On September 8, 2024 Akeso (9926. HK) reported that it is thrilled to unveil groundbreaking data on its internally developed ivonescimab (a first-in-class PD-1/VEGF bispecific antibody) at the IASLC 2024 World Conference on Lung Cancer (WCLC24) (Press release, Akeso Biopharma, SEP 8, 2024, View Source [SID1234646413]). The data, presented as a Late-Breaking Abstract (LBA) with an oral presentation, comes from a registration Phase III head-to-head clinical trial comparing ivonescimab monotherapy to pembrolizumab monotherapy as a first-line treatment for PD-L1 positive (PD-L1 TPS ≥1%) locally advanced or metastatic non-small cell lung cancer (NSCLC).

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The trial results were presented by Professor Caicun Zhou, MD, PhD, Chief Physician and Director of the Department of Medical Oncology at Shanghai Pulmonary Hospital, Tongji University School of Medicine, and President-Elect of IASLC. Furthermore, Professor Zhou participated in the official WCLC press conference, discussing the clinical significance of this study.

In the HARMONi-2 study, baseline characteristics were well-balanced between the experimental and control groups. In the intention-to-treat (ITT) population, ivonescimab significantly improved progression-free survival (PFS) compared to pembrolizumab, markedly reducing the risk of disease progression or death. Subgroup analyses revealed that ivonescimab outperformed pembrolizumab across various factors, including age, sex, ECOG performance status, PD-L1 expression, histological type, and the presence of liver or brain metastases. This is the first randomized phase III study to demonstrate a clinically significant improvement in efficacy with a novel drug compared to pembrolizumab in NSCLC.

PFS Stratified HR 0.51, mPFS 11.14 Months

Ivonescimab as first-line treatment for PD-L1 positive NSCLC significantly extends median progression-free survival (mPFS) compared to pembrolizumab, with both statistical and clinical significance.

In the ITT population, ivonescimab demonstrated a median progression-free survival (mPFS) of 11.14 months compared to 5.82 months for pembrolizumab. The PFS hazard ratio (HR) was 0.51 (P<0.0001), indicating a significant 49% reduction in the risk of disease progression or death.
Ivonescimab significantly improved the objective response rate (ORR) and disease control rate (DCR) compared to pembrolizumab in the first-line treatment of PD-L1 positive non-small cell lung cancer (NSCLC) patients. The ORR for ivonescimab was 50.0%, versus 38.5% for pembrolizumab, while the DCR was 89.9% for ivonescimab versus 70.5% for pembrolizumab. These results highlight ivonescimab’s effective anti-tumor effect.
Overall survival data was not yet mature at the time of the data cutoff and will be evaluated in the future.
Significant Progression-Free Survival Benefits of Ivonescimab Across PD-L1 Expression Subgroups

Ivonescimab demonstrated significant progression-free survival benefits in patients with both low and high PD-L1.

The HARMONi-2 study enrolled participants with PD-L1 TPS ≥50%, accounting for 42.2%, aligning with the distribution in real-world populations.
In the PD-L1 TPS ≥50% population, the PFS HR for ivonescimab versus pembrolizumab was 0.46, reducing the risk of disease progression/death by 54%.
In the PD-L1 TPS 1-49% population, the PFS HR for ivonescimab versus pembrolizumab was 0.54, reducing the risk of disease progression/death by 46%.
Ivonescimab showed meaningful progression-free survival benefits in both squamous and non-squamous subgroups

In the HARMONi-2 study, 45.5% of the enrolled patients had sq-NSCLC, and 54.5% had nsq-NSCLC.
In sq-NSCLC subgroup, the PFS HR for ivonescimab and pembrolizumab was 0.48.
In nsq-NSCLC subgroup, the PFS HR for ivonescimab and pembrolizumab was 0.54.
Ivonescimab monotherapy demonstrated significant efficacy regardless of liver metastasis, brain metastasis, or a history of hemoptysis.

In this study, 12.6% of patients treated with ivonescimab had liver metastasis, and 16.7% had brain metastasis.
The PFS HR for ivonescimab and pembrolizumab in patients with brain metastasis was 0.55; in those without brain metastasis, the PFS HR was 0.53.
The PFS HR for ivonescimab and pembrolizumab in patients with liver metastasis was 0.47; in those without liver metastasis, the PFS HR was 0.53.
Ivonescimab Demonstrated Acceptable and Manageable Safety Profile Across Subgroups

In the HARMONi-2 study, 72.2% of patients with squamous cell carcinoma (sq-NSCLC) treated with ivonescimab had centrally located tumors, 10.0% had tumors with cavitation or necrosis, and 6.7% had tumors encasing large blood vessels. Despite these factors, which typically contraindicate traditional anti-VEGF therapies due to bleeding risks, ivonescimab did not significantly increase bleeding compared to the control group. The study confirms that ivonescimab has an acceptable and manageable overall safety profile, consistent with prior research.

The incidence of grade 3 or higher treatment-related adverse events (TRAEs) in sq-NSCLC patients treated with ivonescimab was comparable to that in the pembrolizumab group (22.2% vs. 18.7%).
HRQoL with ivonescimab was comparable to pembrolizumab.
Based on the results of HARMONi-2, Akeso’s partner, Summit, plans to initiate HARMONi-7 in early 2025. HARMONi-7 is currently planned as a multi-regional Phase III clinical trial that will compare ivonescimab monotherapy to pembrolizumab monotherapy in metastatic NSCLC patients whose tumors have high PD-L1 expression (PD-L1 TPS≥50%)

Dr. Michelle Xia, Founder, Chairwoman, President, and CEO of Akeso, said: "The research outcomes of HARMONi-2 are very encouraging. Pembrolizumab has been one of the most commercially successful innovative drugs globally in recent years. The clinically meaningful outcomes of ivonescimab versus pembrolizumab in a randomized, double-blind Phase III study, coupled with its demonstrated superior efficacy and manageable safety profile, affirm the immense potential of ivonescimab as a cornerstone treatment in cancer immunotherapy. This further substantiates the clinical benefit and market potential of ivonescimab on a global scale. The HARMONi-2 results presented today encourages Akeso and our partner SUMMIT to expand the clinical development of ivonescimab globally in more cancer indications for the benefit of patients with unmet medical needs. We are very impressed by Summit’s ability to execute on clinical development since the start of our collaboration, and we are excited to work with them to pave the way for approvals in the US, Europe, and the rest of the license territories in the future."

About ivonescimab
Ivonescimab is a novel global first-in-class PD-1/VEGF bi-specific immunotherapy drug internally developed by Akeso. Ivonescimab has been approved in China for treating EGFR mutated locally advanced or metastatic non-squamous NSCLC patients who have progressed after EGFR TKI treatment. It is the world’s first approved bispecific antibody with a "cancer immunotherapy + anti-angiogenesis" synergistic mechanism.

Akeso out-licensed Summit Therapeutics exclusive rights to ivonescimab for the development and commercialization in certain territories including United States, Canada, Europe, Japan, Latin America, Africa and the Middle East. Ivonescimab is known as AK112 within Akeso and SMT112 in the territories licensed to Summit.

Currently, a Phase III study of ivonescimab monotherapy versus pembrolizumab monotherapy as first-line treatment for PD-L1+ NSCLC has met its primary endpoint of progression-free survival (PFS) in an interim analysis, achieving a decisive positive outcome. Based on this study, a supplemental New Drug Application (sNDA) for ivonescimab monotherapy as first-line treatment for PD-L1+ NSCLC has been submitted and granted priority review. Additionally, a Phase III clinical study of ivonescimab combined with chemotherapy versus tislelizumab combined with chemotherapy as first-line treatment for squamous NSCLC is ongoing. The HARMONi study, an international multicenter Phase III clinical study led by Akeso’s partner Summit, is investigating ivonescimab combined with chemotherapy for EGFR-mutated, locally advanced or metastatic nsq-NSCLC that has progressed after third-generation EGFR-TKI therapy. Another international multicenter Phase III study is comparing ivonescimab combined with chemotherapy to pembrolizumab combined with chemotherapy as first-line treatment for squamous NSCLC.

Furthermore, 3 new Phase III clinical studies are either initiated or about to start, including ivonescimab combined with AK117 (CD47) as first-line treatment for PD-L1 positive squamous cell carcinoma of the head and neck (vs. pembrolizumab), ivonescimab combined regimen as first-line treatment for cholangiocarcinoma (vs. durvalumab combined regimen), and ivonescimab combined regimen as first-line treatment for pancreatic cancer. Overall, ivonescimab is engaged in over 25 clinical trials across 17 indications, including lung cancer, pancreatic cancer, breast cancer, hepatocellular carcinoma, and colorectal cancer, through both monotherapy and combination therapy approaches.