As an unplanned overall survival (OS) analysis of ivonescimab’s Keytruda head-to-head trial rocked the PD-(L)1xVEGF world, Akeso CEO Michelle Xia, Ph.D., figured it’s high time the company recalibrated investors’ expectations.
The market’s interpretation of the initial OS data from the phase 3 HARMONi-2 trial has “deviated from the core of the issue,” Xia said during a Chinese investor call Monday.
During an unplanned interim analysis of HARMONi-2, ivonescimab reduced the risk of death by 22.3% versus Merck & Co.'s blockbuster cancer treatment Keytruda among Chinese patients with first-line PD-L1-positive non-small cell lung cancer, a showing that didn’t cross the statistical significance bar.
Even though the readout was not mature, disappointed investors sent Akeso partner Summit Therapeutics’ stock price plummeting by about 36% Friday April 25. German biopharma BioNTech, which is working on a PD-L1xVEGF bispecific, also saw its share price down by about 15% on Friday. Akeso’s own stock in Hong Kong dropped about 12% Monday, April 28.
The “core of the issue,” according to Xia, is that Akeso designed HARMONi-2 to win an approval in China specifically to benefit Chinese patients with first-line PD-L1-positive NSCLC. And the company achieved that.
The trial uses progression-free survival (PFS) as the primary endpoint following consultation with Chinese regulators, Xia said. Drug reviewers at China’s National Medical Products Administration requested to see an OS analysis before handing out an approval to make sure that patients benefited clinically, even though they knew that the study was not designed for OS, she added.
By stressing HARMONi-2’s purpose as a vehicle to win approval, Xia seems to be delivering a message that it wouldn’t be the end of the world for ivonescimab even if HARMONi-2 didn’t meet statistical significance on OS at the final analysis.
Xia directed investors’ attention to Summit Therapeutics’ HARMONi-7, a global phase 3 trial that’s again pitting ivonescimab head to head against Keytruda, albeit in a PD-L1-high population in first-line NSCLC.
As Leerink Partners analyst Daina Graybosch. Ph.D., pointed out in a Friday note, HARMONi-2 is a relatively small study with 398 patients. Therefore, it has lower power to demonstrate statistical significance than other head-to-head studies in first-line NSCLC, which typically had more than 500 patients.
Besides, it’s more difficult to demonstrate OS benefit in first-line settings when patients have access to effective later-line therapies, Graybosch noted.
By comparison, HARMONi-7 adopts both PFS and OS as primary endpoints.
With planned enrollment of about 780 patients, HARMONi-7 is well powered on OS and “would in all likelihood” meet the OS endpoint with a similar 22.3% death risk reduction, Citi analyst Yigal Nochomovitz, Ph.D., said in a Friday note.
Based on the current HARMONi-2 data, “we are very confident that our collaborator will be successful with HARMONi-7,” Xia said. “That’s our hypothesis and logic and goal.”
To both Graybosch and Nochomovitz, the 22.3% survival improvement is clinically meaningful to most oncologists. Graybosch raised the example of how Bristol Myers Squibb’s PD-1/LAG-3 combo of Opdualag became a standard-of-care therapy in first-line melanoma after showing a 20% patient survival improvement over active Opdivo control, BMS' older checkpoint inhibitor.
The two analysts each suggested that it would be important to examine the absolute OS delta between ivonescimab and Keytruda. This information is not available as Akeso plans to share its detailed analysis at an upcoming medical meeting.