Akeso, Summit's PD-1 bispecific outperforms Merck's Keytruda in lung cancer study

Akeso and Summit Therapeutics have revealed promising results for their PD-1/VEGF bispecific antibody, ivonescimab, in the treatment of first-line non-small cell lung cancer (NSCLC). The Phase 3 HARMONi-2 trial, conducted exclusively in China, demonstrated that ivonescimab significantly outperformed Merck’s Keytruda in delaying disease progression or death in patients with PD-L1-positive NSCLC. The findings were presented at the 2024 World Conference on Lung Cancer (WCLC) and suggest ivonescimab could become a new standard of care in this patient population.

The HARMONi-2 study showed that ivonescimab reduced the risk of disease progression or death by 49% compared to Keytruda, a statistically significant result. Ivonescimab extended the median progression-free survival (PFS) to 11.14 months, which is 5.32 months longer than the median PFS for Keytruda. This benefit was consistent across various subgroups, including patients with squamous and nonsquamous histology, high and low PD-L1 expression, brain metastases, and different smoking statuses.

Caicun Zhou, Ph.D., who presented the data at WCLC, highlighted ivonescimab's potential as a new standard of care in first-line PD-L1-positive NSCLC. The dual targeting strategy of PD-1 and VEGF pathways is not entirely novel; Roche’s Tecentriq, for instance, is approved in combination with Avastin and chemotherapy for nonsquamous NSCLC. However, Avastin is not suitable for squamous patients due to bleeding risks. Ivonescimab seemed to avoid this issue, with hemorrhages occurring in 14.7% of patients in the ivonescimab arm, compared to 11.1% in the Keytruda arm.

Bing Wang, Ph.D., Akeso’s CFO, attributes ivonescimab’s safety profile to its unique mechanism. The PD-1 component helps attach the antibody to the tumor surface, while the VEGF inhibition is more targeted, reducing the likelihood of bleeding. Akeso’s Tetrabody technology, which creates antibodies with four antigen-binding sites, also contributes to its stability and binding specificity.

Ivonescimab did show higher rates of VEGF-related adverse events such as proteinuria and hypertension, but these were manageable and did not lead to treatment discontinuations. In squamous patients, serious treatment-related adverse events were almost equal between ivonescimab (18.9%) and Keytruda (18.7%).

Despite the promising results, the trial's China-only scope means it may not suffice for FDA approval, which typically requires global studies. Nevertheless, Akeso remains confident that the trial’s findings can be replicated in a global phase 3 study. They plan to start an international trial, HARMONi-3, comparing ivonescimab and chemotherapy against Keytruda and chemotherapy in first-line squamous NSCLC.

Keytruda has set a high bar with its combination therapies, especially for patients with low or no PD-L1 expression. However, ivonescimab’s PFS of 11.14 months is comparable to the 11.1 months achieved by Keytruda and chemotherapy in PD-L1-high nonsquamous patients from the KEYNOTE-189 trial. Such cross-trial comparisons should be interpreted cautiously due to differences in patient populations and characteristics.

The HARMONi-2 study has yet to report overall survival (OS) data, which remains crucial for gaining broader acceptance. Analysts from Citi believe a PFS improvement above 30% in NSCLC trials often translates to a statistically significant OS benefit. Ivonescimab’s 49% reduction in progression or death risk offers strong encouragement for its potential OS benefits.

Ivonescimab has already received approval in China for use with chemotherapy in previously treated EGFR-mutant NSCLC, based on positive data from the HARMONi-A trial. Summit Therapeutics, which has rights to ivonescimab in several key markets, plans to add further studies to bolster the drug's profile.

Bob Duggan, Summit’s executive chairman, expressed optimism about ivonescimab’s future, emphasizing the company's commitment to advancing the drug without needing external partners or additional funding.

In conclusion, Akeso and Summit’s ivonescimab has shown substantial promise in outpacing Keytruda in first-line PD-L1-positive NSCLC, potentially reshaping the treatment landscape. The ongoing and future global trials will be pivotal in determining its wider acceptance and regulatory approval.

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