Clinical Insights: The HARMONi-6 Trial and Dual PD-1/VEGF Blockade in Squamous Lung Cancer

During a Clinical Insights session hosted by OncUpdates, 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, to examine the implications of the phase 3 HARMONi-6 trial. 

The panel focused on ivonescimab, a first-in-class bispecific antibody targeting both PD-1 and VEGF, which was evaluated in combination with chemotherapy for treatment-naïve patients with advanced squamous NSCLC. Following its presentation at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, HARMONi-6 quickly emerged as one of the most discussed thoracic oncology studies of the year, largely because it demonstrated a statistically significant overall survival (OS) benefit in a disease setting that has seen relatively few therapeutic advances over the past decade.

A Meaningful Survival Signal in a Historically Challenging Disease

HARMONi-6 enrolled patients with stage IIIB or IV squamous NSCLC who had not received prior systemic therapy and randomized them to receive either ivonescimab plus carboplatin and paclitaxel followed by ivonescimab maintenance, or chemotherapy combined with the PD-1 inhibitor tislelizumab followed by maintenance tislelizumab. Importantly, the trial included patients regardless of PD-L1 expression level. Progression-free survival (PFS) was the primary end point, with OS as a key secondary end point.

Although PFS served as the primary end point, the discussion centered largely on the OS results. The interim analysis, conducted after approximately 21 months to 22 months of follow-up, demonstrated a significant improvement in OS favoring the ivonescimab-containing regimen, with a hazard ratio of 0.66. In contrast to adenocarcinoma, where targeted therapies and immunotherapy combinations have transformed outcomes, squamous NSCLC has historically lagged behind in therapeutic innovation. Since the establishment of pembrolizumab plus chemotherapy as a standard through KEYNOTE-407, few studies have demonstrated meaningful improvements over existing first-line treatment approaches.

The panel emphasized that HARMONi-6 compared ivonescimab not against chemotherapy alone, but against an active immunotherapy-based standard. This distinction elevates the significance of the findings because demonstrating superiority over a PD-1 inhibitor plus chemotherapy regimen represents a substantially higher bar than earlier immunotherapy trials faced. While all three physicians acknowledged that additional follow-up is necessary, they agreed that the survival signal appears credible and clinically meaningful.

Interpreting the Limitations: Follow-Up, Patient Population, and Generalizability

Despite the enthusiasm surrounding the results, the panel devoted considerable attention to important limitations of the study. One frequently discussed issue was the relatively early timing of the OS analysis. However, the investigators noted that the analysis was prespecified and conducted according to the study design. At approximately 38% OS maturity, the timing was consistent with many interim analyses presented in oncology. Furthermore, the Kaplan-Meier curves appeared to continue separating over time, suggesting that the observed benefit may persist with longer follow-up.

Another area of discussion involved the patient population itself. HARMONi-6 was conducted exclusively in China, and more than 90% of enrolled patients were male. Although these characteristics have prompted questions about global applicability, the panelists generally viewed them as reflective of the epidemiology of squamous NSCLC rather than major threats to the validity of the findings. Smoking-associated squamous lung cancer remains disproportionately prevalent among men worldwide, and the experts noted that they are unaware of compelling biological reasons why the disease would fundamentally behave differently across geographic regions.

Nevertheless, the panel acknowledged that regional differences in trial conduct, toxicity reporting, and patient management could influence outcomes. The forthcoming HARMONi-3 trial, a global phase 3 study evaluating ivonescimab across broader populations, was repeatedly cited as the study that will ultimately determine whether the HARMONi-6 findings can be generalized internationally.

The panel also examined age-related findings. Although the median age of participants was comparable to other landmark NSCLC studies, patients older than 75 years were excluded. In addition, subgroup analyses suggested less apparent benefit among patients older than 65 years. However, the experts cautioned against overinterpreting these observations because the analyses were not powered to evaluate treatment effects within specific age groups. Factors such as treatment exposure, comorbidities, disease burden, and toxicity profiles may have contributed to the observed trends. As a result, the physicians viewed age as an important unanswered question rather than a limitation severe enough to undermine the study’s overall conclusions.

Balancing Efficacy and Safety With Dual PD-1/VEGF Blockade

The final major focus of the discussion centered on toxicity and patient selection. Because ivonescimab incorporates VEGF inhibition, concerns regarding hemorrhage, hypertension, proteinuria, and other VEGF-associated adverse events (AEs) were expected. Rates of hemorrhage were higher in the ivonescimab arm than in the control arm. However, severe hemorrhagic events remained uncommon, with grade 3 or higher bleeding occurring in fewer than 3% of treated patients.

The HARMONi-6 protocol allowed physician discretion regarding patients with factors traditionally associated with bleeding risk, including cavitary tumors, prior hemoptysis, and major blood vessel involvement. Although these patients were represented within the study population, serious bleeding events remained relatively infrequent, providing some reassurance regarding the feasibility of using the regimen in carefully selected patients.

Still, the panel emphasized that patient selection will be critical if ivonescimab becomes broadly available. The risk-benefit calculation may differ substantially depending on the magnitude of benefit ultimately confirmed in global studies. If HARMONi-3 reproduces the impressive efficacy observed in HARMONi-6, clinicians may be more willing to accept modest increases in manageable toxicity. Conversely, if the efficacy advantage proves smaller, the threshold for tolerating VEGF-related AEs could become more restrictive.

Ultimately, the panel agreed that HARMONi-6 represents one of the most important developments in squamous NSCLC in recent years. The study demonstrated that a novel dual-targeting immunotherapy strategy can improve survival beyond current standards, offering renewed optimism for a patient population that has historically had limited treatment advances. While important questions remain regarding global applicability, optimal patient selection, and long-term safety, the trial provides compelling evidence that combined PD-1 and VEGF inhibition may represent a meaningful new therapeutic direction.