On September 30, 2024 Akeso (9926. HK) reported that its internally developed PD-1/CTLA-4 bispecific antibody, cadonilimab, has received approval from the National Medical Products Administration (NMPA) for a new indication: cadonilimab in combination with fluoropyrimidine and platinum-based chemotherapy for first-line treatment of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (Press release, Akeso Biopharma, SEP 30, 2024, View Source [SID1234646953]). This is the second indication approval for cadonilimab in China, following its initial approval for marketing in June 2022.

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The approval of the new indication for cadonilimab combination therapy for first-line treatment of gastric/GEJ cancer is based on the COMPASSION-15/AK104-302 study. In the COMPASSION-15 study, the proportion of patients with PD-L1 CPS < 5 and PD-L1 CPS < 1 in the Intention-to-Treat (ITT) population reached 49.8% and 23%, respectively, which is significantly higher than the data disclosed in previous phase III studies of other immunotherapies for first-line treatment.

In November 2023, the interim analysis of the study achieved the primary endpoint of overall survival (OS). The results showed that the cadonilimab combination therapy significantly reduced the risk of death in advanced gastric cancer patients across all PD-L1 expression levels (including those with PD-L1 CPS ≥5 and <5), extending overall survival benefits and demonstrating notable advantages in objective response and long-term survival. Previous phase III trials of PD-1 inhibitors combined with chemotherapy showed limited or no clinical benefit for patients with low or negative PD-L1 expression.

The results of the COMPASSION-15 study were presented as an oral report at the 2024 AACR (Free AACR Whitepaper). In the ITT population, the median overall survival (mOS) for the cadonilimab regimen reached 15.0 months, compared to 10.8 months in the control group, extending overall survival by 4.2 months and reducing the risk of death by 38% (HR=0.62). In the PD-L1 CPS <5 group, the mOS for the cadonilimab regimen was 14.8 months, with a 30% reduction in the risk of death compared to the control group (11.1 months, HR=0.70). For the PD-L1 CPS ≥5 group, the mOS had not yet been reached, but the risk of death was reduced by 44% compared to the control group (10.6 months, HR=0.56).

COMPASSION-15’s principal investigator, Professor Ji Jiafu from Peking University Cancer Hospital, stated:

" The prognosis for advanced gastric cancer is poor. While currently approved immunotherapy options have improved efficacy compared to traditional chemotherapy, there remains significant potential for enhancement. The cadonilimab combination therapy has substantially increased the objective response rate and overall survival in the general population while reducing disease-related mortality. Remarkably, cadonilimab shows significant overall survival benefits not only in patients with high PD-L1 CPS expression but also in those with low or negative PD-L1 CPS expression.

The approval of cadonilimab as a first-line treatment effectively addresses the efficacy gap of PD-1/L1 monoclonal antibodies in patients with low or negative PD-L1 expression, providing a more comprehensive and effective immunotherapy option for advanced gastric cancer. This advancement benefits all patient populations and presents new opportunities for the global development of gastric cancer immunotherapy, carrying important clinical implications.

As a clinician, I am enthusiastic about the approval of cadonilimab for advanced gastric cancer. This innovative treatment will offer a superior and more comprehensive immunotherapy option for patients, and I look forward to its impact on optimizing the current clinical landscape for advanced gastric cancer."

COMPASSION-15’s principal investigator, Professor Shen Lin from Peking University Cancer Hospital, stated:

"We are delighted by the successful approval of cadonilimab combination therapy for the first-line treatment of advanced gastric cancer. This regimen offers significant advantages over current immunotherapy options in clinical practice, providing a superior choice not only for patients with high PD-L1 expression but also for those with low or negative PD-L1 expression, who previously lacked effective treatment options.

Cadonilimab addresses the limitations of single-target immunotherapy and exemplifies the synergistic mechanism of dual immune therapy with "anti-PD-1 + anti-CTLA-4," thereby filling an important clinical gap in the treatment of advanced gastric cancer. Beyond first-line approval, the phase III clinical study (AK109-301) of cadonilimab combined with pulocimab (AK109, VEGFR-2) for treating advanced gastric cancer that has progressed after PD-1/L1 inhibitor plus chemotherapy has been initiated. There is currently a lack of effective standard treatments for patients with acquired resistance to immunotherapy, and we eagerly anticipate that this new combination regimen will yield improved results in second-line therapy for these patients, ultimately providing clinicians with more effective tools for cancer treatment."

Dr. Xia Yu, Founder, Chairwoman, President, and Chief Executive Officer of Akeso Biopharma, stated:

"We thank all researchers, participants, and patients involved in this clinical study. Their collective efforts have led to the approval of cadonilimab combination therapy for first-line treatment of advanced gastric cancer, introducing a novel bispecific immune therapy combined with chemotherapy.

As immunotherapy evolves, global regulators and the medical community are reassessing the real-world benefits of PD-1 therapies across different PD-L1 expression levels in gastric and esophageal cancers.

Cadonilimab, a novel bispecific antibody targeting both PD-1 and CTLA-4, is supported by robust evidence demonstrating significant clinical benefits for the entire gastric cancer population. Differentiating from PD-1 monoclonal antibody combinations, cadonilimab also shows substantial advantages for patients with low or negative PD-L1 expression. Akeso will continue to explore the global clinical value of cadonilimab."

Gastric cancer is one of the most common malignant tumors worldwide. According to the International Agency for Research on Cancer (IARC) 2022 statistics, there are nearly one million new cases each year, making it the fifth most common cancer. China accounts for about half of these cases and deaths, with HER2-negative patients representing around 88%. For those ineligible for surgery or with metastatic gastric cancer (including gastroesophageal junction cancer), immunotherapy using PD-1/L1 monoclonal antibodies has shown success in first-line treatment, though survival benefits remain limited. Cadonilimab combination therapy is expected to provide a more effective treatment option.