The story of Ivonescimab began with two core pathways in cancer therapy: immune checkpoint inhibitors and anti-vascular endothelial growth factor (VEGF) agents.

In 2018, as overseas products like Keytruda entered the Chinese market and domestic innovations launched, the PD-1 monoclonal antibody (mAb) race gained intense attention. Nevertheless, attempts to combine PD-1 and VEGF were already in the works.

As Akeso Biopharma's second PD-1-based bispecific antibody, Ivonescimab submitted its first Investigational New Drug (IND) application in China in 2020. At that time, Roche's combination therapy of the PD-L1 antibody Atezolizumab and the VEGF antibody Bevacizumab had doubled the survival benefit in first-line liver cancer and subsequently gained approvals in renal cell carcinoma and NSCLC.

The potential demonstrated by Ivonescimab's preclinical results proved Akeso was not merely following the crowd.

Based on its unique tetravalent structure, Ivonescimab binds PD-1 and VEGF synergistically, forming a more stable "cluster" complex, which significantly enhances the candidate therapy's binding affinity for both targets.

Specifically, the presence of VEGF increases Ivonescimab's binding affinity for PD-1 by over 18-fold, greatly boosting its blockade of the PD-1/PD-L1 signaling pathway. Conversely, the presence of PD-1 also enhances Ivonescimab's binding affinity for VEGF by more than 4-fold, strengthening its inhibition of the VEGFR signaling pathway.

During the 2021 ASCO and CSCO conferences, Akeso Biopharma released positive preliminary Phase I and Phase II clinical data for Ivonescimab, respectively.

A year later, based on updated Phase II data for Ivonescimab combined with chemotherapy in advanced NSCLC, and Ib/II data as monotherapy in advanced NSCLC, Ivonescimab became the only innovative drug in China to receive three Breakthrough Therapy Designations (BTDs) in lung cancer, and the only one to receive a BTD for the treatment of PD-(L)1-resistant lung cancer.

Akeso's progress ultimately led to a landmark licensing deal. In 2022, Summit Therapeutics announced it had acquired the overseas rights to Ivonescimab for a $500 million upfront payment and a total potential deal value of up to $5 billion, setting a new record for Chinese innovative drugs going global at the time.

This collaboration gave Ivonescimab its passport to the global market, and the next turning point soon emerged.

In 2024, at the WCLC conference, Akeso announced the results of the HARMONi-2 study: in the first-line treatment of PD-L1-positive NSCLC patients, Ivonescimab monotherapy extended median PFS from 5.82 months with Keytruda to 11.14 months, reducing the risk of disease progression or death by 49%.

This was the world's first PD-1/VEGF bispecific antibody to defeat Keytruda in a head-to-head Phase III trial. The room erupted in applause, marking the first time a Chinese innovative drug demonstrated the ability to surpass the "King of Drugs" in lung cancer.

The day after the data release, Akeso Biopharma's stock price surged by 15.77%, and market expectations for the drug quickly escalated.

The NMPA approved Ivonescimab in 2024. However, in May 2025, updated global Phase III data from Summit showed a significant PFS advantage, but OS data had not yet fully met the pre-specified statistical threshold, causing caution in overseas markets.

In a 2025 draft guidance on the evaluation of OS in cancer clinical trials, the FDA explicitly stated that OS should be the primary endpoint when feasible. This changing regulatory landscape subjected Ivonescimab to more stringent approval standards.

Faced with the challenge, Summit and Akeso did not back down. At the WCLC conference in September of the same year, updated results from the HARMONi study were disclosed: after the median follow-up was extended to 13.7 months, data maturity in Western patients improved, and the OS hazard ratio narrowed to 0.78.

While still not meeting the study's pre-specified statistical significance threshold, the trend continued to be positive. More importantly, the Chinese patient subgroup demonstrated a statistically significant OS benefit.

In the fourth quarter of 2025, Summit formally submitted the BLA for Ivonescimab to the FDA.

Although Ivonescimab has not yet received FDA approval, its years of development experience, particularly its success in the head-to-head trial, has been like a stone thrown into a lake, creating ripples that include a wave of asset transactions.

It is no exaggeration to say that Ivonescimab single-handedly directed the gaze of multinational pharmaceutical companies toward China, sparking a buying spree for PD-(L)1/VEGF bispecific assets.

In November 2024, Merck & Co. in-licensed LM-299, a PD-1/VEGF bispecific antibody from Lumicure, for a potential total value of up to $3.288 billion. Just six months later, the technology transfer for LM-299 was completed, triggering a $300 million payment, marking the first major milestone achieved under the agreement.

Around the same time, building on a licensing collaboration, BioNTech acquired Promisome Biologics outright for an $800 million upfront payment plus up to an additional $150 million in milestones, gaining full rights to its PD-L1/VEGF bispecific asset.

Entering 2025, the momentum continued to build. In May, Pfizer in-licensed a PD-1/VEGF bispecific asset from 3SBio Inc. for a rare $1.25 billion upfront payment, plus $4.8 billion in milestones and double-digit royalties, reigniting the sector.

A month later, BioNTech was back in the spotlight: Bristol Myers Squibb (BMS) struck a deal with it to co-develop BNT327, a PD-L1/VEGF bispecific originating from Promisome.

Notably, BioNTech had acquired Promisome for a total consideration of just up to $950 million. In just over six months, this investment had increased more than tenfold—the total value of BioNTech's licensing deal with BMS reached a staggering $11.1 billion.

The latest blockbuster transaction came from Rongchang Biologics and AbbVie.

In January, the two companies signed an exclusive licensing agreement for RC148, a PD-1/VEGF bispecific, with a $650 million upfront payment and a total potential deal value of up to $5.6 billion. Both the upfront payment and the potential maximum transaction value set new records for Rongchang Biologics' out-licensing.

The day after the announcement, Rongchang Biologics' stock price jumped over 13%, ultimately closing with a 20% gain, a clear sign of the market's unwavering enthusiasm for PD-(L)1/VEGF bispecifics.

BMS CEO Chris Boerner was blunt: "Competition in PD-(L)1/VEGF bispecifics will be extremely fierce. We don't want to be number four, because market share will be taken by the first or second place."

According to incomplete statistics from Sleuth Insights, as of March 2025, there were 35 PD-(L)1/VEGF bispecifics in global development, with 20 in China. An analysis by Bloomberg showed that, as of October 2025, approximately 104 clinical trials for PD-(L)1/VEGF bispecifics were ongoing or planned, expected to involve more than 27,000 cancer patients.

Behind this trading frenzy lies multinational pharma's anxiety over the "patent cliff" and an urgent need for the next generation of cancer therapies.

Take Merck's Keytruda, for example. As the world's best-selling oncology drug, it generated nearly $30 billion in sales in 2024, but its patent expires in 2028. This predicament is not unique to Merck. In the coming years, pharmaceutical companies worldwide will face the expiration of drug patents worth approximately $300 billion.

Major pharma firms are desperate to find new therapies that can replace or complement blockbuster products like PD-1 mAbs, and PD-(L)1/VEGF bispecifics are considered one of the most promising candidates.

In other words, existing players in the PD-(L)1 space may not only seek bispecifics to solidify their positions; conversely, players chasing checkpoint inhibitors hope to use these next-generation antibody assets to make up for missed PD-1 opportunities, and potentially even surpass PD-1 leaders like Merck.

Therefore, the narrative around PD-(L)1/VEGF bispecifics is far from over in the foreseeable 2026.

Shortly before the BMS-BioNTech deal was announced, Jake Van Naarden, President of Lilly Oncology, speaking at the ASCO conference, revealed that given the "exciting" data for PD-(L)1/VEGF bispecifics, it made sense for Lilly to have its own. At this stage, the giant had more resources than ever to in-license such drugs and advance their clinical development.

For another major pharma, Novartis, PD-(L)1/VEGF is clearly on the rise.

Following the disclosure of Pfizer's collaboration with 3SBio, Shreeram Aradhye, Novartis' President of Development and Chief Medical Officer, stated, "This is clearly an area we will carefully evaluate and consider all options."

According to him, PD-(L)1/VEGF bispecifics could bring a range of opportunities for Novartis, even beyond the company's internal research into radiopharmaceutical therapies, with Novartis viewing the field as a "potential hedge."

Now, as Ivonescimab enters the final countdown to the FDA's decision, the entire PD-(L)1/VEGF bispecific sector stands at a crossroads.

In a September 2025 report, analysts at Truist Securities noted: "The regulatory path for Ivonescimab in EGFR-mutant lung cancer is uncertain and dependent on FDA leniency."

Indeed, some domestic industry insiders have expressed concerns to Tongxieyi.

For instance, some analysts believe the FDA has tightened its policies, emphasizing OS as the gold standard for clinical benefit. Judging from Summit's final results, the OS data did not show a significant difference, making approval a difficult task.

Summit's trial design appears to have flaws. Experts with clinical backgrounds suggest that due to the small number of Western patients enrolled, Ivonescimab's chance of approval is less than 50%.

However, a domestic reviewer with a statistics background told Tongxieyi that the short enrollment period for Western patients in the HARMONi study led to shorter follow-up times. It is possible that when the required number of events was reached, Ivonescimab's efficacy had not yet fully manifested, thereby diluting the final benefit and leading to a negative result.

In other words, Ivonescimab's true efficacy is still worth anticipating.

Among the respondents contacted by Tongxieyi, there were many with a positive attitude. Looking at precedents, numerous therapies approved for EGFR indications in Europe and the U.S. were based on strong PFS results. By this analysis, Ivonescimab's overseas launch is not impossible.

"Statistical significance in OS is less important than the clinical improvement it brings," a clinical expert told Tongxieyi. An OS hazard ratio between 0.75 and 0.80 already indicates a beneficial drug.

From this, a broader controversy emerges: What is the true value of PD-(L)1/VEGF bispecifics?

Bloomberg Intelligence analysts point out that the industry is trying to build something new with the same Lego bricks; this is not disruptive innovation. Therefore, it remains to be seen whether these PD-(L)1/VEGF bispecifics can truly achieve different effects that previous monotherapies could not.

However, an industry insider who witnessed BioNTech's acquisition of Promisome directs attention to a new angle. In their view, the game is "not about PD-(L)1/VEGF being better than Keytruda, but about PD-(L)1/VEGF combined with ADCs being better than the SOC combination of Keytruda and chemotherapy." Whether the effect comes from the bispecific or the ADC is less important.

Akeso Biopharma has clearly stated that it is internally developing ADC products and also intends to collaborate with other ADC companies. The company's goal is to build a "next-generation cornerstone IO drug."

It is reported that Akeso has conducted multiple combination studies, including its PD-1/CTLA-4 bispecific Cadonilimab and CD47 antibody Ligufaliumab, which have shown impressive data across different indications.

New entrant Pfizer is highly confident in the prospects of PD-(L)1/VEGF bispecifics.

In November 2025, after in-licensing the asset from 3SBio, the giant announced it would initiate seven clinical trials involving over 2,000 patients, with plans to start another 10 studies in 2026. Improving OS will be its primary goal.

Moving forward, as more clinical data accumulates and the regulatory path is clarified by Ivonescimab being the first to "cross the finish line," the PD-(L)1/VEGF bispecific sector will undergo a major reshuffle.

If Ivonescimab is approved, it will set a new benchmark for Chinese innovative drugs going global and likely trigger a rapid follow-up development of more similar products. However, those who ultimately stand out will be players who possess not only scientific innovation but also clinical value, execution efficiency, and strategic patience.