Balancing Efficacy and Safety: Toxicity, Patient Selection, and the Future of Ivonescimab

Benjamin P. Levy, MD, of Johns Hopkins Sidney Kimmel Cancer Center, was joined by Jarushka Naidoo, MB, BCh, MHS, of Beaumont RCSI Cancer Centre, and Bo Wang, MD, of Willamette Valley Cancer Institute and Research Center, for a discussion focused on the safety profile of ivonescimab and the practical considerations that may ultimately determine its role in clinical practice. Building on the efficacy findings from the phase 3 HARMONi-6 trial, the panel examined VEGF-related toxicities, particularly hemorrhage, and explored how clinicians may need to balance potential benefits against treatment-associated risks in patients with advanced squamous non–small cell lung cancer (NSCLC).

The panel agreed that toxicity must be evaluated within the context of clinical benefit. While hemorrhagic events were more common with ivonescimab than with chemotherapy plus tislelizumab, rates of severe bleeding remained relatively low, with grade 3 or higher hemorrhage occurring in fewer than 3% of patients. Dr. Wang emphasized that the key challenge will be identifying patients who can safely receive therapy, particularly those with risk factors such as cavitary tumors, recent hemoptysis, or major blood vessel involvement. He noted that the HARMONi-6 protocol allowed investigators some discretion in evaluating these risks, reflecting the realities of clinical practice where treatment decisions often require individualized assessment rather than strict protocol-driven rules. Both highlighted that many VEGF-associated toxicities, including hypertension and proteinuria, are generally manageable with appropriate monitoring and supportive care.

A recurring theme throughout the discussion was the importance of patient selection and the need to contextualize toxicity within the magnitude of efficacy benefit ultimately confirmed in future studies. Dr. Naidoo noted that clinicians routinely weigh treatment benefits against adverse-event risks and suggested that the acceptability of VEGF-related toxicities will depend heavily on whether the impressive survival benefit observed in HARMONi-6 is replicated in the global HARMONi-3 trial. 

The panel concluded on an optimistic note, describing HARMONi-6 as the first positive phase 3 study in squamous NSCLC since KEYNOTE-407 and highlighting the promise of bispecific immunotherapy approaches. While important questions remain regarding long-term safety and optimal patient selection, the panel agreed that ivonescimab represents a potentially significant advance that warrants continued investigation and could reshape treatment strategies for squamous NSCLC if ongoing global studies confirm the findings.