Lung Cancer Treatment With Ivonescimab, Targeting PD-1 and VEGF Together: HARMONi-6

A New Dual-Targeted Drug: Ivonescimab

Lung cancer has been one of medicine’s most intensively studied fields over the past 50 years. In particular, squamous (flat-cell) non-small cell lung cancer was long considered a group with few treatment options, both because of its strong link to smoking and because it is not easily targeted by targeted drugs. In the early 2000s, there was no effective option beyond chemotherapy; treatments at the time could delay the disease by only a few months.

In the 2010s, immunotherapies began changing this picture. By reactivating the immune system, PD-1 inhibitors produced responses lasting years in some patients. However, this success was more evident in the subtype called adenocarcinoma ; response rates in the squamous type were low and treatment duration was short.

Now a new drug enters the scene: ivonescimab. This molecule combines immune-system-targeting PD-1 blockade with simultaneous suppression of tumor blood vessel growth through VEGF inhibition as a dual-targeted (bispecific) antibody. In other words, the tumor is both freed from “immune suppression” and deprived of its “feeding vessels.” This approach offers the potential for a deeper, more durable response.

At the 2025 meeting in Berlin of the ESMO Congress, the presented HARMONi-6 Phase 3 trial showed that this new drug provided, in squamous lung cancer, a significant survival advantage for the first time . This result was seen as an important development by both the scientific community and patients.

Design of the HARMONi-6 Trial

HARMONi-6, conducted in advanced squamous non-small cell lung cancer, evaluated first-line treatment with ivonescimab in a Phase 3, multicenter, randomized clinical trial.

A total of 532 patients were enrolled and randomly assigned to two arms:

• Experimental arm: Ivonescimab (PD-1 + VEGF-targeted bispecific antibody) + platinum-based chemotherapy
• Control arm: Tislelizumab (PD-1 inhibitor) + the same chemotherapy protocol

Patients began treatment at the initially diagnosed metastatic stage and were followed until disease progression or treatment discontinuation due to side effects. The trial’s primary endpoint was progression-free survival (PFS), meaning the time without disease growth. Secondary endpoints included overall survival (OS), response rate (ORR) and safety profile assessments.

Median follow-up was approximately 10 months . The trial was conducted only at centers in China , but to confirm global efficacy and safety data, the international HARMONi-3 and HARMONi-7 trials are already ongoing.

📊 Main Findings: An Approximately 4-Month PFS Gain

Ivonescimab + chemotherapy, compared with tislelizumab + chemotherapy , significantly prolonged progression-free survival (PFS) :

• Median PFS: 11.14 months (ivonescimab) vs 6.90 months (tislelizumab)
• HR: 0.60 (95% CI: 0.46–0.78; p<0.0001)
• Median follow-up: 10.28 months

This difference means an approximately 4-month gain in time before progression . Moreover, efficacy was clearly maintained not only in patients with high PD-L1 expression, but also at low PD-L1 levels.

Subgroup Analyses by PD-L1 Expression

Ivonescimab’s benefit was observed regardless of PD-L1 level:

In particular, PD-L1-negative (<1%) patients also achieved a significant PFS gain, supporting ivonescimab’s potential to reprogram the immune microenvironment through VEGF blockade.

🩸 Safety: A Low Bleeding Risk Stands Out

Grade ≥3 treatment-related adverse events occurred in 63.9% of the ivonescimab arm and 54.3% of the tislelizumab arm. However, grade ≥3 hemorrhage occurred in only 1.9%.

Compared with the historically high bleeding risk seen with the anti-VEGF agent bevacizumab in squamous histology, this rate is surprisingly low.

20 years ago, anti-VEGF use in this histology had become almost taboo; HARMONi-6 results challenge that paradigm.

🌍 Global Impact and Ongoing Trials

HARMONi-6 was conducted only in China. However, global phase 3 trials (HARMONi-3 and HARMONi-7) are already ongoing, testing ivonescimab’s efficacy against pembrolizumab at different PD-L1 levels.

These trials will show whether the results generalize to global patient populations. If an overall survival (OS) benefit is also confirmed, ivonescimab could usher in a new era in lung cancer treatment .

DROZDOGAN Academy Commentary

• Dual-targeted immunomodulation (PD-1 + VEGF) may represent a real step toward reshaping the immunosuppressive tumor microenvironment.
• The finding of PD-L1-independent efficacy may push the boundaries of conventional monospecific immunotherapies.
• Bleeding safety data offer new hope to the squamous NSCLC population that has long been excluded.
• Although OS data remain immature , the striking superiority in PFS data suggests that this combination may soon become standard treatment.
• However, without OS data, we must remember that these results will not immediately translate into clinical practice.