HARMONi-2: Dr. Liu Discusses Implications, Unanswered Questions, and Next Steps

Stephen V. Liu, MD, of the Georgetown University School of Medicine and Georgetown’s Lombardi Comprehensive Cancer Center in Washington, DC, joined Lung Cancers Today to discuss the implications of recent data from the HARMONi-2 trial.

A team led by Anwen Xiong, PhD, and Lei Wang, PhD, conducted the randomized, double-blind phase 3 trial and reported results from the preplanned interim analysis in The Lancet, with a final analysis to be reported later.

Dr. Liu explained that HARMONi-2 is an important trial in non-small cell lung cancer (NSCLC) and that “history will tell us whether this was the mark of a new era.”

The trial compares ivonescimab with pembrolizumab in locally advanced or metastatic PD–L1–positive NSCLC. Dr. Liu explained that ivonescimab, a bispecific antibody targeting PD1 and VEGF, “features cooperative binding, meaning this agent may be greater than the sum of its parts,” as when the bispecific antibody engages one molecule, “it’s more likely to bind to the other, making it potentially a more powerful agent.”

The multicenter trial included 398 adults with locally advanced or metastatic PD-L1–positive NSCLC without sensitizing EGFR mutations or ALK translocations and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Study investigators randomized 1:1 to receive ivonescimab 20 mg/kg (n=198) or pembrolizumab 200 mg (n=200) IV every 3 weeks. The researchers stratified the randomization by histology, clinical stage, and PD-L1 expression. However, Dr. Liu explained an important nuance to consider regarding the pembrolizumab comparator arm in the HARMONi-2 study.

“Some might argue that pembrolizumab is not our preferred treatment for PD-L1 low non-small cell lung cancer,” Dr. Liu said. “I would agree with that, but based on KEYNOTE-042, it is an approved option.”

The primary end point of the HARMONi-2 trial was progression-free survival (PFS), as assessed by a masked independent radiographic review committee per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in the intention-to-treat population.

Dr. Liu explained that in the general population, ivonescimab was “significantly better in terms of progression-free survival,” as it doubled the PFS rate observed in the pembrolizumab arm (5.8 months), with a median PFS of 11.1 months and a hazard ratio (HR) of 0.51.

“If we look specifically at PD-L1 high, where pembrolizumab is a clear standard of care, the hazard ratio holds up,” he said.

The study showed that ivonescimab was “superior in every meaningful subgroup” of patients, including those with squamous and non-squamous NSCLC, Dr. Liu said.

He also discussed the safety of the bispecific antibody, explaining that “there is more toxicity with the newer agent because we are engaging VEGF.”

“We do see some VEGF-related toxicity such as hypertension, proteinuria but not a significant difference in terms of arterial earth thrombosis, and if you look at the grade 3 immune-related adverse events, those are similar between the two arms,” Dr. Liu said.

However, he explained that questions about the potential impact on clinical practice remain.

“These data are profoundly impressive, [showing] a clear improvement in progression free survival, which begs the question: should ivonescimab replace pembrolizumab across the board?” he asked.

To answer this larger question, Dr. Liu explained that it would be important to show if the study can be replicated in other populations outside of China and if the PFS benefit will translate to improved overall survival (OS) when further data is available.

“If this is a transient improvement in PFS with no OS impact, which we’ve seen with VEGF before in different settings, then I think it’ll be much less impactful,” Dr. Liu said. “But if this translates to an overall survival benefit, one could certainly foresee a future where ivonescimab or other bispecifics replace pembrolizumab or other PD-1 and PD-L1 inhibitors.”

Other questions include how ivonescimab will fit into treatment algorithms and if it may play a role in early-stage disease. Further studies, including HARMONi-3 and HARMONi-7, continue to evaluate the bispecific antibody to address these questions.

As this data is awaited, Dr. Liu explained that although questions remain, HARMONi-2 represents “an exciting chapter in immunotherapy battle against lung cancer.”