On November 7, 2023 Akeso (9926.HK) reported positive results from an interim analysis of AK104-302 study, a randomized, double-blind, multicenter, phase III clinical study evaluating PD-1/CTLA-4 bispecific antibody, cadonilimab (开坦尼) in combination with capecitabine plus oxaliplatin (XELOX) compared to placebo plus XELOX for first-line treatment of unresectable locally advanced or metastatic gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJC) (Press release, Akeso Biopharma, NOV 7, 2023, View Source;gastric-cancer-or-gastroesophageal-junc-301979956.html [SID1234637194]). The trial achieved its primary endpoint by demonstrating a statistically significant overall survival (OS) improvement. The Independent Data Monitoring Committee (IDMC) recommended the early submission of a supplemental new drug application (sNDA) for cadonilimab in this indication based on the interim analysis.

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The interim analysis showed that cadonilimab plus chemotherapy significantly improved OS in the all-comer patients irrespective of PD-L1 status, compared to placebo plus chemotherapy, meeting the pre-defined efficacy criteria. The safety profile remained consistent with previous results, with no new safety signals identified. These data will be presented in future international academic conferences/journals.

Interim Analysis Highlight:

Cadonilimab combined with chemotherapy significantly reduces the risk of death in all-comer patients, including whose with PD-L1 CPS≥5 and PD-L1 CPS<5. The hazard ratios (HRs) for OS in patients with different PD-L1 status were superior to other disclosed PD-1 plus chemotherapy combination treatment.
The combination of cadonilimab and chemotherapy also demonstrated superior OS in patients with PD-L1 CPS<5 as well as PD-L1 negative, maintaining the excellent performance seen in the phase II study.
"We extend our sincere gratitude to all the investigators, participants, and patients who actively took part in the clinical trial," expressed Dr. Yu Xia, Founder, Chairman, President, and CEO of Akeso. " Thanks to your dedication and efforts, an estimated 500,000 gastric cancer patients in China may have access to a new bispecific IO drug combination therapy offering improved treatment efficiency and survival prospects. We will continue to adhere to the recommendations of IDMC, efficiently promote the study, and engage in proactive communication with China’s National Medical Products Administration (NMPA) regarding the marketing application of cadonilimab for this new indication. We eagerly anticipate the early approval of this innovative therapy for the benefit of patients."

ABOUT AK104-302

AK104-302 is a Phase III clinical trial evaluating the use of cadonilimab (which is the world’s first approved PD-1/CTLA-4 bi-specific antibody) in combination with XELOX as first-line treatment for unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (GC/GEJC). This randomized, double-blind, multi-center study aims to assess the efficacy of cadonilimab plus XELOX compared to placebo plus XELOX in the intent-to-treat (ITT) population.

The AK104-302 trial represents the first Phase III clinical study of a PD-1/CTLA-4 bispecific antibody combined with chemotherapy for first-line treatment of gastric cancer. Approximately 60% of patients in the ITT population had a PD-L1 CPS＜5, a proportion comparable to real-world scenarios.

About Cadonilimab

Cadonilimab is a first-in-class bispecific antibody that targets both PD-1 and CTLA-4 developed by Akeso. It is a symmetric tetravalent bispecific antibody with a crystallizable fragment (Fc)-null design. In addition to demonstrating biological activity similar to that of the combination of CTLA-4 and PD-1 antibodies, cadonilimab possesses higher binding avidity in a high-density PD-1 and CTLA-4 setting than in a low-density PD-1 setting, while a mono-specific anti-PD-1 antibody does not demonstrate this differential activity. With no binding to Fc receptors, cadonilimab shows minimal antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and interleukin-6 (IL-6)/IL-8 release. These features all likely contribute to significantly lower toxicities of cadonilimab observed in the clinic. Higher binding avidity of cadonilimab in a tumor-like setting and Fc-null design may lead to better drug retention in tumors and improve safety while achieving anti-tumor efficacy.

The China National Medical Products Administration has approved cadonilimab for recurrent or metastatic cervical cancer. Cadonilimab has been included and recommended in multiple clinical guidelines such as CSCO. Cadonilimab has been engaged in more than 60 ongoing clinical trials including investigator-initiated studies. Patient enrollment has been completed for the phase 3 study of cadonilimab for first-line treatment of advanced cervical cancer. A phase 3 study of cadonilimab as an adjuvant treatment for hepatocellular carcinoma is ongoing. Furthermore, a Phase 3 study comparing cadonilimab with chemotherapy to tislelizumab Injection with chemotherapy is underway for the first-line treatment of PD-L1 expression-negative non-small cell lung cancer.