable toxicity.

Transcript

For so long, we have been treating our patients with RCC with 2 main regimens. One is directed towards angiogenesis by VEGF-directed therapies, and the other one is directed towards immune escape––immunotherapies. They have shown immense progress in the first-line setting, but it is unfortunately inevitable for most of our patients to develop resistance to these therapies. Ivonescimab is a novel drug that inhibits both [pathways] at the same time in the same place. That sparked our attention in studying this agent in the immunotherapy resistance setting for RCC.

As a bispecific mechanistically, it inhibits both pathways in close proximity, and the simultaneous inhibition is potentially another advantage for this medication. The promise is that simultaneous and [proximal] inhibition, both major pathways of RCC pathogenesis, would provide us with a wider coverage to tackle the tumor heterogeneity.

There is some pre-clinical evidence with this agent that shows that VEGF inhibition and PD-1 inhibition in a bispecific methodology may lead to synergy and potentially improve outcomes. In terms of toxicity, the agent has a short half-life and has a favorable toxicity profile reported in other studies. These are the potential advantages of this agent.

Reference

Dizman N. Phase II trial of ivonescimab in patients with advanced clear cell renal cell carcinoma previously treated with immune checkpoint blockade: IVORY trial (NCT06940518). Presented at: 2025 Kidney Cancer Research Summit; July 17-18, 2025. Boston, Massachusetts.