Ivonescimab Looking to Rival Merck’s Keytruda in NSCLC with Phase III Trial Enrollment Complete

Summit Therapeutics Inc. has announced completion of enrollment for its HARMONi clinical trial evaluating ivonescimab in combination with platinum-doublet chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated, locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) who have progressed after treatment with a third-generation EGFR tyrosine kinase inhibitor (TKI).

Summit said the multi-regional Phase III study successfully enrolled patients from sites across North America, Europe and China. The study, which is the first global study for ivonescimab, targets a patient population where previous Phase III global clinical trials using PD-1 monoclonal antibodies have not been successful. This subset of patients has generally shown poor responses to PD-1 antibodies.

At the same time, the biopharmaceutical oncology company also announced that it received Fast Track designation for ivonescimab in its proposed treatment setting from the US Food and Drug Administration (FDA).

The Fast Track designation provides an expedited review process that could lead to faster approval and access to a therapy.

Summit is looking to give Merck’s Keytruda some competition as it aims to position ivonescimab as a new standard of care in NSCLC. The company is planning to explore this in its global Phase III HARMONi-7 trial where ivonescimab will go head-to-head against Keytruda in patients with first-line metastatic NSCLC whose tumors have high PD-L1 (programmed cell death ligand 1) expression.

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Ivonescimab is a PD-1/VEGF (programmed cell death protein 1/vascular endothelial growth factor) bispecific antibody being developed by Summit. The company says more than 1,800 people have been treated with the antibody across all clinical trials to date.

Summit posits that the simultaneous blockade of PD-1 and VEGF could “drive synergistic anti-tumor activity.” Specifically, inhibition of VEGF can help improve the effect of immunotherapy by modulating the tumor microenvironment (TME) while bolstering PD-1 blockade helps activate T cells.

“Completing enrollment in the HARMONi study represents another step towards our goal of bringing to patients a drug that is intended to improve the quality and potential duration of life for those facing serious unmet medical needs,” stated Robert W. Duggan, chairman and CEO of Summit, in the company’s news release. “As our belief in the potential for ivonescimab to make a meaningful, positive difference continues to grow, we are pleased that the FDA has granted Fast Track designation for ivonescimab.”

Summit’s single-region trial of the therapy, HARMONi-A, was sponsored by the company’s collaboration partner, China-based Akeso, which generated and analyzed data for the trial.

In the HARMONi-2 Phase III study conducted only in China, results shared in September showed that ivonescimab cut the risk of disease progression or death by an impressive 49 percent compared with Keytruda in patients previously untreated, PD-L1-positive NSCLC.

Compared to Keytruda, ivonescimab extended the median progression-free survival by 5.32 months, bringing the total to 11.14 months.

Akeso’s positive trial results are fueling a positive outlook for Summit and its global Phase III HARMONi-7 trial of ivonescimab versus Keytruda in the first-line setting.

On May 24, 2024, Akeso received marketing authorization in China from the National Medical Products Administration (NMPA) based on positive results from the HARMONi-A study.

The HARMONi-A trial was designed with a primary endpoint of progression-free survival whereas the HARMONi trial also includes overall survival as a primary endpoint. Summit said the HARMONi analysis will include all patients from the HARMONi-A trial who previously received a third-generation TKI.

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The concept of dual targeting PD-1/L1 and tumor vasculature is not new. Roche’s PD-L1 inhibitor Tecentriq (atezolizumab) is already approved for use alongside its VEGF inhibitor Avastin (bevacizumab) and chemotherapy for first-line treatment of non-squamous NSCLC. However, Avastin is contraindicated in patients with squamous NSCLC due to the risk of lung bleeding, known as hemoptysis.

Ivonescimab did not appear to have the same issue in the HARMONi-2 trial in which hemorrhages were reported in 14.7 percent of patients in the ivonescimab group, with once percent experiencing grade 3 hemorrhage and no more severe cases. In comparison, the rates in the Keytruda group were 11.1 percent for hemorrhages and 0.5 percent for grade 3 cases. Notably, the grade 3 hemorrhage incidents with ivonescimab occurred in non-squamous NSCLC patients.

In an interview with Fierce Pharma, Akeso’s chief financial officer, Bing Wang, PhD, attributed ivonescimab’s ability to two main factors. The first is that anchorage of the antibody to the surface of the tumor via PD-1 would target VEGF to the TME whereas a VEGF drug alone circulates freely in the bloodstream. Second, Akeso’s proprietary Tetrabody technology, which produces antibodies with four antigen-binding sites, creates a stable structure that enables “collaborative binding,” improving the binding specificity of both PD-1 and VEGF.

Topline data from the global HARMONi trial is expected sometime in the middle of 2025.

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