Akeso Inc. has secured clearance from the United States Food and Drug Administration to initiate COMPASSION-37, a global Phase III trial evaluating cadonilimab, a first-in-class PD-1/CTLA-4 bispecific antibody, as part of a first-line treatment regimen for HER2-negative, unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma. The randomized, multicenter trial will compare cadonilimab plus chemotherapy against chemotherapy with or without nivolumab, representing the drug’s second global registrational program after its immunotherapy-refractory hepatocellular carcinoma study.

What the COMPASSION-37 trial signals about regulatory and scientific confidence in cadonilimab

The United States Food and Drug Administration’s green light for COMPASSION-37 places Akeso Inc. among a small but growing group of China-based biopharmaceutical developers whose assets are advancing into pivotal international trials. This authorization reflects not only Akeso Inc.’s maturation as a global sponsor but also growing regulatory receptivity toward novel checkpoint modulation approaches that move beyond conventional PD-1 or PD-L1 inhibition strategies.

Cadonilimab is uniquely designed to bind and block both PD-1 and CTLA-4 receptors within a single bispecific construct. This design aims to harness the combined immune-activating potential of dual checkpoint inhibition without the toxicity burden commonly seen when anti-PD-1 and anti-CTLA-4 antibodies are co-administered as separate agents, such as nivolumab and ipilimumab. By pursuing this strategy in a frontline setting, Akeso Inc. is directly challenging the biomarker-driven status quo that continues to define immunotherapy eligibility in gastric cancer.

Why a PD-L1 agnostic approach is urgently needed in gastric cancer treatment

The underlying rationale for cadonilimab in gastric cancer centers on the limitations of current PD-1-directed therapies in biomarker-unselected populations. While the combination of chemotherapy with PD-1 inhibitors like nivolumab has demonstrated clinical benefit in patients with high PD-L1 expression, particularly those with a combined positive score (CPS) greater than or equal to 5, real-world data show that the majority of patients fall below this threshold.

As of 2024, the United States Food and Drug Administration revised its approvals for PD-1 therapies in gastric cancer, restricting their use to PD-L1-positive patients only. Major guidelines from the National Comprehensive Cancer Network and the European Society for Medical Oncology mirror this approach, creating a bifurcated treatment paradigm that excludes a large segment of patients with PD-L1 CPS less than 5 or CPS below 1.

These patients, representing more than half of the global gastric cancer population, currently face limited benefit from immunotherapy. For Akeso Inc., the unmet need in these groups provides a strong strategic and clinical foundation to position cadonilimab as a potential alternative that operates independently of PD-L1 expression status.

What the COMPASSION-15 data reveal about cadonilimab’s performance across PD-L1 subgroups

The COMPASSION-15 trial, conducted in China, laid the groundwork for this global expansion. The study was notable for its inclusive design, enrolling a diverse cohort with respect to PD-L1 expression. Nearly half of the enrolled patients exhibited low PD-L1 levels (CPS under 5), and nearly a quarter were PD-L1 negative (CPS under 1). These proportions are significantly higher than those seen in prior immunotherapy trials, giving the results broader clinical relevance.

In this study, cadonilimab plus chemotherapy achieved a 39 percent reduction in the risk of death compared to the control group in the overall population. In patients with high PD-L1 expression (CPS of 5 or more), the reduction in mortality risk reached 51 percent. Crucially, even in patients with CPS under 5, cadonilimab showed a 24 percent reduction in the risk of death, a statistically significant and clinically meaningful outcome. These findings were presented at the European Society for Medical Oncology 2025 annual congress and had previously been highlighted at the American Association for Cancer Research in 2024. The full manuscript was later published in Nature Medicine.

If COMPASSION-37 confirms these outcomes across geographies and genetic backgrounds, it could support regulatory filings that move beyond narrow PD-L1 stratification and reframe the immunotherapeutic approach to first-line gastric cancer.

How bispecific antibodies like cadonilimab are redefining immuno-oncology engineering

Cadonilimab’s architecture reflects a wider shift in oncology drug development toward multifunctional biologics. Developed using Akeso Inc.’s proprietary Tetrabody platform, cadonilimab is designed to engage PD-1 and CTLA-4 simultaneously, streamlining immune checkpoint modulation into a single agent that could mitigate additive toxicity.

This approach differs markedly from the sequential or dual-agent strategies seen with legacy checkpoint combinations. While such combinations have worked in indications like melanoma, they remain less viable in gastrointestinal cancers due to heightened risks of adverse events and diminished efficacy in PD-L1 low populations. Cadonilimab’s mechanism is therefore not just additive but mechanistically distinct, potentially enabling a reprogramming of the tumor microenvironment even in immunologically cold tumors.

If cadonilimab’s toxicity profile proves manageable at scale, it could establish a blueprint for next-generation bispecifics that integrate dual checkpoint inhibition without overwhelming the immune system. Industry observers note that other companies are moving toward similar designs, but cadonilimab currently holds a first-mover advantage in gastric cancer.

Why regulatory watchers are seeing strategic significance in FDA clearance

Although cadonilimab is already approved in China, United States Food and Drug Administration clearance to launch a global Phase III study carries far-reaching implications. It validates Akeso Inc.’s clinical development infrastructure, manufacturing compliance, and ability to manage international trial complexity. This is particularly relevant for Chinese biopharmaceutical companies aiming to diversify their market access strategies.

The global reach of COMPASSION-37 will also put Akeso Inc. in a stronger position to attract Western licensing or co-commercialization partners. The company has previously emphasized a dual-track strategy that balances internal development with strategic alliances. Should the trial meet its endpoints, industry analysts expect Akeso Inc. to accelerate partnership discussions for broader commercialization across North America, Europe, and potentially Japan.

Moreover, the trial’s performance will likely influence the United States Food and Drug Administration’s evolving stance on PD-L1-negative indications, especially in therapeutic areas where other checkpoint inhibitors have plateaued.

What clinicians and reimbursement bodies will focus on as data emerges

From a clinical perspective, oncologists will pay close attention to subgroup analyses, particularly for patients with low or negative PD-L1 expression. These patients have historically lacked durable immunotherapy options, and any evidence of broad-spectrum efficacy could rapidly influence treatment guidelines.

However, reimbursement bodies and payers are likely to demand robust evidence of cost-effectiveness across the full spectrum of PD-L1 expression levels. With most immunotherapy regimens already incurring high treatment costs, a bispecific antibody would need to demonstrate either superior efficacy, longer duration of response, or reduced toxicity to justify formulary inclusion.

Health technology assessment agencies may also request head-to-head or indirect comparisons with existing PD-1 plus chemotherapy combinations, especially given the entrenched use of nivolumab-based regimens in PD-L1-positive cases.

What risks remain for cadonilimab as it enters the global spotlight

Despite the strong foundation laid by COMPASSION-15, cadonilimab still faces multiple risks as it expands into international trials. The most immediate concern is generalizability. The global patient population is more genetically and socioeconomically diverse than the Chinese cohort in COMPASSION-15. Differences in baseline disease biology, treatment availability, and comorbidities could affect treatment outcomes.

Toxicity is another area of concern. While bispecific designs offer theoretical safety benefits, the immune system remains highly reactive to checkpoint modulation, and any unexpected immune-related adverse events could derail broader adoption. Close monitoring of safety data from COMPASSION-37 will be essential, especially as trial sites diversify beyond Asia.

Finally, the competitive landscape is intensifying. Other checkpoint combinations and biomarker-targeted therapies are entering development for gastric and gastroesophageal cancers, including candidates targeting CLDN18.2, TIGIT, and LAG-3. These may offer alternative pathways for subtyping or stratification, which could either complement or compete with cadonilimab’s agnostic approach.

Conclusion: a critical inflection point for bispecific IO in gastric oncology

Cadonilimab’s advance into a United States Food and Drug Administration-cleared global Phase III trial marks a pivotal moment for bispecific checkpoint inhibitors in solid tumors. If the COMPASSION-37 study succeeds, it could reshape how clinicians, regulators, and payers view immunotherapy in biomarker-unselected gastric cancer. More importantly, it could expand access to effective immuno-oncology treatment for the majority of patients currently excluded from frontline checkpoint therapy.

Akeso Inc. now faces the dual challenge of proving cadonilimab’s broad efficacy in diverse populations and navigating the global regulatory, manufacturing, and commercial ecosystems that accompany a first-in-class innovation. The outcomes of COMPASSION-37 will not only define the future of cadonilimab but could also set a precedent for bispecific development in immunologically underserved tumors.

  Akeso, bispecific antibodies, cadonilimab, checkpoint inhibitors, COMPASSION-37, gastric cancer, immuno-oncology, PD-1 CTLA-4 bispecific, PD-L1, Phase III trial