In the evolution of immuno-oncology, PD-1/PD-L1 inhibitors and anti-VEGF therapies have long represented the two mainstay strategies for immune activation and anti-angiogenesis, respectively. However, with PD-1 monoclonal antibodies like Keytruda (pembrolizumab) firmly dominating the frontline market, subsequent innovation has faced internal competition. Achieving true clinical breakthroughs based on established therapies has become a core concern for the industry.

It is against this backdrop that PD-(L)1/VEGF bispecific antibodies have rapidly emerged. By simultaneously blocking both immunosuppressive and angiogenic pathways, they aim to unlock new growth opportunities in the immune checkpoint therapy field, where efficacy curves have been flattening. Over the past two years, innovative Chinese companies have driven a surge in clinical trials and investment in this area. According to statistics, global cumulative transaction volume has exceeded US$25 billion.

As the most representative asset, Kangfang Bio's Ivoximab has been approved for marketing in China, achieving a breakthrough and achieving overall survival (OS) benefits in a key Phase III study, attracting great attention from academia, industry and the capital market.

01
Continuous breakthroughs in Ivoximab

As the leading product in this field, the clinical performance of Ivosimab has almost become a weather vane for whether the entire PD-(L)1/VEGF dual antibody can become mainstream.

What truly catapulted ivocizumab into the global spotlight was its performance in the HARMONi-2 study. This Phase III trial, a direct challenge to Merck & Co.'s Keytruda, enrolled first-line patients with advanced PD-L1-positive NSCLC. Results showed that ivocizumab not only significantly prolonged median progression-free survival (PFS), but also surpassed Keytruda in lung cancer for the first time. This breakthrough is highly symbolic in the immuno-oncology field: for the past decade, Keytruda has virtually represented the standard for PD-1 therapy, with few drugs demonstrating overwhelming superiority across key endpoints. Consequently, the HARMONi-2 results are considered a milestone in the entry of bispecific antibodies into the mainstream immuno-oncology arena. Based on these data, ivocizumab received approval from Chinese regulators in April of this year for the first-line treatment of PD-L1-positive NSCLC, becoming its second approved indication. Further OS results are expected later this year, and are being closely watched by both academia and industry worldwide.

In the Phase III HARMONi-A study conducted in China (second-line EGFR-mutant non-squamous NSCLC, following TKI resistance), ivocizumab combined with chemotherapy previously demonstrated a median PFS advantage of 7.1 months versus 4.8 months (a 54% risk reduction). The latest readout in August of this year confirmed a statistically and clinically significant OS benefit for the first time. This not only provided strong support for the approval by Chinese regulatory authorities but also addressed the key question at the international level: whether the PFS advantage can be translated into a true survival benefit.

Meanwhile, the global development of ivocizumab is accelerating. The HARMONi trial, led by Summit Therapeutics (designed similarly to HARMONi-A but encompassing patients from multiple regions, including Europe and the United States), also demonstrated a 48% reduction in PFS risk, highly consistent with HARMONi-A. Although OS did not yet reach significance in the interim analysis, the trend remains positive. With HARMONi-A's positive OS results, the industry is widely anticipating that HARMONi will achieve similar breakthroughs in subsequent follow-up, paving the way for potential approval in the US for second-line EGFR-mutant NSCLC.

Currently, ivocizumab is in eight Phase III or registrational studies in the lung cancer field, covering a variety of clinical scenarios, including squamous cell carcinoma, non-squamous cell carcinoma, TKI resistance, PD-L1 overexpression, and consolidation therapy for small cell lung cancer. Simultaneously, its indications are expanding to include cold tumors and immune-resistant tumors, including TNBC, MSS colorectal cancer, and pancreatic cancer. Through this broad and strategic clinical deployment, ivocizumab aims to achieve dual breakthroughs in both first-line, high-incidence tumors and refractory tumors.

02
The PD-1/VEGF dual antibody "gold rush" driven by Chinese companies

If the clinical progress and launch of Ivosimab fired the first shot in the PD-(L)1/VEGF dual antibody market, then the hot capital market has rapidly transformed this track into a global "gold rush."

Over the past two years, licensing, M&A, and joint development transactions under this mechanism have totaled over $25 billion, with the majority of core assets originating in China. While these assets all operate under the same mechanism, they each possess distinct R&D pathways, collaboration models, and selected indications.

PM8002 (also known as BNT323, BioNTech)

PM8002 is a PD-L1×VEGF-A dual antibody, originally developed by China's Promis Biotechnology. It is designed to combine simplicity and stability and has entered Phase III clinical trials.

Compared to other PD-L1×VEGF bispecific antibodies, it entered registrational studies earlier and, through a collaboration with BioNTech, was incorporated into the global clinical development pipeline. In 2023, BioNTech completed its acquisition of Biotheus for approximately $800 million in down payments and a total of nearly $1 billion. Subsequently, in 2025, BioNTech and BMS reached a strategic co-research agreement for the same molecule, with a $1.5 billion down payment and a total of $11 billion. The collaboration model was a 50/50 split of costs and profits.

This is the largest collaboration in this field to date. Differentiating itself from other assets, it features a joint development model that covers over 10 tumor types, including NSCLC, SCLC, and other high-incidence tumors, making it one of the most extensive bispecific antibodies with an international reach. This transaction not only highlights the potential of BNT323 but also demonstrates that multinational pharmaceutical companies view it as a potential successor to PD-1 monoclonal antibodies.

AMV-2510/IMC-209 (ImmuneOnco → Instil Bio)

AMV-2510, developed by China's Immune Onco, is a dual-antibody targeting PD-1 and VEGF. It targeted NSCLC patients early in its development, aiming to enter the highly competitive lung cancer market with faster clinical advancement. In 2024, Instil Bio acquired the rights to the drug outside of China for an initial payment of US$50 million, totaling approximately US$2 billion. It is currently in Phase II clinical trials.

LM-299 (Lixin Pharmaceuticals → Merck)

LM-299, a dual-antibody PD-1 and VEGF developed by Lixin Pharmaceuticals, has a broader indication, encompassing a variety of solid tumors rather than just lung cancer. In 2024, Merck acquired global rights for an initial payment of US$588 million, totaling US$2.7 billion. Currently in Phase II/III clinical development, LM-299 is viewed as a complementary asset for Merck, which already has a substantial market presence for Keytruda, providing further momentum for its next phase of immuno-oncology development.

SSGJ-707 (3SBio → Pfizer)

SSGJ-707 is a dual-antibody PD-1 and VEGF developed by 3SBio. The collaboration involves an initial payment of approximately US$1.25 billion plus a US$100 million equity investment, for a total of approximately US$4.8 billion. It targets NSCLC and colorectal cancer (CRC), a broader indication than lung cancer alone. While clinical development is still in its early stages, leveraging Pfizer's international development capabilities and 3SBio's foundation in China, the project is expected to accelerate its entry into global pivotal trials.

Ivociimab (Akeso Biopharma → Summit)

Ivocimab is currently the most representative PD-1 x VEGF dual antibody, approved for multiple indications in China. Its differentiated advantages are significant: it is the first therapy to directly surpass Keytruda in a head-to-head Phase III trial for lung cancer. It has been shown to have therapeutic potential in multiple settings, including second-line treatment for EGFR-mutant NSCLC, first-line treatment for PD-L1-positive NSCLC, squamous and non-squamous cell carcinomas, and consolidation therapy for SCLC.

At the end of 2022, Summit acquired the rights outside of China for an initial payment of $500 million, totaling approximately $5 billion, and is currently advancing registrational clinical trials in Europe and the United States. With its broad indications and leading data, Ivosimab has become the most established bispecific antibody leader.

03
Ivosimab and PD-(L)1/VEGF dual antibody from the perspective of PIP

In the global context of oncology drug development, drugs worthy of the designation "Pipeline-in-a-product" (PIP) are rare. The core concept of a PIP is that a single product, leveraging its unique mechanism and broad indications, can simultaneously serve as a strategic player in multiple product lines.

Keytruda is the most typical example: one molecule has supported the expansion of indications for more than ten types of tumors, including melanoma, metastatic non-small cell lung cancer, head and neck cancer, Hodgkin's lymphoma, urothelial carcinoma, gastric cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, esophageal cancer, endometrial cancer, squamous cell carcinoma, breast cancer, biliary tract tumors, malignant pleural mesothelioma, etc., single-handedly laying the foundation for an era.

Now, people are beginning to ask: Can PD-(L)1/VEGF dual antibody also become the next PIP?

Judging from the path forward for ivocizumab, it undoubtedly aligns with the fundamental logic of the PIP. As a leading product in this field, ivocizumab has established a comprehensive development strategy in the lung cancer field, covering the entire disease course and population. From second-line EGFR-mutant NSCLC (HARMONi-A/HARMONi), first-line PD-L1-positive patients (HARMONi-2), and consolidation therapy for squamous cell carcinoma, non-squamous cell carcinoma, and small cell lung cancer, nearly all major subtypes have been included in its Phase III or registrational studies. This comprehensive coverage positions ivocizumab for Keytruda-like status as a "foundational drug" in the lung cancer field.

More importantly, ivocizumab is not limited to lung cancer. It has also entered Phase III or pivotal clinical trials in refractory or "cold" tumors, including biliary tract cancer, head and neck squamous cell carcinoma, TNBC, MSS colorectal cancer, and pancreatic cancer. The head and neck squamous cell carcinoma program is exploring its combination with an anti-CD47 antibody, demonstrating a "multi-pathway combination" approach beyond dual-pathway synergy. This strategy provides a solid foundation for its expansion across cancer types.

However, the significance of PIP lies not only in the diversification of a single product line, but also in whether the entire mechanism is replicable and universal. This is precisely where the PD-(L)1/VEGF dual antibody is more worthy of discussion:

Broad-spectrum mechanism: PD-(L)1 and VEGF represent immune activation and angiogenesis, respectively. Their combination naturally covers the two major tumor dimensions of immunodeficiency and vascular dependence. Compared to PD-1 monoclonal antibodies, they have greater potential across different tumor types, possessing the versatility required for PIP.

Clinical Extrapolation: Currently, nearly all molecules (such as PM8002, LM-299, and SSGJ-707) have chosen to enter NSCLC, the largest and most easily validated market. However, whether these bispecific antibodies can be translated from lung cancer to other indications, such as biliary tract cancer, colorectal cancer, and breast cancer, will determine whether they can truly become PIPs.

Strategic Business: Capital market decisions have demonstrated that multinational pharmaceutical companies view PD-(L)1/VEGF dual antibodies as next-generation platform assets. Whether it's Summit's $5 billion investment in ivocizumab or BMS and BioNTech's $11 billion joint research and development effort, the core rationale is to replicate a Keytruda-like product pipeline.

Therefore, it can be said that Ivosimab has taken the lead in demonstrating the properties of a PIP, but whether the PD-(L)1/VEGF dual antibody can evolve into a PIP as a whole still requires multiple molecules to achieve confirmed breakthroughs in different tumor types.

04
Future Outlook: Can it truly shake up Keytruda?

When discussing the future of PD-(L)1/VEGF dual antibodies, an unavoidable question is: Can they truly shake the dominance of Keytruda and Opdivo in immuno-oncology?

Judging by clinical evidence, ivocizumab has already taken a crucial step forward. In the HARMONi-2 study, it surpassed Keytruda in a head-to-head Phase III lung cancer trial for the first time, a breakthrough of great symbolic significance. It has also recently achieved breakthrough progress in the clinical focus of OS. However, Keytruda has already built a vast indication portfolio and physician trust through over a decade of clinical experience. Even if it achieves a lead in a single trial, further confirmatory results across tumor types and populations are needed to truly reshape the global market.

From a mechanistic perspective, the dual-pathway synergistic mechanism of PD-(L)1/VEGF dual antibodies does offer a theoretical advantage for expansion. The combination of immune activation and anti-angiogenesis can both improve the immune microenvironment and enhance anti-tumor effects. This property suggests that they may have additional potential in "cold tumors" and immune-resistant populations, where traditional PD-1 monoclonal antibodies have limited efficacy. This potential broad spectrum makes them a viable candidate for PIP development and provides the scientific rationale for challenging Keytruda's dominance.

However, the competitive landscape cannot be ignored. Keytruda not only has a first-mover advantage, but also boasts registrations covering nearly twenty indications and a robust payment system. Its global sales channels and strong negotiating power in reimbursement provide it with an unassailable commercial moat. In contrast, PD-(L)1/VEGF dual antibodies are still in the early stages of market exploration, and true global OS data are not yet fully mature. If future clinical results fail to consistently confirm a survival advantage, their competitiveness could be weakened.

Furthermore, regulatory and payment considerations will also be decisive factors. The novelty of the bispecific antibody mechanism also requires more evidence-based data to support cross-indication applications. For both medical insurance and commercial payers, how to pay a premium for a product that appears to be an upgraded PD-1 monoclonal antibody is a pressing question. If pricing is excessively high and the efficacy advantage is only marginal, promotion may become more difficult.

PD-(L)1/VEGF dual antibodies, represented by ivocizumab, have demonstrated potential for PIP and have achieved phased success against Keytruda in clinical trials. However, to truly challenge Keytruda's position, three conditions must be met simultaneously:

The significant OS advantage was replicated in multiple tumor types;

Demonstrate its differentiated value in cold tumors and drug-resistant populations;

Find a balance between price and payment to avoid repeating the mistake of "high price and low popularity".

In the coming years, as the results of the HARMONi series and other global Phase III trials continue to emerge, we will see whether this mechanism becomes the "new Keytruda" or remains a "supplement to Keytruda." Regardless of the final answer, the PD-(L)1/VEGF dual antibody has injected new momentum into the development of immuno-oncology.

Conclusion : From the pioneering breakthrough of Ivosimab in China to blockbuster deals exceeding tens of billions of dollars with multinational pharmaceutical companies, PD-(L)1/VEGF dual antibodies have moved from concept to reality. They represent not only an incremental advancement in the era of PD-1 monoclonal antibodies but also a reshaping of mechanisms and clinical models. While their potential to truly challenge Keytruda remains uncertain, they have rekindled global anti-oncology anticipation for the "next essential drug." Regardless of the outcome, this field will remain a focus of intense attention in the global pharmaceutical landscape over the next few years.

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