Ivonescimab, a PD-1/VEGF bispecific antibody, challenges pembrolizumab monotherapy in PD-L1-positive non-small cell lung cancer: insights from HARMONi-2

Lung cancer remains the leading cause of cancer-related mortality worldwide (1). Of all lung cancer cases, 85% of are non-small cell lung cancer (NSCLC), divided into adenocarcinoma (about 50%) and squamous cell carcinoma (about 30%) histologies. Of these, 40% of patients present with de novo metastatic disease (2).

Over the last decade, immune checkpoint inhibitors (ICIs) have fundamentally changed the treatment landscape of advanced NSCLC. By targeting key regulatory pathways like programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), these therapies have shifted the focus from historically used cytotoxic chemotherapy toward precision immunotherapy, with treatment selection increasingly guided by PD-L1 tumor proportion score (TPS). For patients with PD-L1 TPS ≥50%, pembrolizumab monotherapy improved progression-free survival (PFS) and overall survival (OS) vs. chemotherapy in KEYNOTE-024 (3). Subsequently, KEYNOTE-042 (4), showed that pembrolizumab monotherapy significantly improved PFS and OS in patients with PD-L1 expression of >1% of tumour cells. These two trials established a new standard of care in the first-line setting for patients with PD-L1 expression. In parallel, several chemoimmunotherapy regimens became standards across PD-L1 strata, including pembrolizumab plus platinum-pemetrexed in non-squamous disease (KEYNOTE-189) (5) and pembrolizumab plus platinum-taxane in squamous disease (KEYNOTE-407) (6). Other first-line ICI approaches include atezolizumab monotherapy in PD-L1-high NSCLC (IMpower110) (7) and dual-checkpoint blockade strategies such as nivolumab plus ipilimumab (CheckMate-227) (8). In China and other regions, additional PD-1 inhibitors (e.g., tislelizumab) combined with chemotherapy have also demonstrated benefit in phase III trials (9).

One of the “hallmarks of cancer” is the ability of malignancies to induce angiogenesis (10,11). Anti-angiogenic therapies are included as part of the National Comprehensive Cancer Network (NCCN) practice guidelines for advanced NSCLC. Anti-angiogenic agents have established roles in NSCLC, for example bevacizumab in combination with platinum-based chemotherapy in non-squamous disease, based on the pivotal Eastern Cooperative Oncology Group (ECOG) 4599 clinical trial (12). Ramucirumab is recommended in the second-line setting in combination with docetaxel for patients with disease progression after platinum-based chemotherapy, supported by the key phase III REVEL clinical trial (13). Beyond vascular regression, anti-angiogenic therapies targeting vascular endothelial growth factor (VEGF) may enhance efficacy of PD-1 inhibitors through their inherent immunomodulatory effects, mainly through reversal of VEGF-mediated immunosuppressive tumor microenvironment by reducing VEGF-mediated immune suppression and improving T-cell trafficking (14,15). The phase III IMpower150 study has shown that the addition of atezolizumab to bevacizumab plus chemotherapy as first-line treatment for non-squamous metastatic NSCLC resulted in a significant improvement in PFS and OS, compared with bevacizumab plus chemotherapy, supporting clinical benefit for combining VEGF inhibition with immunotherapy, although the trial was not designed to separate additive from truly synergistic effects (16).

HARMONi-2 was a randomised, double-blind, phase III trial conducted in China comparing ivonescimab, a PD-1/VEGF bispecific antibody, with pembrolizumab in previously untreated PD-L1-positive (TPS ≥1%) locally advanced (unresectable) or metastatic NSCLC without EGFR or ALK alterations (17). The goal of the study was to explore the following hypothesis: does simultaneous targeting of an immune evasion pathway (PD-1/PDL-1) and a tumor angiogenic pathway [VEGF-VEGF receptor (VEGF-R)] offer superior efficacy over immunotherapy alone in advanced NSCLC without a significant increase in treatment-related adverse events (TRAEs) in patients with PD-L1-postive advanced NSCLC. Patients (n=398) with previously untreated stage IIIB/IV and PD-L1 >1% were randomized to either pembrolizumab or ivonescimab. Patients with EGFR or ALK alterations were excluded. The primary endpoint was PFS assessed by an independent radiology review committee (IRRC) in the intention-to-treat population; key secondary endpoints included OS, objective response rate (ORR), duration of response, and safety (17). Subgroup analyses by PD-L1 TPS and histology were pre-specified and have been reported in conference materials and publications (17,18).

At the interim analysis, at a median follow-up 8.7 months, ivonescimab significantly improved PFS vs. pembrolizumab (median 11.1 vs. 5.8 months; hazard ratio 0.51, 95% confidence interval: 0.38–0.69; P<0.0001) (17,18). PFS benefit was observed across PD-L1 TPS strata (TPS 1–49% and TPS ≥50%) and in both squamous and non-squamous disease (Table 1, Figure 1) (18). These findings are notable because pembrolizumab monotherapy is an accepted option for PD-L1 TPS ≥1%; however, in many practices, patients with PD-L1 TPS 1–49% are frequently treated with chemoimmunotherapy given the more modest monotherapy benefit in this subgroup. If validated, a chemo-free bispecific approach could be particularly attractive for patients who are poor candidates for cytotoxic chemotherapy.

Figure 1 Forest plot of PFS hazard ratios for selected subgroups in HARMONi-2. mets, metastases; PD-L1, programmed cell death ligand 1; PFS, progression-free survival; TPS, tumour proportion score.

Safety profile was generally manageable, with permanent treatment discontinuation in 2% of the patients in ivonescimab group and 3 % in pembrolizumab group. There were no treatment-related deaths on ivonescimab. The most common TRAEs associated with ivonescimab, certainly driven by its antiangiogenic properties, were proteinuria (grade 3 or higher in 3.0% vs. 0.0% for pembrolizumab) and hypertension (grade ≥3 in 5% vs. 1%). Most importantly, grade 3 or worse hemorrhage was similar in both groups (1% vs. 1%) (17,18). The squamous NSCLC cohort is clinically important because bevacizumab is typically contraindicated due to the risk of life-threatening hemorrhagic events, particularly in centrally located tumours or those with cavitation. The published HARMONi-2 report does not provide granular detail on central tumour location or cavitation; therefore, clinicians should apply standard VEGF-inhibitor risk mitigation when applying the trial results to real-world practice.

Mechanistically, ivonescimab is designed for cooperative binding to PD-1 and VEGF, which potentially increases drug avidity within the tumor microenvironment and promotes T-cell activation while counteracting VEGF-driven immune exclusion (17,19). In fact, preclinical studies have shown that VEGF inhibits dendritic cells, promotes the proliferation of regulatory T cells and reduces T cell infiltration. VEGF, with its angiogenic properties, promotes abnormal tumor vasculature growth, which creates a hypo-perfused tumor microenvironment, therefore preventing effective T-cell infiltration and contributing to tumor immune evasion (20).

Although EGFR-VEGF pathway crosstalk is highly relevant to EGFR-mutant disease and was emphasised in HARMONi-A, the core biological rationale for HARMONi-2 in driver-negative NSCLC is broader: VEGF can impair dendritic cell maturation, expand regulatory T cells, and create abnormal vasculature that limits effector-cell infiltration (14,15).

Positioning ivonescimab within the emerging bispecific landscape is also important, as delineated in Table 2. Differences between different molecules include target choice (PD-1 vs. PD-L1), VEGF-binding modality (antibody or trap), dosing, and safety in populations at bleeding risk. Head-to-head comparative evidence is not yet available; therefore, caution should be used when performing cross-trial comparisons.

Limitations of HARMONi-2 should be taken into consideration, tempering immediate generalization. First, the patients enrolled were exclusively Chinese, and multi-regional validation is important. Second, OS data remains somewhat immature as follow-up was relatively short at the interim analysis (17,18). Finally, providing granular detail on central cavitating tumors in regard to bleeding risk in the squamous subgroup would be of major interest for clinical implementation. Future studies should clarify patient selection strategies, including whether ivonescimab can meaningfully replace chemoimmunotherapy in PD-L1 TPS 1–49% disease.

In conclusion, HARMONi-2 showed that ivonescimab delivers nearly double the median PFS compared to pembrolizumab in first-line PD-L1-positive NSCLC, with consistent subgroup results and an acceptable safety profile and encouraging activity in both squamous and non-squamous histologies. This marks a major milestone: it is the first-ever randomized phase III trial that describes a significant improvement over pembrolizumab in first-line PD-L1 positive NSCLC. The results of HARMONI-2 must be validated in diverse populations optimally in a multi-regional clinical trial and with longer follow-up. Several ongoing trials are underway which will hopefully confirm the benefit of this dual inhibition of these critical pathways.

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-25-125/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-25-125/coif). M.A.S. reports grant/research support from Genentech, Spectrum, Lilly (Loxo), Cullinan, Enliven, BeOne, Mirati, Nuvalent, Nuvation, AstraZeneca, OncoC4, Elephas, and Summit; speakers bureau/honoraria from AstraZeneca, Jazz, Janssen, Regeneron, Genentech, Guardant, and Nuvation; and membership on Data Safety Monitoring Boards, Steering Committees, or Advisory Boards for BMS, Summit, BeOne, and AstraZeneca. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [Crossref] [PubMed]
2. Molina JR, Yang P, Cassivi SD, et al. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83:584-94. [Crossref] [PubMed]
3. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
4. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019;393:1819-30. [Crossref] [PubMed]
5. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:2078-92. [Crossref] [PubMed]
6. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med 2018;379:2040-51. [Crossref] [PubMed]
7. Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med 2020;383:1328-39. [Crossref] [PubMed]
8. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2019;381:2020-31. [Crossref] [PubMed]
9. Lu S, Wang J, Yu Y, et al. Tislelizumab plus chemotherapy as first-line treatment of locally advanced or metastatic nonsquamous non-small-cell lung cancer (final analysis of RATIONALE-304: a randomized phase III trial). ESMO Open 2024;9:103728. [Crossref] [PubMed]
10. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-6. [Crossref] [PubMed]
11. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70. [Crossref] [PubMed]
12. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50. [Crossref] [PubMed]
13. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014;384:665-73. [Crossref] [PubMed]
14. Oyama T, Ran S, Ishida T, et al. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol 1998;160:1224-32.
15. Manegold C, Dingemans AC, Gray JE, et al. The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC. J Thorac Oncol 2017;12:194-207. [Crossref] [PubMed]
16. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med 2018;378:2288-301. [Crossref] [PubMed]
17. Xiong A, Wang L, Chen J, et al. Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in China. Lancet 2025;405:839-49. [Crossref] [PubMed]
18. HARMONi-2 PD-L1 subgroup poster (data cutoff Jan 29, 2024). Available online: https://s206.q4cdn.com/652410165/files/doc_downloads/publications/2025/HARMONi-2-PD-L1-Subgroup-Poster_L2_83955698.pdf
19. Zhong T, Zhang L, Huang Z, et al. Design of a Fc-engineered tetravalent bispecific antibody targeting PD-1 and VEGF with cooperative effects. iScience 2024;28:111722.
20. Meder L, Schuldt P, Thelen M, et al. Combined VEGF and PD-L1 Blockade Displays Synergistic Treatment Effects in an Autochthonous Mouse Model of Small Cell Lung Cancer. Cancer Res 2018;78:4270-81. [Crossref] [PubMed]