A New Drug on the Lung Cancer Scene: Ivonescimab Shows Impressive Results Against Keytruda

Is a new turning point approaching in lung cancer treatment? The eagerly awaited data on ivonescimab, developed by Akeso Biopharma and Summit Therapeutics, have finally emerged. The PD-1/VEGF bispecific antibody has the potential to become a new standard treatment for non-small cell lung cancer (NSCLC). Results from the HARMONi-2 study in China are particularly striking.

Ivonescimab’s Impressive Data

Ivonescimab reduced the risk of disease progression or death by 49% compared with Merck’s immunotherapy Keytruda as monotherapy. This result, obtained in PD-L1-positive NSCLC patients in HARMONi-2, was presented at the 2024 World Conference on Lung Cancer. The data show how effective ivonescimab is in preventing disease progression.

Ivonescimab also extended the time patients lived without tumor progression by 5.32 months, bringing median progression-free survival to 11.1 months. This is a substantial difference from Keytruda’s progression-free survival of 5.8 months.

How Does Ivonescimab Work?

A PD-1/VEGF bispecific antibody is designed to help the immune system act more effectively against cancer cells. Bispecific antibodies can bind to two different targets simultaneously. In this case, the two important molecules targeted are PD-1 and VEGF:

1. PD-1: a molecule that prevents immune cells, particularly T cells, from attacking cancer cells. Blocking PD-1 can trigger the immune system to attack them.

2. VEGF: a molecule that promotes new blood vessel formation (angiogenesis), supporting cancer cell growth. Blocking VEGF prevents cancer cells from obtaining nutrients and growing.

The HARMONi-2 Study Design

HARMONi-2 was a clinical study conducted in China. This was its study setting.

It tested the bispecific antibody ivonescimab against Keytruda, an immunotherapy containing pembrolizumab. It specifically included previously untreated, PD-L1-positive patients.

The study’s main features were:

• Patient Population: patients with PD-L1-positive NSCLC were included. Participants had varying PD-L1 levels, including high TPS scores of 50% or above and lower PD-L1 levels. Subgroups included people who had smoked, never-smokers, and patients with brain metastases.

• Treatment Arms: patients were divided into two groups, one receiving ivonescimab and the other Keytruda. Key outcomes, such as progression-free survival (PFS) and overall survival (OS), were compared between the groups.

• Primary Objective: the main aim was to assess ivonescimab’s effect, compared with Keytruda, on patients’ time alive without tumor progression (progression-free survival, PFS). This was the treatment outcome evaluated.

• Safety Assessment: treatment-related adverse effects, particularly those associated with VEGF inhibition, such as bleeding risk, were an important focus.

A Dual-Targeting Strategy

Ivonescimab targets PD-1 and VEGF simultaneously. This strategy is not entirely new. For example, Roche’s PD-L1 inhibitor Tecentriq is used with Altuzan, containing the VEGF inhibitor bevacizumab, to treat NSCLC. Altuzan is not preferred in squamous cell lung cancer because of pulmonary bleeding risk. Ivonescimab, however, does not face this problem. Bleeding occurred in 14.7% of patients receiving ivonescimab versus 11.1% receiving Keytruda, but serious cases were very rare.

Compared with Keytruda, Ivonescimab Improved Progression-Free Survival in These Subgroups:

• Squamous NSCLC: 50% improvement
• Nonsquamous NSCLC: 45% improvement
• High PD-L1 (TPS score 50% or above): 52% improvement
• Low PD-L1 (≥1% – <50%): 46% improvement
• Patients with brain metastases: 45% improvement
• Never-smokers: 61% improvement
• Current smokers: 49% improvement
• Former smokers: 43% improvement

Safety and Adverse Effects

Some VEGF-related adverse effects occurred with ivonescimab. Proteinuria occurred in 31.5% and hypertension in 15.7%, compared with 10.5% and 2.5%, respectively, with Keytruda. None exceeded grade 3 or caused treatment discontinuation. Serious adverse effects occurred in 18.9% of squamous NSCLC patients receiving ivonescimab versus 18.7% with Keytruda. Treatment-related mortality was 0.5% with ivonescimab and 1% with Keytruda.

What Is Expected Globally?

An important step is needed for global acceptance of ivonescimab. Because HARMONi-2 was conducted only in China, its results may not suffice for approval by the FDA (US Food and Drug Administration) or other major regulators. A global phase 3 study is planned. Its results will determine whether ivonescimab becomes a new worldwide standard.

Commentary

Ivonescimab’s median progression-free survival (11.14 months) is similar to results from studies in high-PD-L1 nonsquamous NSCLC using Keytruda plus chemotherapy, which achieved 11.1 months. However, differences between study populations mean such comparisons require caution. For example, a Japanese subgroup analysis found progression-free survival of 16.5 months with Keytruda plus chemotherapy.

Ivonescimab’s overall survival data are not yet mature and are still being collected. Keytruda previously increased median survival in KEYNOTE-042, its earlier study, to 16.7 months. Overall survival results are therefore considered critical for ivonescimab to receive FDA approval.

Conclusion: Ivonescimab’s Future

Ivonescimab has significant potential in non-small cell lung cancer treatment. HARMONi-2 results suggest promise in delaying progression and extending life in PD-L1-positive NSCLC. However, more data and studies are needed for global acceptance and FDA approval. Akeso and Summit believe ivonescimab is rapidly progressing toward becoming a “next-generation immunotherapy”.