Akeso Announces Significant Data from Phase III Registration Study of Dual PD-1/VEGF Inhibitor

Recently, at the 25th World Conference on Lung Cancer (WCLC), Akeso revealed positive data from its Phase III registration study, AK112-303 (HARMONi-2), comparing Ivonescimab monoclonal antibody against Pabolizumab (Drug K) monotherapy for first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with PD-L1 expression positive (PD-L1 TPS≥1%). 

Additionally, the company also delivered an oral presentation on the Phase II AK112-205 study data of Ivonescimab. The study data showed that either as a monotherapy or in combination with chemotherapy during the perioperative period for resectable NSCLC provided substantial benefit to patients in achieving optimal pathologic complete response (pCR) and major pathologic response (MPR) rates, and was consistent across various tumor stages and PD-L1 expression subgroups.

About the Phase III AK112-303 Study

The HARMONi-2 trial had a balanced baseline population between the test group and the control group, with 42.2% of patients exhibiting a PD-L1 TPS of ≥50%, mirroring the distribution in the real-world population. The HARMONi-2 study is the first global randomized, double-blind, controlled Phase III clinical trial to show significant positive results when compared to Drug K.

The study demonstrated that, 

·In the intent-to-treat (ITT) population, Ivonescimab antibody significantly extended patients' progression-free survival (PFS), markedly reducing the risk of disease progression or death (11.14 vs. 5.82 months, HR=0.51, P<0.0001).

·as compared to Drug K monotherapy. Compared to Drug K, Ivonescimab also significantly improved the objective response rate (50.0% vs. 38.5%) and the disease control rate (89.9% vs. 70.5%). 

·Sub-group results were consistent with the ITT findings, including variations by age, gender, ECOG score, PD-L1 expression, pathological type, presence of liver or brain metastases among other groups.

As of now, the overall survival (OS) data from the study remains immature. The adverse reactions observed were consistent with previous studies.

About the Phase II AK112-205 Study

The AK112-205 study enrolled a total of 60 NSCLC (non-small cell lung cancer) patients, with 78.3% in clinical stage III and 90% of participants testing positive for lymph node involvement (N+), of which 70% were N2. The results revealed that，

·As of August 2024, in the combination chemotherapy group, the rates of complete pathological response (pCR) and major pathological response (MPR) increased to 52.7% and 72.7% respectively. Specifically for squamous carcinoma patients, the pCR rate reached 63.6% and the MPR rate reached 84.1%, indicating superior efficacy compared to PD-1/L1 blockers combined with chemotherapy.

·In the monotherapy group, the pCR was 30.0%, MPR was 60.0%, and only 50.0% of patients had a residual viable tumor (RVT) less than 5%. 

·The progression-free survival (PFS) data is not yet mature. 

Regarding adverse effects, the drug was well-tolerated; during the study, there were no incidents of surgery cancellations or delays or wound healing complications due to treatment-related adverse events (TRAEs).

About Ivonescimab

Ivonescimab (AK112, Ivonescimab) is a humanized, IgG1 subtype, bispecific antibody that targets vascular endothelial growth factor-A (VEGF-A) and programmed cell death protein-1 (PD-1). It binds simultaneously to both VEGF-A and PD-1, competitively blocking their interactions with their respective ligands, and exhibits anti-tumor activity. In May 2024, the drug was approved by the NMPA for the treatment of patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) with EGFR gene mutations, who have progressed following treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).

In December 2022, the company granted exclusive development rights for AK112 to Summit Company in the United States, Europe, Canada, and Japan, with a total transaction value of up to $5 billion — including a $500 million upfront payment and a double-digit percentage of net sales. This deal set a record for the highest transaction amount for the licensing of a single innovative Chinese drug.

Ivonescimab is designed using Akeso 's unique Tetrabody technology. Given the co-expression of VEGF and PD-1 in the tumor microenvironment, Ivonescimab, as a single agent blocking these two targets, could potentially be more effective in inhibiting these pathways and thus enhance anti-tumor activity compared to combination therapies. The drug's indications cover various cancers including lung, gastrointestinal, breast, head and neck, hepatocellular, and colorectal cancers, with clinical research extending to the entirety of the NSCLC population. Previously, Ivonescimab had received designations as a breakthrough therapy for three lung cancer indications from the CDE.

In March 2024, the company presented updated data from the Phase II clinical study (AK112-201) of Ivonescimab combined with first-line chemotherapy for the treatment of advanced NSCLC at the European Lung Cancer Congress (ELCC). Earlier study results had been consecutively published at the 2023 ASCO Annual Meeting and in eClinical Medicine, a subsidiary journal of The Lancet.

As of October 2023, with a median follow-up time extended to 21.3 months, results indicated:

·In Cohort 1, which included patients with EGFR/ALK wild-type NSCLC receiving Ivonescimab combined with chemotherapy, showed an Objective Response Rate (ORR) of 54.2%, a Disease Control Rate (DCR) of 95.8%, and a median Duration of Response (mDOR) of 15.4 months. The median Progression-Free Survival (mPFS) stood at 13.3 months, with a 9-month PFS rate of 58.9% and a 9-month Overall Survival (mOS) rate of 81.9%.

·In Cohort 2, treating patients with advanced non-squamous NSCLC with EGFR mutations who progressed after EGFR-TKI treatment, showed, at a median follow-up of 25.8 months, an ORR of 68.4%, a DCR of 94.7%, a mDoR of 8.7 months; mPFS of 8.5 months, and mOS of 22.5 months with a 12-month OS rate of approximately 73.7%.

·In Cohort 3, which included patients with advanced NSCLC progressing after anti-PD-1 therapy combined with platinum-based doublet chemotherapy, showed, at a median follow-up time of 24.7 months, an ORR of 40%, DCR of 80%, mDoR of 12.7 months; mPFS of 7.1 months, and mOS of 17.1 months, with a 12-month OS rate of 65%.

It was also observed that no intracranial hemorrhages occurred in patients with brain metastases undergoing treatment.

Targeted PD-(L)1/VEGF Bispecific Antibodies 

As of May 2024, there are approximately 18 PD-(L)1/VEGF bispecific antibodies under investigation, with only one drug, Evolocumab, approved for use.

About Akeso

Akeso is a leading enterprise integrating research, development, production, and commercialization of globally innovative or best-in-class biopharmaceuticals. The company has developed the unique end-to-end Akeso Comprehensive New Drug Research and Development Platform (ACE Platform), establishing an innovative R&D system centered around Tetrabody bispecific antibody technology, Antibody Drug Conjugate (ADC) technology platform, mRNA technology platform, and cell therapy technology.

In August 2024, the company announced its mid-year results, showing that revenue from innovative drugs reached 940 million yuan in the first half of 2024, representing a nearly 24% year-on-year increase. The company has a substantial cash reserve, with cash and other short-term financial assets in fixed deposits totaling 5.69 billion yuan as of June 30.

The company has developed over 50 innovative drug candidates for the treatment of major diseases such as cancer, autoimmune diseases, inflammation, and metabolic disorders. By August 2024, a total of 4 new drugs were approved for market sale, and applications for market approval of 5 new drugs in 7 indications within both oncology and non-oncology fields have been accepted. There are 12 new drugs in Phase III or approved for marketing. In total, 24+ Phase III clinical trials have been completed or are underway.

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