Akeso, Inc. announced that the first patient has been enrolled in COMPASSION-37 (AK104-311), a global, multicenter Phase III head-to-head trial evaluating cadonilimab, Akeso's first-in-class PD-1/CTLA-4 bispecific antibody, in combination with chemotherapy versus chemotherapy with or without nivolumab as first-line treatment for patients with HER2-negative, previously untreated, unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

The study is designed to further evaluate the efficacy and safety of cadonilimab as first-line therapy for advanced gastric cancer across geographically and ethnically diverse patient populations worldwide, and to investigate whether dual PD-1/CTLA-4 immune checkpoint blockade can further improve outcomes beyond the current standard of care.

COMPASSION-37 is co-led by a distinguished international group of global principal investigators, including Dr. Yelena Y. Janjigian, Chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center (MSK); Professor Markus Möhler of Johannes Gutenberg University Mainz, Germany; Professor Jiafu Ji, Director of the Gastrointestinal Cancer Center at Peking University Cancer Hospital & Institute; and Professor Lin Shen, Director of the Department of Gastrointestinal Oncology at Peking University Cancer Hospital.

Dr. Janjigian, Professor Möhler, and Professor Shen were investigators on the CheckMate 649 trial, which established the clinical value of nivolumab plus chemotherapy as first-line treatment for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma and led to the adoption of PD-1 inhibitor plus chemotherapy as a key first-line treatment strategy for HER2-negative advanced gastric cancer.

As immunotherapy has become widely adopted in the first-line setting for gastric cancer, the relationship between PD-L1 expression and treatment benefit has drawn increasing attention. Studies including CheckMate 649 have shown that the benefit of PD-1 inhibitor plus chemotherapy is more pronounced in patients with high PD-L1 expression, while how to further improve immunotherapy outcomes in patients with low PD-L1 expression remains an important area of clinical investigation.

Chemotherapy with or without a PD-1 inhibitor remains the international standard of care for advanced gastric cancer; however, the disease is biologically and clinically heterogeneous. In the U.S., first-line PD-1 inhibitor indications in advanced gastric cancer are currently limited to PD-L1-positive patients, and current NCCN and ESMO guidelines preferentially recommend nivolumab-based regimens for patients with PD-L1 CPS ≥5. Consequently, effective immunotherapy options for PD-L1-low advanced gastric cancer remain a significant global unmet need.

"Immunotherapy has transformed the treatment of stomach and esophagus cancers, helping patients live longer and better," said Yelena Y. Janjigian, MD, FASCO, Chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center (MSK) and global principal investigator for the COMPASSION-37 study. "Through our evaluation of cadonilimab as a potential first-line treatment for advanced disease, we aim to better understand its potential to improve outcomes and support longer-term survival for patients." Dr. Janjigian previously served as the lead principal investigator for the CheckMate 649 trial, which established nivolumab-based therapy as a global standard of care.

Professor Jiafu Ji said: "COMPASSION-15 has already shown that cadonilimab plus chemotherapy significantly improves overall survival in patients with HER2-negative advanced gastric cancer, with a favorable survival trend also seen in patients with PD-L1 CPS <5, suggesting that dual PD-1/CTLA-4 blockade may expand the population that benefits from immunotherapy. COMPASSION-37 takes this further by evaluating the regimen in a global, multicenter, head-to-head Phase III trial against current international standards of care. Its greater value lies in rigorously testing the evidence we have generated on a worldwide scale. As clinicians, the key question is whether this innovation can offer more effective and broadly applicable first-line options for patients with advanced gastric cancer across different PD-L1 levels, regions, and populations. We look forward to COMPASSION-37 providing high-quality global evidence that can help bring clinically meaningful treatments to patients worldwide."

"Advanced gastric cancer is characterized by substantial biological and clinical heterogeneity. Previous studies have shown that the magnitude of benefit from PD-1 inhibitor therapy is closely associated with PD-L1 expression, and that there remains room to further improve outcomes, particularly in patients with low PD-L1 expression. How to broaden the population that effectively benefits from immunotherapy is an important and not yet fully addressed clinical question in gastric cancer. We look forward to COMPASSION-37 further clarifying the value of dual PD-1/CTLA-4 immune checkpoint blockade across PD-L1 expression subgroups," said Professor Lin Shen.

From COMPASSION-15 to COMPASSION-37: From Chinese Phase III Evidence to Global Head-to-Head Validation

COMPASSION-15 is a randomized, double-blind, placebo-controlled Phase III study that enrolled 610 patients with HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma. The study enrolled a notably high proportion of patients with low PD-L1 expression (49.8%) and PD-L1-negative disease (23%), far exceeding rates in comparable historical studies. This provides strong support for the benefit of cadonilimab in the overall population, irrespective of PD-L1 expression.

Results from COMPASSION-15 study showed that, in the overall population, cadonilimab plus chemotherapy significantly reduced the risk of death compared with the control group, regardless of PD-L1 expression status. These findings suggest that dual PD-1/CTLA-4 immune checkpoint blockade may offer new therapeutic options for gastric cancer patients across different PD-L1 expression levels and provide an important scientific basis for further international head-to-head Phase III validation.

Gastric Cancer Immunotherapy: From "Whether" to "Who Benefits Most"

At present, PD-1 inhibitor plus chemotherapy has become one of the key first-line treatment strategies for HER2-negative advanced gastric cancer. However, multiple studies consistently suggest that the magnitude of immunotherapy benefit is closely associated with PD-L1 expression, with more definitive survival benefits in high-expressing patients and relatively modest absolute benefit in low-expressing patients.

PD-L1 expression thresholds and treatment recommendations vary across regions and guidelines. A single CPS cutoff should not be applied uniformly across all settings.This means that the central question in gastric cancer immunotherapy is gradually shifting from "whether immunotherapy should be added" to "how to select the most appropriate immunotherapy strategy based on tumor biology, and how to further broaden the population that truly derives long-term benefit." COMPASSION-37 is being conducted against this backdrop.

Advancing Global Clinical Development

In addition to COMPASSION-37, an international study of cadonilimab in the perioperative setting for gastric cancer has also been initiated. A single-arm Phase II study (NCT07631000), led by Dr. Yelena Y. Janjigian at Memorial Sloan Kettering Cancer Center, is currently enrolling patients in the United States. The study evaluates cadonilimab in combination with FLOT chemotherapy as perioperative treatment in patients with locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma, exploring whether dual PD-1/CTLA-4 immune checkpoint blockade can be extended to earlier-stage, curable gastric cancer.

From the randomized Phase III COMPASSION-15 study conducted in China, to the perioperative Phase II study being conducted in the United States, and now to the global, multicenter, head-to-head Phase III COMPASSION-37 study, the clinical development of cadonilimab in gastric cancer is progressively forming a complete pathway that spans from advanced disease to the perioperative setting and from Chinese evidence to global validation.

Whether COMPASSION-37 can further improve patient survival beyond the current standard of care—and, in particular, whether it can offer a new treatment option for patients with low PD-L1 expression—will ultimately be answered by the results of this rigorous Phase III trial. This is the key scientific question that COMPASSION-37 is designed to answer.

In addition to the COMPASSION-37 study, a Phase II study (NCT07631000) of perioperative cadonilimab with neoadjuvant chemotherapy in patients with localized, resectable HER2-negative gastric or gastroesophageal junction (GEJ) tumors, led by Dr. Yelena Janjigian, is currently enrolling patients in the United States. This study is expected to generate robust clinical evidence to support the initiation of an international multicenter Phase III trial evaluating the cadonilimab-based combination regimen for the perioperative treatment of patients with GC/GEJ adenocarcinoma.

As the first approved bispecific antibody for cancer treatment, cadonilimab continues to demonstrate clinical value across multiple pivotal registrational and Phase III studies. It is currently approved in China for first-line gastric cancer, first-line cervical cancer, and recurrent/metastatic cervical cancer, and is widely used in clinical practice. Cadonilimab is being evaluated in more than 13 registrational or Phase III trials globally, spanning major tumor types including gastric, liver, lung, cervical, and pancreatic cancers. Two of these trials are international multicenter registrational/Phase III studies.