ASCO21 | Latest Updates on Two Akeso’s AK104 (PD-1/CTLA-4 Bispecific Antibody) Clinical Trials

1. Phase 2 study of AK104 (PD-1/CTLA-4 bispecific antibody) plus lenvatinib as first-line treatment of unresectable hepatocellular carcinoma


Abstract #: 4101


First Author: Li Bai, MD, PhD, The General Hospital of the People's Liberation Army, Beijing, China

Anti–PD-(L)1 plus anti-CTLA-4 therapies (e.g. nivolumab/ipilimumab, tremelimumab/durvalumab) produce durable immune responses in patients (pts) with advanced hepatocellular carcinoma (HCC). More recent data suggests that the combination of immune checkpoint inhibitors (ICIs) with a multi-kinase inhibitor is efficacious against unresectable HCC (uHCC). Its novel Tetrbody design makes Fc receptor removable with activity. AK104 is a humanized IgG1 bispecific antibody that simultaneously binds to PD-1 and CTLA-4. Early data suggests that AK104 possesses encouraging anti-tumor activity in selected tumour types and an improved safety profile compared to the co-administration of anti-PD-1 plus anti-CTLA-4 antibodies. Lenvatinib is a multi-kinase inhibitor and approved for first-line treatment of uHCC. Here, we report results from a phase 2 study of AK104 plus lenvatinib in pts with uHCC.



In this single-arm, multicenter phase II study (NCT04444167), pts with uHCC received AK104 (6 mg/kg IV q2w or 15 mg/kg IV q3w) and lenvatinib (8 mg [bodyweight < 60 kg] or 12 mg [weight ≥ 60 kg] PO QD). Primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints include disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS).



As of February 1 2021, 30 pts (86.7% male, median age 52.5yrs [31-71], 30% was ECOG 1, 93.3% was HBV+) had received the combination therapy. Of 18 pts evaluable for antitumor activity (defined as pts with the opportunity to be followed for at least 2 scans [≥13 weeks]), ORR per RECIST v1.1 was 44.4% (8/18), DCR was 77.8%. 2 pts who had close to 30% reduction in tumor size from baseline. Median PFS has not been reached. Treatment-related adverse events (TRAEs) occurred in 83.3% of pts (G3 TRAEs occurred in 26.7% [8/30], and no G4 TRAEs or TRAEs leading to death). Most common TRAEs (≥15%) were increased AST (36.7%) and ALT (36.7%), decreased platelet count (33.3%), decreased neutrophil count (30.0%), and increased blood bilirubin (26.7%), with the vast majority being grades 1 or 2.



Thus it can be seen that AK104 plus lenvatinib as first-line therapy for uHCC has showed promising antitumor activity and an acceptable safety profile. Toxicities were manageable, with no unexpected safety signals. Enrollment for AK104 15 mg/kg q3w plus lenvatinib is currently ongoing, and longer follow-up is needed to further evaluate the durability of response.


2. A Phase I study of AK119, an anti-CD73 monoclonal antibody, in combination with AK104, an anti-PD-1/CTLA-4 bispecific antibody, in patients with advanced or metastatic solid tumors.


Abstract #: TPS2675


First Author: Ben Markman, FRACP, MBBS, Alfred Hospital, Australia

AK119 is a humanized IgG1 monoclonal antibody (mAb) that selectively binds to and inhibits the ectonucleotidase activity of CD73, a cell surface enzyme that converts adenosine monophosphate (AMP) into adenosine. Adenosine has been shown to facilitate tumor-mediated evasion. CD73 inhibition may therefore reduce adenosine accumulation and promote anti-tumor immunity. AK104 is a recombinant humanized IgG1 bispecific antibody that simultaneously binds to programmed cell death protein 1 (PD-1) and cytotoxic T- lymphocyte-associated antigen protein 4 (CTLA-4). Preliminary data from phase I and II studies suggest that AK104 has encouraging anti-tumor activity in selected tumor types and an improved safety profile compared to the co-administration of anti-PD-1 plus anti-CTLA-4 mAbs. Preclinical studies show that CD73 inhibition synergistically increases the anti-tumor activity of PD-1 and CTLA-4 immune checkpoint inhibitors (ICIs). Published early clinical data suggests that anti-CD73 therapy in combination with ICIs produces improved clinical outcomes. Thus, AK119 plus AK104 is postulated to have synergistically enhanced anti-tumor activity compared to the administration of anti-CD73 monotherapy or ICIs alone.


AK119-102 is a phase 1a/1b, first-in-human, multicenter, open-label study (NCT04572152) in patients with advanced solid tumors that are refractory to standard therapies. The primary objective is to assess safety, tolerability and dose limiting toxicity; and to determine the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of AK119 in combination with AK104. Secondary objectives are to evaluate antitumor activity, PK and AK119 immunogenicity. The dose-escalation phase will evaluate 5 dose levels of AK119 (1mg/kg to 40 mg/kg Q2W IV) in combination with 6mg/kg AK104 Q2W IV using a 3+3+3 study design (Figure 1).

Figure1  AK119-102 Study Design


Eligible pts will receive a single dose of AK119 on C0D1 of a 14-day lead-in period. Thereafter, from C1D1 pts will receive AK119 in combination with AK104 on a 28-day cycle, until unacceptable toxicity, confirmed progressive disease, subject withdrawal, or for a maximum of 24 months. The lead-in period is only applicable for dose-escalation cohorts. Any dose-escalation cohort not exceeding the MTD may be expanded to a maximum of 18 subjects with selected solid tumor types for further evaluation of safety, PK/ PD, immunogenicity, and preliminary anti-tumor activity.


As of April 12 2021, five research centers have launched the study in Australia. No DLT occurred in AK119 (1mg/kg) + AK104 (6mg/kg) Q2W cohort; the safety evaluation of cohort AK119 (3mg/kg) + AK104 (6mg/kg) Q2W is in process. AK104 in combination with AK119 has showed a good tendency of safety profile.




Cadonilimab (AK104) is a novel, potential next-generation, first-in-class bi-specific PD-1/ CTLA-4 immuno-oncology backbone drug independently developed by the Company, and its major indications include liver cancer, cervical cancer, lung cancer, gastric cancer, esophageal squamous cell cancer and nasopharyngeal carcinoma. The preliminary research data of cervical cancer, gastric cancer and other tumors shows that, as compared with the combination therapy of PD-1 and CTLA-4, Cadonilimab has much lower toxicity and demonstrated promising safety profile and efficacy. Our AK104 project has been incorporated in the Major New Drug Innovation Program under the 13th Five-year Plan for Major Technology Project (十三五「重大新药创制」科技重大专项支持项目) issued by National Health Commission and Ministry of Science and Technology in 2017 and has been enlisted in the 2017 Pearl River Talent Program of Guangdong Province Introduction of Innovation and Entrepreneurship Team Support Program (2017年广东省「珠江人才计划」引进创新创业团队支持项目). It was also jointly rated by China Medical Biotechnology Association and Chinese Medicinal Biotechnology as one of the 2017 Top Ten Medicinal Biotechnology Advancements in China (2017年中国医药生物技术十大进展).



The Company is a biopharmaceutical company dedicated to the research, development, manufacturing and commercialization of new innovative antibody drugs that are affordable to patients worldwide. Since the Companys establishment, the Company has established an end-to-end comprehensive drug development platform (ACE Platform) and system, encompassing fully integrated drug discovery and development functions, including target validation, antibody drug discovery and development, CMC production process development, and GMP compliant scale production. The Company has also successfully developed a bi-specific antibody drug development technology (Tetrabody technology). The Company currently has a pipeline of over 20 innovative drugs for the treatment of major diseases like tumors, autoimmune diseases, inflammation and metabolism diseases, 13 of which have entered clinical stage, including two first-in-class bi-specific antibody drugs (PD-1/CTLA-4 and PD-1/VEGF). The Companys vision is to become a global leading biopharmaceutical company through research and development of high efficacy and breakthrough new drugs that are first-in-class and best-in-class therapies.