This is a micro-learning module summary of a presentation by Prof. Edward Garon which you can find here. Before participating, please read our CME and disclosure information which can be found here.

This activity is supported by an independent education grant from BioNTech-BMS Alliance. This online education program has been designed for healthcare professionals globally.

PD-(L)1 × VEGF bispecific antibodies combine checkpoint blockade with anti-angiogenic activity in a single molecule. For ivonescimab, preclinical studies suggest cooperative binding between its targets, providing a biological rationale beyond simply combining two mechanisms. Ivonescimab (PD-1 × VEGF) and pumitamig/BNT327 (PD-L1 × VEGF-A) are two of the most clinically advanced agents in this class. The session reviewed three randomized phase 3 trials of ivonescimab conducted in China. The presented pumitamig NSCLC and SCLC data were from phase 2 development; ROSETTA Lung-01 is an ongoing phase 3 trial, while ROSETTA Lung-02 is an ongoing phase 2/3 trial with its phase 3 portion underway.

In HARMONi-A, in patients with EGFR-mutated nonsquamous NSCLC after progression on EGFR-TKI therapy, ivonescimab plus chemotherapy improved PFS (7.1 vs 4.8 months; HR 0.46) and OS (16.8 vs 14.1 months; HR 0.74) versus chemotherapy alone. In HARMONi-2, ivonescimab improved PFS versus pembrolizumab in untreated, PD-L1-positive advanced NSCLC (11.14 vs 5.82 months; HR 0.51). HARMONi-6 demonstrated PFS and OS benefit for ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy in untreated squamous NSCLC. Together, these studies provide evidence of activity across different NSCLC populations and histologies, although confirmation in broader global populations remains important.

Early pumitamig data also support continued investigation. In the phase 2 ROSETTA Lung-02 dataset presented, confirmed ORRs were 48%, 78% and 100% in tumors with PD-L1 TPS <1%, 1–49% and ≥50%, respectively; these early subgroup findings require confirmation in larger studies.

Safety reflects both components of the approach, including VEGF-related hypertension, proteinuria and bleeding alongside the established spectrum of immune-related adverse events. Other reported events include stomatitis and ocular toxicity. Baseline risk assessment, early toxicity recognition and multidisciplinary input are important components of management.

Overall, PD-(L)1 × VEGF bispecifics represent a promising, evolving therapeutic strategy. Ivonescimab is approved in China for select NSCLC indications but remains investigational in the US, while ongoing randomized studies will further define the efficacy, safety and optimal clinical positioning of this therapeutic approach.