Dual Checkpoint and Angiogenic Blockade: The Emergence of PD-1/VEGF Bispecific Antibodies for Genitourinary Malignancies

The emergence of immune checkpoint inhibitors has transformed the treatment landscape for many solid tumors, including lung, renal, and urothelial cancers. Antibodies targeting programmed cell death protein 1 (PD-1) or its ligand, PD-L1, have produced durable responses across multiple malignancies; however, the majority of patients ultimately fail to achieve long-term disease control. One mechanism underlying resistance to immune checkpoint blockade is the persistence of an immunosuppressive tumor microenvironment characterized by aberrant angiogenesis. Vascular endothelial growth factor (VEGF), a key mediator of tumor angiogenesis, not only promotes tumor vascularization but also suppresses antitumor immunity by impairing dendritic cell maturation, reducing T-cell infiltration, and facilitating the accumulation of regulatory T cells and myeloid-derived suppressor cells.¹ Consequently, simultaneous inhibition of the PD-1/PD-L1 and VEGF pathways has emerged as an attractive therapeutic strategy to enhance antitumor immune responses and overcome resistance to immunotherapy.²

The clinical rationale for dual PD-(L)1/VEGF blockade was initially established through combinations of immune checkpoint inhibitors and antiangiogenic agents. In renal cell carcinoma (RCC), for example, combinations such as pembrolizumab plus axitinib³ and nivolumab plus cabozantinib⁴ demonstrated substantial improvements in progression-free survival (PFS), overall survival (OS), and response rates compared with sunitinib. Similar observations have been reported in hepatocellular carcinoma⁵ and endometrial cancer,⁶ supporting the concept that angiogenesis inhibition may potentiate immune-mediated tumor eradication. While effective, combination approaches require administration of multiple agents and may be associated with additive toxicities, especially when multi-kinase inhibitors are used that lack perfect specificity for the VEGF pathway. This has led to the development of bispecific antibodies capable of simultaneously targeting both PD-1 and VEGF within a single molecular construct.²

Among these agents, ivonescimab has emerged as the most clinically advanced PD-1/VEGF bispecific antibody. Ivonescimab is a humanized tetravalent antibody that binds both PD-1 and VEGF-A. The most compelling evidence supporting this strategy has come from non–small cell lung cancer (NSCLC). The randomized, phase 3 HARMONi-2 trial compared ivonescimab monotherapy with pembrolizumab in patients with untreated PD-L1-positive advanced NSCLC. In this study, ivonescimab achieved a statistically significant improvement in PFS, with a median PFS of 11.1 months compared with 5.8 months for pembrolizumab alone (HR 0.51, 95% CI 0.38-0.69).⁷ Importantly, benefit was observed across multiple clinical subgroups, including patients with both low and high PD-L1 expression. These results generated substantial enthusiasm because they represented one of the first instances in which a novel immunotherapy strategy demonstrated superiority over pembrolizumab in a head-to-head, randomized phase 3 study.

The success of ivonescimab in lung cancer has reinvigorated interest in PD-1/VEGF bispecific antibodies across solid tumors. Genitourinary malignancies represent a particularly attractive setting for PD-(L)1/VEGF bispecific development. Clear-cell RCC is characterized by dysregulation of the hypoxia-inducible factor (HIF)-VEGF axis, and VEGF-targeted therapies have long served as a cornerstone of treatment. In RCC, tumor angiogenesis contributes to an immunosuppressive microenvironment that limits T-cell trafficking and function, while immune checkpoint signaling promotes T-cell exhaustion. By targeting both mechanisms simultaneously, PD-1/VEGF bispecific antibodies may enhance antitumor immunity beyond what is achievable with either strategy alone. Urothelial tumors exhibit substantial immune infiltration and have demonstrated responsiveness to PD-1/PD-L1 blockade, while angiogenic signaling has been implicated in disease progression and resistance mechanisms. Meanwhile, metastatic castration-resistant prostate cancer (mCRPC) has historically shown limited sensitivity to single-agent checkpoint inhibition, in part because of a relatively immunologically “cold” tumor microenvironment. Emerging evidence suggests that VEGF-mediated immunosuppression may contribute to this resistance, providing a rationale for combined VEGF and PD-1 blockade.

Collectively, the development of PD-(L)1 and VEGF bispecific antibodies represents a promising evolution of immuno-oncology. The impressive activity of ivonescimab in NSCLC has provided proof of concept that simultaneous targeting of immune checkpoint signaling and angiogenesis can translate into meaningful clinical benefit. As this therapeutic class advances, genitourinary malignancies are poised to become a major area of investigation. Ongoing studies, listed below, will determine whether the success observed in lung cancer can be replicated for our patients with genitourinary malignancies.

Highlighted ongoing trials for genitourinary cancer patients using bispecific antibodies that target PD-(L)1 and VEGF

• NCT06940518 – phase 2 trial with ivonescimab for patients with previously treated RCC
• NCT07226544 – ivonescimab neoadjuvant RCCA trial
• NCT06683846 – phase 2 trial of ivonescimab for patients with advanced solid tumors (prostate, RCC, urothelial, germ cell)
• NCT07421700 – phase 1/2 trial of PF-08634404 for patients with urothelial carcinoma in combination with enfortumab vedotin (SYMBIOTIC-GU-06)
• NCT07227415 – phase 1/2 trial of PF-08634404 for patients with RCC (SYMBIOTIC-GU-08)
• NCT07293351 – Phase 1/2 trial for patients with RCC with Pumitamig alone or in combination with ipilumumab or cabozantinib
• NCT04895709 – Phase 1/2 trial for patients with RCC or urothelial carcinoma with Pumitamig alone or in combination
• NCT06741644 – Phase 1/2 trial of CS2009 for patients with solid tumors solid tumors
• NCT06764836 – Phase 1 trial of IMM2510 + tazlestobart (CTLA-4 monoclonal antibody) for patients with solid tumors

References:

1. Geindreau M, Ghiringhelli F, Bruchard M. Vascular Endothelial Growth Factor, a Key Modulator of the Anti-Tumor Immune Response. Int J Mol Sci 2021; 22(9):4871.
2. Dammeijer F, Dumoulin DW, Aerts JGJV. Anti–Vascular Endothelial Growth Factor/Programmed Cell Death Protein 1 Bispecific Antibodies: Using Nunchucks to Fight an Old Adversary. J Thorac Oncol. 2024; 19(3):366-369.
3. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019; 380(12):1116-1127.
4. Choueiri T, Powles T, Burotto M, et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021; 384(9):829-841.
5. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020; 382(2):1894-1905.
6. Makker V, Colombo N, Herraez AC. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. N Engl J Med. 2022; 386(5):437-448.
7. Xiong A, Wang L, Chen J, et al. Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in China. Lancet. 2025; 405(10481):839-849.