Aikang Biopharma's Breakthrough First
Introduction: Sparking the "Gold Rush" of PD-1/VEGF Bispecific Antibodies
In the evolution of immuno-oncology, PD-1/PD-L1 inhibitors and anti-VEGF therapies have long represented two mainstream strategies: immune activation and anti-angiogenesis, respectively. However, as the frontline market has been firmly dominated by PD-1 monoclonal antibodies like Keytruda (pembrolizumab), further innovation has faced the challenge of "market saturation" or "involution."
How to achieve genuine clinical breakthroughs beyond existing therapies has become a central focus of the industry.
How to achieve genuine clinical breakthroughs beyond existing therapies has become a central focus of the industry.
It is against this backdrop that PD-(L)1/VEGF bispecific antibodies have rapidly emerged. By simultaneously blocking both immune suppression and angiogenesis pathways, they aim to open new therapeutic ceilings in the increasingly plateaued field of immune checkpoint therapy. Over the past two years, innovative companies from China have driven a surge in both clinical momentum and capital interest. According to estimates, the global cumulative deal value in this space has already exceeded $25 billion.
As the most representative asset, ivonescimab (brand name: 依沃西单抗, developed by Aikang Biopharma) has achieved a first-in-China regulatory approval, marking a breakthrough. It has also demonstrated overall survival (OS) benefit in pivotal Phase III studies, drawing high attention from academia, industry, and capital markets.
01
Ivonescimab's Continuous Breakthroughs
As the leading product in this field, ivonescimab's clinical performance is almost becoming the bellwether for whether the entire class of PD-(L)1/VEGF bispecifics can move into the mainstream.
What truly propelled ivonescimab into the global spotlight was its performance in the HARMONi-2 study-a head-to-head Phase III trial directly challenging Merck's Keytruda. The study enrolled first-line, PD-L1-positive advanced non-small cell lung cancer (NSCLC) patients. The results showed that ivonescimab not only significantly prolonged median progression-free survival (PFS) but also achieved the first-ever direct superiority over Keytruda in lung cancer.
In the field of immuno-oncology, this breakthrough is highly symbolic: for the past decade, Keytruda has set the gold standard for PD-1 therapy, with few drugs able to demonstrate overwhelming advantages in key endpoints. As a result, the HARMONi-2 results are seen as a milestone for bispecific antibodies entering the mainstream of IO (immuno-oncology). Based on these data, ivonescimab was approved in China in April 2024 for the first-line treatment of PD-L1-positive NSCLC, making it its second approved indication. Additional OS data is expected to be updated later in 2024, and the global scientific and investment communities are watching closely.
In China's Phase III HARMONi-A study (for second-line EGFR-mutated non-squamous NSCLC after TKI resistance), ivonescimab combined with chemotherapy previously demonstrated a median PFS of 7.1 months vs. 4.8 months (a 54% risk reduction) and, in the latest data readout in August 2024, confirmed for the first time a statistically and clinically meaningful OS benefit. This not only provides solid support for approval in China but also answers the key international question: "Can PFS advantage translate into real survival gains?"
Meanwhile, ivonescimab's global expansion is accelerating. The HARMONi trial, led by Summit Therapeutics (with a design similar to HARMONi-A but covering patients in the U.S., Europe, and other regions), also showed a 48% reduction in PFS risk, highly consistent with HARMONi-A. Although OS significance has not yet been reached in the interim analysis, the trend is positive. With HARMONi-A now confirming OS benefit, the industry widely expects HARMONi to achieve a similar breakthrough in follow-up analyses, laying the foundation for a potential U.S. filing in second-line EGFR-mutated NSCLC.
Currently, ivonescimab has eight Phase III or registration studies in lung cancer, covering squamous and non-squamous histologies, TKI-resistant populations, high PD-L1 expressors, and SCLC consolidation therapy, among other scenarios. Its indications are also expanding into "cold tumors" and immunotherapy-resistant cancers, such as triple-negative breast cancer (TNBC), MSS colorectal cancer, and pancreatic cancer. Through this broad and strategic clinical layout, ivonescimab aims to achieve dual breakthroughs in both high-incidence and hard-to-treat cancers.
02
The "Gold Rush" of PD-1/VEGF Bispecifics Driven by Chinese Companies
If ivonescimab's clinical progress and approvals represent the first shot in this race, then the surge in capital market activity has quickly turned this space into a global gold rush.
Over the past two years, the total value of deals-including licenses, acquisitions, and co-development agreements-centered around this mechanism has surpassed $25 billion, with most core assets originating from China. While all leveraging the same scientific mechanism, these assets differ in development paths, collaboration models, and target indications.
PM8002 (also known as BNT323, developed by Pumeng Biotech → BioNTech)
A PD-L1 × VEGF-A bispecific antibody, initially developed by China's Pumeng Biotech, known for its simplicity and stability, and now in Phase III.
Entered registration-enabling studies earlier than peers, and through collaboration with BioNTech, became part of a global clinical development plan.
In 2023, BioNTech acquired Biotheus (developer) for an 800millionupfrontpayment∗∗,withatotaldealvalueapproaching∗∗1 billion.
Then in 2025, BioNTech entered into a strategic co-development agreement with BMS, featuring a 1.5billionupfrontpayment∗∗anda∗∗totalpotentialdealvalueofupto11 billion, with a 50/50 profit-sharing model.
This is the largest collaboration in this field to date. What sets BNT323 apart is its broad internationalization, covering more than 10 tumor types, including NSCLC, SCLC, and others, making it one of the most globally advanced bispecifics.
This deal not only highlights BNT323's potential but also signals that Big Pharma views it as a potential successor to PD-1 monoclonals.
AMV-2510 / IMC-209 (Yiming Angke → Instil Bio)
A PD-1 × VEGF bispecific developed by China's Yiming Angke, initially focused on NSCLC to quickly penetrate the competitive lung cancer market.
In 2024, Instil Bio acquired ex-China rights for a 50millionupfrontpayment∗∗andatotaldealvalueofapproximately∗∗2 billion.
Currently in Phase II.
LM-299 (Liming Pharmaceutical → Merck)
A PD-1 × VEGF bispecific from Liming Pharma, with a broader indication strategy not limited to lung cancer but covering multiple solid tumors.
In 2024, Merck acquired global rights for a 588millionupfrontpayment∗∗andatotalpotentialdealvalueof∗∗2.7 billion.
Currently in Phase II/III.
For Merck, whose Keytruda already dominates the market, LM-299 is seen as a complementary asset to sustain its next phase of growth in IO.
SSGJ-707 (3SBio → Pfizer)
A PD-1 × VEGF bispecific from 3SBio, with a deal size of approximately 1.25billionupfront+100 million equity investment, totaling around $48 billion.
Targets NSCLC and colorectal cancer (CRC), broader than lung-only indications.
Still in early-stage clinical development, but with Pfizer's global development strength and 3SBio's China base, it is expected to accelerate into global pivotal trials.
Ivonescimab (Aikang Biopharma → Summit Therapeutics)
The most representative PD-1 × VEGF bispecific, already approved in China for multiple indications.
Differentiated by being the first to demonstrate superiority over Keytruda in a head-to-head Phase III lung cancer trial.
Validated efficacy in second-line EGFR-mutated NSCLC, first-line PD-L1-positive NSCLC, squamous/non-squamous, and SCLC consolidation.
In late 2022, Summit acquired ex-China rights for a 500millionupfrontpayment∗∗andatotaldealpotentialof∗∗5 billion, and is advancing registration studies in the U.S. and Europe.
With broad indications and leading clinical data, ivonescimab is currently the most promising bispecific leader.
03
Ivonescimab & PD-(L)1/VEGF Bispecifics from a PIP Perspective
In the global oncology drug development landscape, very few products can be called a PIP (Pipeline-in-a-Product) - a single asset that, due to its unique mechanism and broad adaptability, can simultaneously serve multiple pipeline strategies.
Keytruda is the classic example: one molecule has enabled indications across more than 10 tumor types, including melanoma, NSCLC, head & neck, Hodgkin's lymphoma, urothelial, gastric, cervical, liver, Merkel cell, renal cell, esophageal, endometrial, squamous cell, breast, biliary tract, and malignant pleural mesothelioma - effectively defining an era.
Now, the question arises: Can PD-(L)1/VEGF bispecifics become the next PIP?
Looking at ivonescimab's trajectory, it clearly aligns with the core logic of a PIP. As the leading product, it has built a comprehensive development strategy across the full spectrum of lung cancer:
Second-line EGFR-mutated NSCLC (HARMONi-A/HARMONi)
First-line PD-L1-positive NSCLC (HARMONi-2)
Squamous, non-squamous, and SCLC consolidation
Almost all major subtypes are included in Phase III or registration studies, positioning ivonescimab to potentially become the "foundation drug" in lung cancer, much like Keytruda.
More importantly, ivonescimab is not limited to lung cancer. It has also initiated Phase III or pivotal studies in difficult-to-treat or "cold tumors" such as biliary tract cancer, head & neck squamous cell carcinoma, TNBC, MSS colorectal cancer, and pancreatic cancer. Notably, the head & neck project is exploring combination with anti-CD47 antibodies, showcasing a multi-pathway synergy beyond dual pathway targeting. These efforts lay a strong foundation for cross-indication expansion.
However, the true meaning of PIP lies not only in a product's multi-indication potential but also in whether the underlying mechanism is broadly replicable. This is where PD-(L)1/VEGF bispecifics offer even greater discussion value:
✅ Mechanistic Breadth:
PD-(L)1 and VEGF represent immune activation and angiogenesis, respectively. Their combination naturally covers both immune dysfunction and vascular dependence in tumors. Compared to PD-1 monotherapy, they have greater potential to span multiple tumor types, providing the "universality" needed for PIP status.
✅ Clinical Extrapolatability:
Most molecules (e.g., PM8002, LM-299, SSGJ-707) initially target NSCLC - the largest and most validated market. But whether efficacy translates to biliary tract, colorectal, breast, and other cancers will determine if these bispecifics can truly evolve into PIPs.
✅ Commercial Strategy:
The capital markets have already shown that Big Pharma views PD-(L)1/VEGF bispecifics as next-generation platform assets. Whether it's Summit's 5billionacquisitionofivonescimab∗∗orthe∗∗11 billion BMS-BioNTech collaboration, the underlying logic is to replicate a Keytruda-like product pipeline.
Thus, ivonescimab has already demonstrated PIP-like attributes, but whether the entire PD-(L)1/VEGF bispecific class can evolve into PIPs depends on multiple molecules achieving confirmed breakthroughs across various tumor types.
04
Future Outlook: Can They Really Challenge Keytruda?
When discussing the future of PD-(L)1/VEGF bispecifics, one unavoidable question is: Can they truly challenge the dominance of Keytruda and Opdivo in immuno-oncology?
From a clinical evidence standpoint, ivonescimab has taken a critical first step. In HARMONi-2, it achieved the first-ever head-to-head superiority over Keytruda in a Phase III lung cancer trial - a highly symbolic breakthrough. Recent progress in OS endpoints has also been promising. However, Keytruda has built an extensive indication portfolio and deep physician trust over more than a decade. Even with a single trial win, reshaping the global landscape will require more cross-indication and cross-population confirmatory results.
From a mechanistic advantage perspective, the dual-pathway synergy of PD-(L)1/VEGF bispecifics does offer theoretical benefits. Immune activation plus anti-angiogenesis can improve the tumor microenvironment and enhance efficacy. This suggests potential in "cold tumors" and immunotherapy-resistant populations where PD-1 monos have limited impact. This broad-spectrum potential gives them PIP-like promise and a scientific rationale to challenge Keytruda.
But the competitive landscape cannot be ignored. Keytruda has not only first-mover advantage but also nearly 20 approved indications, a mature reimbursement infrastructure, and global commercial reach that creates a formidable moat. In contrast, PD-(L)1/VEGF bispecifics are still in early-stage market exploration, with global OS data not yet fully mature. If future results fail to consistently confirm survival benefits, their competitiveness could weaken.
Additionally, regulatory and payer considerations will be decisive. Bispecific mechanisms are novel, requiring extensive evidence for cross-indication approvals. For payers, the question remains: How much premium should be paid for a product that is essentially an "upgraded PD-1"? If pricing is too high and benefits are marginal, adoption could be limited.
Summary
Represented by ivonescimab, PD-(L)1/VEGF bispecifics have shown a potential path to PIP status and have achieved stage wins against Keytruda. But to truly challenge Keytruda's dominance, three conditions must be met:
Replicate significant OS benefits across multiple cancer types
Demonstrate differentiated value in cold tumors and resistant populations
Achieve a balance between pricing and accessibility to avoid the pitfall of "high-cost, low-adoption"
In the coming years, as results from the HARMONi series and other global Phase III trials emerge, we will see whether this mechanism becomes the "next Keytruda" or remains a "complement to Keytruda." Regardless of the outcome, PD-(L)1/VEGF bispecifics have already injected new momentum into immuno-oncology.
Conclusion
From ivonescimab's first approval in China to multibillion-dollar deals by multinational companies, PD-(L)1/VEGF bispecifics have moved from concept to reality. They are not just an incremental attempt beyond the PD-1 era, but an exploration of new mechanisms and clinical paradigms. While the question of whether they can truly dethrone Keytruda remains open, they have at least reignited the global immuno-oncology community's hope for the "next foundational therapy."
In the years ahead, regardless of the final outcome, this field will remain one of the most closely watched areas in the global pharmaceutical landscape.
References:
Usmani, S. The PD‑1×VEGF Bispecific Gold Rush. LinkedIn.
Interim results announcement for the six months ended June 30, 2025. Akeso. August 26, 2025.
Wosen, J. Akeso says its closely watched drug improved patient survival in a lung cancer trial. STAT. August 26, 2025.
Seymour, C. Ivonescimab Outperforms Pembrolizumab as Frontline Therapy in PD-L1+ Advanced NSCLC. OncLive. September 8, 2024.
