Akeso's Ivonescimab Trial Results Shake PD-(L)1xVEGF Bispecific Landscape

In a development that has sent ripples through the pharmaceutical industry, Akeso's recent trial results for its bispecific antibody ivonescimab have prompted a reassessment of expectations in the PD-(L)1xVEGF space. The unplanned overall survival (OS) analysis from the phase 3 HARMONi-2 trial has not only impacted Akeso's market position but also affected other players in the bispecific antibody arena.

HARMONi-2 Trial Results and Market Reaction

The HARMONi-2 trial, which pitted ivonescimab against Merck & Co.'s Keytruda in first-line PD-L1-positive non-small cell lung cancer (NSCLC) patients, showed a 22.3% reduction in the risk of death. However, this result did not reach statistical significance, leading to a significant market reaction. Akeso's partner, Summit Therapeutics, saw its stock price plummet by approximately 36% on April 25, while BioNTech, another company working on a PD-L1xVEGF bispecific, experienced a 15% drop in share price. Akeso's own stock in Hong Kong declined by about 12% on April 28.

Dr. Michelle Xia, CEO of Akeso, addressed the market's interpretation of the data during a Chinese investor call, stating that it had "deviated from the core of the issue." She emphasized that the primary goal of HARMONi-2 was to secure approval in China for first-line PD-L1-positive NSCLC patients, which the company achieved. The trial was designed with progression-free survival (PFS) as the primary endpoint, following consultations with Chinese regulators.

Global Implications and Future Prospects

Despite the market's initial reaction, analysts remain cautiously optimistic about ivonescimab's potential. Leerink Partners analyst Daina Graybosch noted that HARMONi-2's relatively small sample size of 398 patients might have contributed to its lower power to demonstrate statistical significance compared to larger studies in first-line NSCLC.

Attention has now shifted to Summit Therapeutics' HARMONi-7, a global phase 3 trial that will again compare ivonescimab to Keytruda in PD-L1-high NSCLC patients. With a planned enrollment of about 780 patients and both PFS and OS as primary endpoints, HARMONi-7 is expected to be better powered to demonstrate efficacy. Citi analyst Yigal Nochomovitz suggested that a similar 22.3% reduction in death risk would likely meet the overall survival endpoint in this larger trial.

Dr. Xia expressed confidence in the potential success of HARMONi-7, stating, "Based on the current HARMONi-2 data, we are very confident that our collaborator will be successful with HARMONi-7. That's our hypothesis and logic and goal."

Clinical Significance and Industry Impact

Despite not reaching statistical significance, the 22.3% survival improvement observed in HARMONi-2 is considered clinically meaningful by many oncologists. Analysts drew comparisons to Bristol Myers Squibb's Opdualag, which became a standard-of-care therapy in first-line melanoma after demonstrating a 20% patient survival improvement over Opdivo.

As the industry awaits more detailed data from the HARMONi-2 trial, expected to be presented at an upcoming medical meeting, the focus remains on the absolute OS delta between ivonescimab and Keytruda. This information, along with the results of the HARMONi-7 trial, will likely play a crucial role in determining the future of PD-(L)1xVEGF bispecific antibodies in cancer treatment.