About two years ago, a head-to-head progression-free survival win made Akeso and Summit Therapeutics’ ivonescimab—and the PD-1xVEGF class—the most promising agent to replace Keytruda as the new cancer immunotherapy king. Now, that same trial has met its overall survival endpoint, but to a far more measured reception.
The Harmoni-2 trial in Chinese patients with first-line PD-L1-positive non-small cell lung cancer has shown a statistically significant and clinically meaningful overall survival improvement for ivonescimab over Merck & Co.’s Keytruda, Akeso and Summit announced Wednesday.
Unlike the shock that spread across the oncology world when the then little-known Chinese biotech telegraphed the trial’s PFS win in May 2024, Akeso’s stock price rose just 3.4% in Hong Kong Thursday.
Harmoni-2 is now the fourth phase 3 trial for ivonescimab to meet its OS endpoint. Yet as expectations have ballooned, so has debate over whether the first-in-class PD-1xVEGF drug, so far proven entirely in China, can succeed on a global stage.
That debate likely will not rest until Summit reads out the global Harmoni-3 trial, with its final PFS results expected this year. But “at a certain point you have to ask if the market has an appropriate [probability of success] for ivo’s global development program,” Evercore ISI analysts wrote in a Thursday note.
Meeting OS in the Keytruda head-to-head trial supports “the broader narrative that ivo is outperforming PD1/Keytruda in multiple settings,” Citi analysts said in a Wednesday note.
Ivonescimab’s quest to dethrone Keytruda has proven anything but smooth sailing.
After an initial excitement that came with Harmoni-2’s PFS win, questions started to swirl around whether it can translate into an OS benefit. Past explorations of PD-1 plus VEGF inhibitions using separate drugs have produced some positive PFS signals but struggled to offer life extension benefits.
Last year, an unplanned interim analysis requested by Chinese authorities linked ivonescimab to a preliminary 22.3% death risk reduction versus Keytruda in Harmoni-2. The revelation in April 2025 led to a bloodbath in Summit’s stock price as investors were concerned over the size of the early benefit. At the time, Akeso CEO Michelle Xia, Ph.D., noted that the trial was not designed for OS, which is only a secondary endpoint.
Following Wednesday’s announcement, analysts again started crunching the numbers, albeit with limited information on Akeso’s statistical analysis plan.
Based on the previous OS reported at 39% data maturity and a very high statistical bar, Citi analysts figured the latest readout “likely” involves an OS benefit stronger than 30%.
Evercore analysts suspected that the magnitude could be nearing 30% or even better, calling the fact that Harmoni-2 met OS at another interim analysis—instead of the final analysis—an “important nugget.”
For his part, Jefferies analyst Faisal Khurshid figured OS “likely didn’t worsen by much (if at all)” across multiple scenarios.
Detailed data will be presented at the World Conference on Lung Cancer, which will take place in Seoul from Sept. 12 to 15. The results may not hold much practical significance for clinicians except for the PD-L1-high subgroup because Keytruda plus chemo—rather than Keytruda alone—is the standard of care for the rest of first-line NSCLC populations.
Summit’s global Harmoni-3 trial is evaluating ivonescimab combined with chemo against Keytruda plus chemo. The company has been under a lot of pressure after the squamous cohort surprisingly missed statistical significance on PFS during a rushed PFS interim analysis.
That study’s Chinese counterpart trial, Harmoni-6, showed both a PFS and OS benefit for ivonescimab-chemo over BeOne Medicines’ PD-1 inhibitor Tevimbra plus chemo. However, a deteriorating PFS benefit in a longer follow-up again made Summit investors nervous.
On the bright side, the global phase 3 Harmoni trial for ivonescimab in previously treated EGFR-mutated NSCLC showed improved OS data in the Western subgroup with longer follow-up, even though the trial had already missed OS in the overall population no thanks to immature Western data. Summit is gunning for a first U.S. approval for ivonescimab based on those results, with a PDUFA date of November 14.
The drug was first approved in China in 2024 for certain non-small cell lung cancer patients.
Last week, in ivonescimab’s first phase 3 win beyond lung cancer, Akeso reported that the bispecific, used alongside chemo, beat AstraZeneca’s Imfinzi and chemo in first-line biliary tract cancer in the Chinese Harmoni-GI1 trial.