On December 5, 2023 Akeso (9926.HK) reported results from three investigator-initiated trials (IITs) of its bispecific IO drug, cadonilimab (a PD-1/CTLA-4 bispecific antibody), at the 2023 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Asia Congress (ESMO Asia) (Press release, Akeso Biopharma, DEC 5, 2023, View Source [SID1234638176]).

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1. Real-world outcomes of cadonilimab（PD-1/CTLA-4 bispecific antibody）plus chemotherapy as first-line treatment in advanced gastric (G) or gastroesophageal junction (GEJ) cancer with PD-L1 CPS≤5

This real-world study aimed to investigate the efficacy of cadonilimab in advanced G/GEJ cancer patients with PD-L1 CPS <5 gastric cancer, a population that exhibits poor responses to current immunotherapies (up to 60% of real-world cases), to address a current unmet clinical need.

The objective response rate (ORR) reached 68.2%, the disease control rate (DCR) reached 100%, and the median progression-free survival (mPFS) was 7.5 months. Cadonilimab combination therapy demonstrates good safety in real-world settings.

The study findings are consistent with the previously disclosed phase II randomized clinical trial results at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. They further confirm the promising efficacy and safety of cadonilimab plus chemotherapy as first-line treatment in advanced G/GEJ cancer patients with PDL1 CPS≤5.

The phase III study of cadonilimab plus chemotherapy as first-line therapy for G/GEJ cancer has achieved its primary endpoint. Akeso is actively engaging in discussions with the Chinese regulatory authorities regarding the marketing application of cadonilimab for this new indication.

The combination of immune checkpoint inhibitors and chemotherapy has been approved as first-line treatment for advanced HER2-negative G/GEJ cancer. However, its effectiveness has been limited in patients with low PD-L1 expression or PD-L1-negative G/GEJ cancer. In light of relevant studies, cadonilimab has demonstrated encouraging efficacy and safety in advanced G/GEJC, especially among the PD-L1 CPS <5 population, showing remarkable performance. This combination therapy is expected to revolutionize the treatment approach for all-comers with advanced gastric cancer.

This research is led by Professor Xu Qi from Zhejiang Cancer Hospital.

2. A phase II study of cadonilimab + FOLFOXIRI and bevacizumab as initial therapy for unresectable proficient mismatch repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer (mCRC)

pMMR/MSS CRC, which constitutes approximately 95% of all CRC cases, is recognized as a "cold cancer" in immunotherapy. Traditional chemotherapy has demonstrated restricted efficacy in addressing this condition. Despite efforts to explore immunotherapy as a potential treatment, satisfactory outcomes have not been achieved, and there are currently no globally approved immunotherapeutic agents. Thus, there is an urgent need for novel and more effective treatment options.

Relevant studies have shown that combining CTLA-4 monoclonal antibody with PD-1 monoclonal antibody has demonstrated promising anti-tumor activity in patients with pMMR/MSS mCRC who have undergone multiple lines of therapy. Additionally, numerous clinical trials have revealed that the PD-1/CTLA-4 bispecific antibody, cadonilimab, exhibits encouraging anti-tumor efficacy against a wide range of tumors that have limited or no response to immunotherapy, including PD-(L)1 inhibitors.

This phase II clinical study aims to investigate the efficacy and safety of combining cadonilimab with FOLFOXIRI and bevacizumab as a first-line therapy for pMMR/MSS mCRC. The study is currently in the enrollment phase. Cadonilimab is currently being evaluated in over 60 clinical studies worldwide, targeting more than 20 types of malignant tumors, including gastric, hepatocellular, lung, cervical, pancreatic, renal, esophageal squamous, colorectal, nasopharyngeal, and pleural mesothelioma. These studies include multiple therapeutic clinical trials for solid tumors that are refractory/recurrent to standard treatments or have no standard treatment.

This IIT is led by Professor Lin Rongbo from Fujian Cancer Hospital.

3. Neoadjuvant cadonilimab (PD-1/CTLA-4 bispecific antibody) plus transhepatic arterial infusion chemotherapy (haic) with folfox for resectable multinodular cnlc Ib/IIa hepatocellular carcinoma(car_hero)

The recurrence rate of hepatocellular carcinoma (HCC) is high after surgery. However, there are no approved standard-of-care neoadjuvant or adjuvant therapies. This ongoing study preliminarily demonstrated that neoadjuvant cadonilimab plus HAIC shows a promising antitumor activity with manageable safety for HCC.

The disease control rate (DCR) among all treated patients reached 100%. All patients who received two doses of cadonilimab after FOLFOX-HAIC therapy achieved major pathological remission (MPR), indicating that the proportion of tumor-active cells remaining in the tumor bed was less than 50%. Additionally, the size of the tumor necrosis area significantly increased compared to the group receiving FOLFOX-HAIC alone. According to the RECIST1.1 criteria, one-third of patients treated with two doses of cadonilimab in the 1-time FOLFOX-HAIC sequence achieved partial remission (PR), indicating a strong synergistic effect between cadonilimab and FOLFOX-HAIC in promoting tumor necrosis. Cadonilimab showed a favorable safety profile as neoadjuvant therapy for HCC.

The results showed that using 1 FOLFOX-HAIC treatment followed by two doses of cadonilimab treatment regimen demonstrated the potential for enhanced clinical efficacy compared to the clinically used FOLFOX-HAIC regimen. Data disclosure for this study is as of November 26, 2023, and the study is still ongoing.

Akeso is currently conducting a randomized, double-blind, controlled Phase III clinical trial (AK104-306, NCT05489289) to evaluate the efficacy and safety of cadonilimab as adjuvant therapy for high-risk hepatocellular carcinoma after curative resection. Previous studies presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Meeting 2023 and Frontiers in Immunology have also demonstrated the promising anti-tumor activity and favorable safety profile of cadonilimab when combined with lenvatinib for the first-line treatment of advanced HCC. Collectively, these clinical studies indicate that cadonilimab exhibits significant potential efficacy across different clinical stages of HCC, potentially reshaping the landscape of HCC immunotherapy.

This IIT is led by Professor Peng Tao, Director of the Hepatobiliary Surgery Department at the First Affiliated Hospital of Guangxi Medical University. The study results were previously presented at the American Association for the Study of Liver Diseases’ The Liver Meeting 2023.

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. Phase 3 study of cadonilimab for first-line treatment of gastric cancer has met its endpoint of PFS. 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.