Ivonescimab: promise or reality for advanced non-small cell lung cancer?

The published results of the HARMONi-2 trial once again demonstrate the interesting role that bispecific antibodies can play in the treatment of non-small cell lung cancer (NSCLC). Ivonescimab, an antibody against programmed cell death protein 1 (PD-1) and vascular endothelial growth factor (VEGF)-A receptors, has shown favorable results compared to pembrolizumab in the treatment of patients with advanced NSCLC and programmed death-ligand 1 (PD-L1)-positive tumors (1). The HARMONi‑2 trial presents both strengths and limitations and therefore warrants a critical evaluation. Although the results are positive, their extrapolation to the entire population with advanced NSCLC is uncertain and opens an important path that is currently unclear.

HARMONi-2 is a phase 3 study that randomized 398 patients to receive first-line ivonescimab versus pembrolizumab in patients with advanced PD-L1-positive NSCLC. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. The rationale for dual action on PD-1 and VEGF offers the advantages of greater tumor permeability by cytotoxic T lymphocytes and a lower presence of immune regulatory cells such as regulatory T cells or myeloid-derived suppressor cells, in addition to the already known effects of antiangiogenic agents (2,3). The results of the trial, with immature overall survival (OS) data, showed a PFS benefit for the ivonescimab group compared to pembrolizumab in the overall sample [11.1 vs. 5.8 months; hazard ratio (HR), 0.51; P<0.0001]. This benefit was consistent across subgroups by histology, PD-L1 (≥50% or 1–49%) or presence of liver metastases. In contrast, no benefit was seen in patients with central nervous system metastases. The toxicity profile was acceptable, with a grade ≥3 adverse event rate of 22% for ivonescimab, with 10% of grade ≥3 adverse events being VEGF-related.

Without a doubt, the study is a very clear promise of a possible therapy that offers advantages over the anti-PD(L)1 drugs used to date. Obviously, there are some points in the trial that must be analyzed with caution. The selection of the population, the control therapy used, the toxicity of antiangiogenic drugs, and the lack of OS data with a more in-depth statistical analysis mean that further studies are needed before this therapy can become standard in clinical practice. Firstly, all the patients selected are Asian, with the limitations that this entails in extrapolating the results to the Western population. This is made more important by the absence of data on molecular biomarkers that may have a key influence on the response to ivonescimab, such as KRAS, TP53, or STK11 (4,5). In addition, patient selection had a significant influence on squamous tumors, as the exclusion criteria meant that patients with significant hemoptysis, significant tumor necrosis/cavitation, invasion of large vessels and/or those considered to be at high risk of hemorrhage were not eligible for selection. All of this makes it very complex to extrapolate the results to the Western population, patients with squamous tumors, and certain tumors with specific genomic alterations.

Secondly, and probably the most controversial point in this study, is the selection of the PD-L1 cut-off point. It is particularly striking that in the study, patients with PD-L1 1–49% tumors do not receive standard treatment with chemotherapy plus immunotherapy. Current trends even suggest this therapy for PD-L1 ≥50% tumors, where the use of immunotherapy is often insufficient, especially in the initial induction phase (6). This leads to a PFS with pembrolizumab for PD-L1 1–49% NSCLC tumors of 5.4 months, which is much lower than expected based on extrapolation from studies with these populations (7-9). Likewise, the population with PD-L1 1–49% was the largest, accounting for 58% of the total. It is true that PFS in these patients with ivonescimab was 8 months, but these are still promising data that cannot be extrapolated to clinical practice.

The next point of debate in the study is the primary endpoint. The absence of OS as the primary endpoint is unclear and does not make sense in a study of this nature. This concern is reinforced by the fact that previous phase III antiangiogenic trials in advanced NSCLC, such as AVAiL (first-line cisplatin-gemcitabine ± bevacizumab) (10), VITAL (second-line docetaxel ± aflibercept) (11) and LUME-Lung 1 (second-line docetaxel ± nintedanib) (12), consistently achieved improvements in PFS without a corresponding or robust OS benefit, highlighting that PFS gains with VEGF-targeted strategies have historically not translated into meaningful survival prolongation. Various reasons can be considered, such as the fact that pembrolizumab has already demonstrated OS data in these indications (basically, in PD-L1 ≥50%) or an a priori expectation of a very high benefit from ivonescimab. However, all these assumptions, although partially true, do not remedy the fact that the study probably required a more robust primary endpoint due to its characteristics. Finally, another unknown factor is the toxicity of the treatment, where the use of antiangiogenic agents is not currently standard in many cases, even in non-squamous tumors, due to the high symptomatology of lung cancers associated with these drugs. Although it is true that the toxicity profile of ivonescimab in terms of grade ≥3 adverse events is favorable according to the study data (hypertension 5%, proteinuria 3% or hemorrhage 1%), the high selection of patients, as indicated above, means that only clinical practice will truly reveal the true safety profile of this drug.

Given all the questions raised, we can answer the question in the title. In our opinion, ivonescimab is currently a promise rather than a reality, with very high future potential but which cannot yet be translated into clinical practice. In all respects, the KEYNOTE trials 042 (7), 189 (8), 407 (9) and 024 (13), which compared first-line pembrolizumab to platinum-based doublet chemotherapy in the first line treatment of advanced NSCLC, are more robust in supporting the current evidence (Table 1). Many of the unresolved issues in HARMONi-2 are expected to be clarified by the ongoing HARMONi-3 trial, which will assess firstline ivonescimab plus chemotherapy versus pembrolizumab plus chemotherapy in metastatic NSCLC regardless of PD-L1 status in a multiregional population (14). With OS and PFS as its co‑primary endpoints, this study will address the uncertainties regarding PD-L1 stratification, the choice of primary endpoint, and limitations inherent to the control arm in HARMONi-2.

In conclusion, ivonescimab should be viewed as a promising drug for the future, opening an interesting direction in advanced NSCLC. Bispecific antibodies are the present and future of NSCLC treatment, and their implementation will undoubtedly be widespread in different indications. It is possible that ivonescimab will be used in our clinical practice in the coming years, although its data must be more robust and answer questions that are currently more doubts than realities.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Lung Cancer Research. The article has undergone external peer review.

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1146/coif). The authors have no conflicts of interest to declare.

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