HARMONi-6: Evaluating the Safety and Generalizability of Ivonescimab in NSCLC

The therapeutic landscape for non–small cell lung cancer (NSCLC) is shifting with the introduction of ivonescimab (SMT112), a novel PD-1 and VEGF-targeted bispecific antibody. Commenting on the phase 3 HARMONi-6 trial (NCT05840016) safety findings presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, Sivraj Muralikrishnan, MD, noted that while the trial demonstrated a meaningful overall survival (OS) advantage, establishing global generalizability remains essential since the data came predominantly from an Asian population.

A primary clinical concern with introducing VEGF inhibition into squamous NSCLC has historically been the risk of severe toxicities, particularly hemoptysis. According to Muralikrishnan, HARMONi-6 delivered reassuring safety data, including a 2.6% rate of grade 3 hemorrhage with ivonescimab compared with 0.8% in the immunotherapy comparator arm. While ivonescimab led to numerically more grade 3 adverse effects, most VEGF-related toxicities were low-grade, treatment discontinuation rates remained low, and the increase in toxicity was outweighed by the magnitude of clinical benefit.

Muralikrishnan is a medical oncologist and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School.

Transcript:

Ivonescimab is a PD-1 and VEGF inhibitor. It is making some inroads. Most of these studies, including HARMONi-6, were predominantly conducted in an Asian population, predominantly in China, so in terms of making its way into frontline settings [in the US] or globally, that is what these studies are trying to do in terms of making it more generalizable. Until we have real-world data outside of China and Asia, [the broader applicability] remains to be seen. The results of the HARMONi-6 study, however, were impressive; it delivered a meaningful OS advantage and kept toxicity within a range that most oncologists find manageable with this bispecific regimen.

Historically, we have avoided VEGF inhibition in squamous NSCLC due to risks of hemoptysis, high blood pressure, proteinuria, and other VEGF-related toxicities. That has always been the challenge with using those types of treatments, including ivonescimab. Interestingly, the safety profile showed a rate of grade 3 hemorrhage of 2.6% compared with 0.8% in the immunotherapy comparator arm, which is not terribly high. Most of the…toxicities from VEGF inhibition were grade 1 to 2; there were numerically more grade 3 events in the ivonescimab arm.

In general, the safety profile was within reason and [did] not necessarily scare us away from using this bispecific in the future. Even though it did not show a major reduction in severe toxicity and had higher grade 3 adverse events, the increase in toxicity was still relatively modest given the magnitude of benefit. The severe bleeding rates remained surprisingly low with this VEGF strategy, and there was still relatively low treatment discontinuation. Those are all important things regarding its safety. The focus has been on the hemorrhagic signal, which was not as bad as we thought.

Reference

Zhiwei C, Yang F, Luo Y, et al. Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy in previously untreated advanced squamous non–small cell lung cancer: overall survival results of the phase 3 HARMONi-6. J Clin Oncol. 2026;44(suppl 17):LBA4. doi:10.1200/JCO.2026.44.17_suppl.LBA4