HARMONi-6 trial: a further development in the management of advanced squamous non-small-cell lung cancer

Lung cancer is the primary cause of cancer-related mortality globally (1). In particular, the squamous subtype of non-small cell lung cancer (sqNSCLC) is characterized by a poor prognosis, attributed to both its clinical and molecular features, such as its typically central location, rapid growth, and high genomic complexity with frequent absence of actionable driver mutations (2). Unlike the non-squamous subtype of NSCLC, EGFR mutations and ALK gene rearrangements are rare in sqNSCLC (approximately 2.7% and 1.5–2.5%, respectively), effectively excluding these patients from the benefits of targeted therapies with tyrosine kinase inhibitors (3).

The advent of immune checkpoint inhibitors (ICIs), specifically those targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis, has radically altered the treatment paradigm for advanced-stage squamous NSCLC. Several ICIs have been approved in recent years, either alone or in combination with chemotherapy, showing superior outcomes compared with chemotherapy alone, prolonging overall survival (OS) and offering a lower rate of chemotherapy-related adverse events (4). Following the results of the KEYNOTE-407 and IMpower131 trials, which established the combination of chemoimmunotherapy as the standard of care, subsequent efforts to further improve outcomes through incremental modifications have been largely unsuccessful (5,6).

In more recent times, focus has shifted toward the use of combined therapies that integrate ICIs and anti-vascular endothelial growth factor (VEGF) agents. In fact, it is known that VEGF inhibitors can enhance the efficacy of immunotherapy due to crosstalk between the two molecular pathways: the inhibition of tumor angiogenesis facilitates the infiltration of cytotoxic T cells into the tumor microenvironment, while ICIs prevent the functional exhaustion of these cells (7).

In this context, ivonescimab emerges as a “first-in-class” bispecific antibody that simultaneously targets PD-1 and VEGF-A, with distinctive features that improve the safety profile and antitumor effects. Among these, the enhanced binding avidity due to its molecular structure promotes durable drug retention in the tumor microenvironment, leading to an enhanced antitumor effect. Furthermore, the anti-VEGF component promotes the modulation of blood vessels, improving intratumoral blood perfusion and immune restoration, favoring the differentiation of immune cells and the activity of effector T cells (8,9).

The HARMONi-6 trial represents a potential practice-changing development in the first-line treatment of sqNSCLC (10). For the first time in a phase 3 setting, a novel immunotherapy-based strategy has demonstrated clear superiority over an established PD-1 inhibitor–chemotherapy backbone, a benchmark that has remained largely unchallenged since the introduction of ICIs into routine care.

The magnitude of progression-free survival benefit observed in HARMONi-6 with ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy [11.1 vs. 6.9 months, hazard ratio (HR) 0.60], together with its consistency across PD-L1 subgroups (both PD-L1 <1% and ≥1%), is particularly convincing. However, it should be noted that the PD-L1 ≥50% subgroup included 49 patients (18%) in the ivonescimab group vs. 62 patients (23%) in the tislelizumab group, with an HR of 0.71 (95% confidence interval: 0.37–1.33); these data are not robust enough to confirm a consistent benefit across PD-L1 subgroups. Furthermore, the overall response rate (ORR; 76% vs. 66.5%) as well as the duration of response (DoR; 11.2 vs. 8.4 months) were higher in patients treated with ivonescimab plus chemotherapy compared to the control group.

Thus, in a disease where actionable oncogenic drivers are uncommon and biomarker-guided treatment options remain limited, a regimen that delivers benefits regardless of PD-L1 expression carries clear clinical appeal. Despite the promising progression-free survival results with a reduction of disease progression risk of 40%, updates about the OS data with longer follow-up are expected, as they are not mature enough to be evaluated; such data will be needed before this regimen can be considered a standard of care.

Historically, the use of anti-angiogenic drugs, such as bevacizumab, in the squamous subtype of lung cancer was contraindicated due to the risk of severe hemoptysis and related deaths, often associated with tumor localization near major blood vessels, necrosis, and cavitation (11). The success of ivonescimab represents a shift in direction compared to previous studies of anti-angiogenic agents in squamous NSCLC; ivonescimab showed a tolerable safety profile. Despite a numerical increase in grade ≥3 adverse events, immune-related toxicities and serious hemorrhagic events remained comparable to the control group. A key factor is the design of ivonescimab’s Fc region, which has been modified to reduce binding to Fcγ receptors and minimize antibody-mediated cytotoxicity (12).

In HARMONi-6, hemoptysis occurred in 32 patients (12%) in the ivonescimab group and 10 patients (4%) in the tislelizumab group; among these groups, however, only 4 patients (2%) and 1 patient (<1%), respectively, showed grade ≥3 hemoptysis, i.e., severe or life-threatening condition. This statistical difference between the two groups could be related to anti-VEGF effects of ivonescimab. Furthermore, the lack of quantification of the risk of hemorrhage for every patient could have altered the results. It is essential to note that the study directly excludes patients with obvious cavitated or necrotic tumors, or those with invasion of major vessels, who are considered to be at “high hemorrhagic risk” based on subjective opinion. However, the eligibility criteria for antiangiogenic drugs should be carefully evaluated and sharpened in a more reproducible way, as in clinical practice, considering clinical and radiological aspects of the tumor to really assess the risk of bleeding of the patients, such as central cavitation, tumor extension to a large vessel with a 180° branching angle, hemoptysis >3 mL during the previous 3 months, prior thromboembolic events, among others (13).

This balance between efficacy and tolerability suggests that ivonescimab could potentially be integrated into existing treatment algorithms for advanced squamous NSCLC: the results show that, compared with tislelizumab plus chemotherapy, ivonescimab plus chemotherapy significantly prolonged median progression-free survival by 4.2 months, with a higher response rate and longer DoR, regardless of PD-L1 status.

However, it must be considered that there is still a subset of patients with higher hemorrhagic risk who are not eligible for this therapy, unless sharpened inclusion criteria are used. In some cases, rescue surgery could help reduce the risk of bleeding prior to the oncologic therapy in a multidisciplinary team. More studies are expected to define the OS benefit of ivonescimab plus chemotherapy in advanced squamous NSCLC, as well as new trials to compare this novel therapy against the current standard of care in Europe, namely pembrolizumab plus chemotherapy, in a wider and multiethnic population. In fact, the lack of multiethnicity could generate genetic bias, especially for evaluating immune-mediated responses and adverse events with this new bispecific antibody, decreasing the generalizability of the study. We look forward to a comparison of ivonescimab with pembrolizumab, the real global benchmark.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-26-0012/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0012/coif). The authors have no conflicts of interest to declare.

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