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ESMO 2025 Lung Cancer

CME

Key Studies in Lung Cancer: Independent Conference Coverage of ESMO 2025

European Learners: 1.50 EBAC® CE Credit

Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™

Released: December 16, 2025

Expiration: June 15, 2026

Luis Paz-Ares
Luis Paz-Ares, MD, PhD
David Planchard
David Planchard, MD, PhD
CME/CE Information

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HARMONi-6: Ivonescimab + CT vs Tislelizumab + CT as 1L Therapy for Stage IIIB-IV Squamous NSCLC

David Planchard, MD, PhD:
The key question addressed by the HARMONi-6 trial is whether the addition of ivonescimab, a novel bispecific antibody targeting both PD-1 and VEGF, to platinum-based chemotherapy can improve progression-free survival (PFS) and ultimately OS in patients with previously untreated metastatic squamous NSCLC.3

This question is of major clinical importance because the current standard first-line treatment for metastatic squamous NSCLC consists of platinum-based chemotherapy combined with an immune checkpoint inhibitor (PD-1 or PD-L1 inhibitor), which has demonstrated significant improvements in PFS and OS. However, despite these advances, outcomes remain suboptimal, and there are no established targeted therapies for this histologic subtype. By evaluating ivonescimab in comparison with tislelizumab (a PD-1 inhibitor) plus chemotherapy, this trial seeks to determine whether dual blockade of PD-1 and VEGF pathways can provide additional clinical benefit and potentially redefine the standard of care in the first-line treatment of advanced squamous NSCLC.

Several aspects of the trial conduct warrant consideration. First, the study was conducted entirely in China, and therefore enrolled a Chinese patient population. This raises the question of ethnic generalizability, as pharmacogenomic and biological differences may influence treatment efficacy and safety. Replication of these findings in non-Asian populations will be essential to confirm the broader applicability of the results.

Second, given that ivonescimab is a bispecific antibody targeting PD-1 and VEGF, its mechanism of action may be associated with VEGF-related toxicities, including an increased risk of hemoptysis or bleeding events. Consequently, the trial excluded patients with active hemoptysis or tumors at high risk of bleeding, leading to a selected study population. This exclusion criterion should be taken into account when interpreting the safety and generalizability of the results.

Finally, the eligibility of patients with brain metastases warrants clarification. At baseline, few patients were enrolled with brain metastases and the trial report does not specify whether patients with untreated brain metastases were included, an important consideration since a substantial proportion of patients with advanced squamous NSCLC present with CNS involvement at baseline. Further data on the management and outcomes of these patients would enhance understanding of ivonescimab’s clinical utility.

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HARMONi-6: PFS by IRRC (Primary Endpoint)

David Planchard, MD, PhD:
The key finding of this trial is that it met its primary endpoint, demonstrating a significant improvement in PFS with ivonescimab plus chemotherapy compared with tislelizumab plus chemotherapy in patients with metastatic squamous NSCLC. This represents the first trial in this setting to show a clinically meaningful and statistically significant PFS benefit favoring a bispecific antibody targeting PD-1 and VEGF pathways. The observed median PFS improvement of approximately 4 months and the early and sustained separation of the Kaplan–Meier curves indicate a robust and durable treatment effect.

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HARMONi-6: PFS by IRRC in Key Patient Subgroups

David Planchard, MD, PhD:
Of importance, the PFS benefit was consistent across patient subgroups based on PD-L1 expression level, including both PD-L1–low and PD-L1–high populations, suggesting that ivonescimab’s efficacy is not dependent on PD-L1 status. 

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HARMONi-6: ORR and DoR by IRRC

David Planchard, MD, PhD:
In addition, the overall response rate (ORR) was higher in the ivonescimab arm compared with the tislelizumab control arm, further supporting the enhanced antitumor activity of this regimen.

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HARMONi-6: Most Common TRAEs (Incidence ≥15%)

David Planchard, MD, PhD:
Regarding safety, the observed adverse events were consistent with the known toxicity profiles of both platinum-based chemotherapy and VEGF/PD-1 pathway inhibition. The most common treatment-related toxicities were hematologic and gastrointestinal, attributable to chemotherapy, and were largely manageable and in line with expectations for this regimen.

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HARMONi-6: Safety

David Planchard, MD, PhD:
As anticipated, immune-related adverse events occurred but were generally low grade and consistent with those observed with other immune checkpoint inhibitors. In addition, toxicities associated with VEGF blockade were reported, including hemorrhagic events, hypertension, thromboembolic complications, and proteinuria. These events were predominantly grade 1-2, with only a small proportion of grade ≥3 events.

Overall, the safety profile of ivonescimab plus chemotherapy was acceptable and manageable, with no unexpected signals. Nevertheless, healthcare professionals (HCPs) should remain vigilant for VEGF-related toxicities, particularly the risk of bleeding and hypertension, which are well recognized with agents targeting the VEGF pathway.

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HARMONi-6: Clinical Implications

Luis Paz-Ares, MD, PhD:
From my perspective, this is a very important trial. The data presented suggest that ivonescimab, as a bispecific antibody, may actually be a better agent to combine with chemotherapy compared with a standard-of-care PD-1 inhibitor such as tislelizumab in the first-line treatment of squamous cell carcinoma—specifically in patients without actionable genomic aberrations. We are seeing improvements in PFS, with a hazard ratio of 0.60 favoring the ivonescimab arm. The safety profile is also reassuring overall, with only mild increases in hypertension and proteinuria, which are typically manageable and not clinically prohibitive for most patients.

Of course, this was primarily a Chinese population trial, so I am very much looking forward to global confirmation. The global HARMONi-3 trial (NCT05899608) is already actively recruiting patients with both squamous and nonsquamous advanced NSCLC and will be essential to determine whether these promising findings extend to more diverse patient populations.

David Planchard, MD, PhD:
I completely agree that the results are impressive and certainly encouraging. However, from a clinical practice standpoint I would emphasize that this study does not yet represent an immediate change in the standard of care. Although the PFS improvement with ivonescimab plus chemotherapy over tislelizumab plus chemotherapy is significant, we need longer follow-up to determine whether this translates into a meaningful OS advantage. We have seen in prior studies that PFS benefits in this setting do not always convert into OS gains, so mature OS data will be key before we consider altering established treatment paradigms.

The trial nevertheless provides a strong signal; ivonescimab is clearly emerging as a promising therapeutic option in first-line metastatic squamous NSCLC. But confirmation is required, not only in terms of OS outcomes but also through validation in non-Chinese populations. Only with consistent global data will this regimen become a candidate for widespread adoption.

Luis Paz-Ares, MD, PhD:
Absolutely; confirmation will be critical. But if these results hold up in the global trial, ivonescimab could offer more benefit than the current PD-1 standards. The possibility of having a bispecific antibody outperform established immunotherapy in this setting would be a meaningful advance.

David Planchard, MD, PhD:
Yes, this is a highly positive and convincing trial and a valuable addition to the growing body of evidence in squamous NSCLC. We just need to let the data mature and await global validation before determining whether it will shift practice.

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