Akeso Enrolls First Patient in Global Phase III COMPASSION-37 Testing Cadonilimab Against Nivolumab in First-Line Gastric Cancer
核心洞察
Akeso has enrolled the first patient in COMPASSION-37, a global Phase III head-to-head trial of cadonilimab plus chemotherapy versus chemotherapy with or without nivolumab in first-line gastric cancer (搜索).
The trial targets HER2 (搜索)-negative, previously untreated, unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma (搜索), including patients with low PD-L1 (搜索) expression.
COMPASSION-15 previously showed cadonilimab plus chemotherapy significantly reduced the risk of death in the overall population regardless of PD-L1 (搜索) status, with a favorable trend in PD-L1 CPS <5 disease.
Akeso, Inc. has enrolled the first patient in COMPASSION-37 (AK104-311), a global, multicenter Phase III head-to-head trial evaluating cadonilimab plus chemotherapy versus chemotherapy with or without nivolumab as first-line treatment for patients with HER2 (搜索)-negative, previously untreated, unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.
The study is designed to assess the efficacy and safety of cadonilimab, Akeso's first-in-class PD-1 (搜索)/CTLA-4 (搜索) bispecific antibody, across geographically and ethnically diverse patient populations, and to test whether dual PD-1/CTLA-4 immune checkpoint blockade can improve outcomes beyond the current standard of care.
Trial Leadership and Design
COMPASSION-37 is co-led by an international group of principal investigators: 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 (搜索) & Institute; and Professor Lin Shen, Director of the Department of Gastrointestinal Oncology at Peking University Cancer Hospital.
Janjigian, Möhler and Shen were investigators on CheckMate 649, the trial that established the clinical value of nivolumab plus chemotherapy in first-line advanced gastric, gastroesophageal junction and esophageal adenocarcinoma and led to adoption of PD-1 (搜索) inhibitor plus chemotherapy as a key first-line strategy for HER2 (搜索)-negative advanced gastric cancer (搜索).
"Immunotherapy has transformed the treatment of stomach and esophagus cancers, helping patients live longer and better," said Janjigian, global principal investigator for COMPASSION-37. "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."
The PD-L1 Question
As immunotherapy has become widely adopted in the first-line setting, the relationship between PD-L1 (搜索) expression and treatment benefit has drawn increasing attention. Studies including CheckMate 649 have shown that the benefit of PD-1 (搜索) inhibitor plus chemotherapy is more pronounced in patients with high PD-L1 expression, while improving outcomes in patients with low PD-L1 expression remains an area of active clinical investigation.
Chemotherapy with or without a PD-1 (搜索) inhibitor remains the international standard of care for advanced gastric cancer (搜索), but the disease is biologically and clinically heterogeneous. In the United States, first-line PD-1 inhibitor indications in advanced gastric cancer are currently limited to PD-L1 (搜索)-positive patients, and current NCCN and ESMO guidelines preferentially recommend nivolumab-based regimens for patients with PD-L1 CPS ≥5. Effective immunotherapy options for PD-L1-low advanced gastric cancer therefore remain a significant global unmet need.
"Advanced gastric cancer (搜索) is characterized by substantial biological and clinical heterogeneity," said Lin Shen. "Previous studies have shown that the magnitude of benefit from PD-1 (搜索) inhibitor therapy is closely associated with PD-L1 (搜索) 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."
From COMPASSION-15 to Global Validation
COMPASSION-15, a randomized, double-blind, placebo-controlled Phase III study, enrolled 610 patients with HER2 (搜索)-negative advanced gastric or gastroesophageal junction adenocarcinoma (搜索). The trial enrolled a notably high proportion of patients with low PD-L1 (搜索) expression (49.8%) and PD-L1-negative disease (23%), far exceeding rates in comparable historical studies.
Results showed that cadonilimab plus chemotherapy significantly reduced the risk of death compared with the control group in the overall population, regardless of PD-L1 (搜索) expression status. Those findings provided the scientific basis for international head-to-head Phase III validation.
"COMPASSION-15 has already shown that cadonilimab plus chemotherapy significantly improves overall survival in patients with HER2 (搜索)-negative advanced gastric cancer (搜索), with a favorable survival trend also seen in patients with PD-L1 (搜索) CPS <5, suggesting that dual PD-1 (搜索)/CTLA-4 (搜索) blockade may expand the population that benefits from immunotherapy," said Jiafu Ji. "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."
Perioperative Development and Broader Program
Beyond the advanced-disease setting, a single-arm Phase II study (NCT07631000) led by Janjigian at MSK is enrolling patients in the United States. It evaluates cadonilimab in combination with FLOT chemotherapy as perioperative treatment in patients with locally advanced, resectable gastric or gastroesophageal junction adenocarcinoma (搜索), exploring whether dual PD-1 (搜索)/CTLA-4 (搜索) blockade can be extended to earlier-stage, curable disease. The study is expected to generate evidence supporting an international multicenter Phase III trial of a cadonilimab-based perioperative regimen.
Cadonilimab received initial marketing approval from China's National Medical Products Administration (搜索) in June 2022 for relapsed or metastatic cervical cancer (搜索) progressing on or after platinum-based chemotherapy. In September 2024 it was approved in combination with fluoropyrimidine- and platinum-based chemotherapy for first-line locally advanced unresectable or metastatic G/GEJ adenocarcinoma, and in May 2025 cadonilimab plus platinum-based chemotherapy, with or without bevacizumab, was approved for first-line persistent, recurrent or metastatic cervical cancer.
By simultaneously targeting PD-1 (搜索) and CTLA-4 (搜索), cadonilimab is designed to deliver synergistic antitumor activity, with the company reporting markedly lower toxicity and improved tolerability compared with conventional combination regimens and activity across multiple tumor types independent of PD-L1 (搜索) expression. The agent has been evaluated in more than 40 clinical studies spanning over 20 indications, including gastric, lung, liver, cervical and pancreatic cancers. Thirteen Phase III or registrational studies are ongoing, three have met their primary endpoints, and two global Phase III or registrational trials are advancing.