On the evening of May 31, just ahead of its oral presentation at the ASCO Annual Meeting, Akeso released an announcement disclosing the highly anticipated results of its Phase III clinical trial HARMONi-6/AK112-306.

 

The combination of the PD-1/VEGF bispecific antibody ivonescimab plus chemotherapy demonstrated positive results compared to tislelizumab plus chemotherapy as first-line treatment for advanced squamous non-small cell lung cancer (sq-NSCLC), showing a 34% reduction in the risk of death and a median overall survival (OS) advantage of 4.2 months.

 

The study results will be formally presented during the Plenary Session of the ASCO Annual Meeting on June 1. This marks the first time in ASCO's 61-year history that an original Chinese innovative drug study has been selected for the Plenary Session. The findings are simultaneously published in The Lancet.

For Akeso and ivonescimab, this is a long-awaited moment in the spotlight.

 

Over the past year or so, this once-celebrated molecule, famous for its "head-to-head" victory over Keytruda, has experienced a bumpy journey – the OS data from its overseas Phase III study fell short of market expectations; substantial price reductions in national reimbursement negotiations compressed profit margins; competitors entered the field with heavy investment.

 

The industry moved from euphoria to sobriety, and then from sobriety to searching for the next certainty. The positive OS results from the HARMONi-6 study have arrived precisely at this critical juncture.

 

TONACEA 01: Reading Certain Value from Multi-Faceted Data

 

The HARMONi-6 study enrolled 532 patients, a sufficiently complex and representative population – approximately 63% had central-type squamous cell carcinoma, 39% had PD-L1-negative tumors, and about 33.8% had baseline liver metastases, brain metastases, or metastases at multiple sites.

 

What do these numbers mean? They mean the researchers did not select an "advantageous population" likely to yield easier data; they faced the real clinical dilemmas of advanced lung squamous cell carcinoma treatment. Under these conditions, ivonescimab plus chemotherapy delivered data worth scrutinizing.

 

As of February 27, 2026, with a median follow-up of 21.36 months, the ivonescimab group achieved a median OS of 27.9 months, compared to 23.7 months in the control group, with an HR of 0.66 and a P-value of 0.0017 – a 34% reduction in the risk of death.

 

Where does a median OS of 27.9 months stand in first-line lung cancer treatment?

 

In the era of targeted therapy, OS for EGFR-mutant patients can be measured in years. But for patients with driver-gene-negative advanced lung squamous cell carcinoma, crossing the two-year threshold is already progress. More importantly, the effect size (HR=0.66) exceeded the industry's general expectation of a 30% improvement threshold, with the P-value still having ample room from the prespecified boundary of 0.0049.

 

Looking at subgroups, the benefit was universal, with virtually no gaps.

 

The HR for the PD-L1 high-expression population was 0.64, and for the PD-L1-negative population it was also 0.64 – nearly identical. Patients with high tumor burden also showed significant benefit, with the HR in the subgroup with three or more metastatic sites as low as 0.47. This characteristic of universal coverage is rare in oncology therapeutics, meaning physicians do not need to spend much time筛选 patients – this regimen is highly likely to work.

 

Beyond OS, key secondary endpoints were also met: the HR for PFS was 0.60 (median PFS of 11.1 months versus 6.9 months in the control group), and the 24-month OS rate was 64.7% versus 48.6%. The gap in survival curves continued to widen with longer follow-up. On safety, discontinuation rates and mortality were similar between the two groups, and overall manageable.

 

Dr. Lu Shun, Principal Investigator of the HARMONi-6 study, Director of the Lung Cancer Clinical Medical Center at Shanghai Chest Hospital, and Tenured Professor, commented that ivonescimab fills a critical clinical gap where anti-angiogenic agents have been "unusable" in lung squamous cell carcinoma. Historically, bevacizumab has been routinely contraindicated in patients with lung squamous cell carcinoma due to bleeding risk. Ivonescimab, through its bispecific structure, achieves precise targeting, breaking this prohibition.

 

TONACEA 02: The Path of Ivonescimab – How Did It Reach the World?

 

Ivonescimab's story began with a scientific concept around 2018.

 

At the time, the combination of PD-1 inhibitors and VEGF inhibitors had been clinically attempted, but the toxicity and administration complexity of combination therapy limited its widespread use.

 

Akeso's scientists proposed a smarter approach: putting both targets on a single molecule. Ivonescimab features a unique tetravalent structure, synergistically binding PD-1 and VEGF to form stable "cluster" complexes. The presence of VEGF enhances the drug's affinity for PD-1 by more than 18-fold, while the presence of PD-1 enhances its affinity for VEGF by more than 4-fold – a biological positive feedback loop.

 

In December 2022, Akeso granted overseas rights to ivonescimab to Summit Therapeutics, with an upfront payment of US500 million and total deal value reaching up to US500millionandtotaldealvaluereachinguptoUS5 billion, setting a record at the time for out-licensing of a Chinese innovative drug.

 

In hindsight, this transaction was not just about setting a new number – it opened up a new realm of possibility: an original molecule from a Chinese pharmaceutical company could be entrusted with the mission of challenging the global "blockbuster king."

 

At the 2024 World Conference on Lung Cancer (WCLC), that possibility became reality.

 

In a "head-to-head" Phase III trial, ivonescimab monotherapy extended median progression-free survival (PFS) from 5.82 months (Keytruda) to 11.14 months, reducing the risk of disease progression or death by 49% – the first drug globally to demonstrate superiority over Keytruda in a head-to-head Phase III trial. The audience erupted in sustained applause.

 

The next day, Akeso's stock price jumped 15.77%, pushing market sentiment to a peak. In May of the same year, ivonescimab received its first approval in China for EGFR-TKI-resistant non-squamous NSCLC, becoming the world's first approved PD-1/VEGF bispecific antibody.

 

However, the applause was followed by more sober scrutiny.

 

In May 2025, Summit announced updated data from the global Phase III HARMONi study. Although PFS in the squamous NSCLC cohort was significantly improved, the OS data did not meet the prespecified statistical threshold. Coupled with FDA guidance issued that year explicitly recommending that OS should serve as the primary endpoint in clinical studies when feasible, market doubts about ivonescimab's global prospects emerged.

 

The shorter enrollment period for the Western cohort in the HARMONi study led to insufficient follow-up and low event numbers, diluting the treatment effect – but numbers themselves are cold. Summit's stock price suffered a sharp decline that day.

 

However, in January 2026, the FDA formally accepted the filing application for ivonescimab in EGFR-TKI-resistant NSCLC, setting a Prescription Drug User Fee Act (PDUFA) target action date of November 14, 2026. This marked the first time the FDA had accepted a filing application for a PD-1/VEGF bispecific antibody.

 

Today, the positive OS results from the HARMONi-6 study in the Chinese population represent the latest link in the clinical evidence chain for ivonescimab and add critical confidence to the FDA review – if it can so successfully meet the "head-to-head" challenge with an OS endpoint in a Chinese population, there is no reason not to expect similar performance in a Western population.

 

TONACEA 03: A Crowded but Yet-Unsettled "Golden Track"

 

The period from 2024 to 2026 can be called the "MNC buying spree" era for the PD-1/VEGF bispecific antibody track.

 

In November 2024, Merck & Co. licensed LM-299 (MK-2010) from LaNova Medicines with an upfront payment of US588 million and milestone payments of up to US588millionandmilestonepaymentsofuptoUS2.7 billion.

 

Soon after, in May 2025, Pfizer licensed SSGJ-707 from 3SBio with a record upfront payment of US1.25 billion and milestone payments of US1.25billionandmilestonepaymentsofUS4.8 billion. In July of the same year, BioNTech and BMS reached a US11.1 billion collaboration to co-develop BNT327 – this PD-L1/VEGF bispecific antibody originated from Biotheus. BioNTech had acquired Biotheus for a total consideration of no more than US11.1billioncollaborationtoco−developBNT327–thisPD−L1/VEGFbispecificantibodyoriginatedfromBiotheus.BioNTechhadacquiredBiotheusforatotalconsiderationofnomorethanUS950 million; in just over half a year, the value of that investment had increased more than tenfold.

 

In January 2026, AbbVie licensed RC148 from RemeGen with an upfront payment of US650 million and a total deal value of up to US650millionandatotaldealvalueofuptoUS5.6 billion.

 

If ivonescimab ignited this fire, what ultimately pushed the track to a white-hot intensity was the common anxiety among multinational pharmaceutical companies: the impending patent cliff for PD-1 monotherapies.

 

Keytruda's core patent is expected to expire in 2028. According to analyses, drugs with a total value of approximately US$300 billion are expected to lose patent protection in the coming years. Major players are eager to find the next-generation immunotherapy backbone that can supersede PD-1 monotherapies. PD-1/VEGF bispecific antibodies happen to offer that possibility.

 

But behind the excitement lies an unavoidable reality: looking at the data disclosed so far, the ORR figures for various PD-1/VEGF bispecific antibodies in early-stage studies are very close, with differences typically within 10 percentage points, and most come from small-sample, non-head-to-head Phase I/II studies.

 

In other words, with nearly identical target combinations, similar structural designs, and comparable clinical data, the ultimate differentiator will likely be determined by Phase III and long-term survival data.

 

This is why the positive OS results from HARMONi-6 are particularly critical – it is the first Phase III study globally to demonstrate, through a head-to-head comparison with an OS endpoint, that a PD-1/VEGF bispecific antibody can surpass PD-1 plus chemotherapy in lung cancer. On this track, the evidentiary value of this finding cannot be compared to early-stage ORR data.

 

Beyond the contest of Phase III data, the rules of the competitive game are undergoing profound changes.

 

After Pfizer licensed SSGJ-707, it rapidly launched 7 global clinical trial initiatives, planning to cover over 2,000 patients. The BioNTech-BMS collaboration is also rapidly advancing BNT327 into Phase III.

 

At the same time, nearly all leading players are positioning for "PD-1/VEGF bispecific + ADC" combination therapies: Akeso has internally launched studies combining its bispecific with ADCs, and Pfizer is also planning combinations of SSGJ-707 with its vedotin ADC assets. BD deals have escalated from acquiring single molecules to securing systematic combination treatment regimens.

 

Ivonescimab's current leading position is clear. It is the only PD-1/VEGF bispecific antibody approved globally, with two indications approved in China, over 60,000 real-world patients treated, and the first head-to-head evidence with an OS endpoint in squamous NSCLC.

 

But how long will this lead last? This depends on three factors.

 

First, will ivonescimab successfully receive FDA approval in the November 2026 review, and will its efficacy data persuade overseas regulators? Second, can it secure a first-mover position in the new "bispecific + ADC" era, identifying the most synergistic combination regimens? Third, how will it respond to competitors with powerful partners, maintaining a gap in development speed and indication expansion?

 

Returning to the HARMONi-6 study itself: ivonescimab has proven the clinical value of the PD-1/VEGF bispecific antibody direction in first-line lung squamous cell carcinoma treatment in the most robust manner. For other players on this track, this result serves both as a strong endorsement and as a countdown for an arms race.

 

References:

• OS significantly positive, HR=0.66! Ivonescimab plus chemotherapy beats PD-1 plus chemotherapy – OS results unveiled at ASCO for first-line sq-NSCLC

• PD-1/VEGF: The track has gone "over the top" – where is the next BD opportunity?

• Crossing the FDA threshold: The crossroads for PD-(L)1/VEGF bispecifics