Shanghai, China, June 10, 2025 — Shanghai Henlius Biotech, Inc. (2696.HK) announced that the first subject has been dosed for HLX43-NSCLC201, a phase 2 international muticenter clinical trial of HLX43, the novel Programmed Death-Ligand 1 (PD-L1)-targeting antibody-drug conjugate (ADC) that developed by the company based on the collaboration with MediLink Therapeutics, for the treatment of patients with advanced non-small cell lung cancer (NSCLC). The results from the phase 1 clinical trial of HLX43 has been first released at the 2025 ASCO Annual Meeting，demonstrating manageable safety profile and encouraging efficacy across multiple tumor types, particularly in various types of NSCLC, including squamous and non-squamous NSCLC patients (sqNSCLC and nsqNSCLC), patients with or without EGFR mutation, patients with or without brain/liver metastasis, and PD-L1 positive or negative patients. At present, no PD-L1 targeting ADC has been approved for marketing globally. HLX43 is the first PD-L1 ADC progressed to phase 2 clinical trial development globally.
Immune checkpoint inhibitors represented by PD-（L）1 monoclonal antibodies have emerged in recent years and revolutionised all lines of treatment for tumor patients. However, there are still many patients with positive PD-L1 expression who do not respond to or develop resistance to PD-1/PD-L1-targeted therapy [1]. To date, there has been no subsequent-line treatment for patients who are resistant to PD-1/L1 immunotherapy or failed to benefit from the standard treatments including immunotherapy, indicating a significant unmet medical need to further improve the clinical benefits for these patients. As a novel targeting therapy with the most prominent anti-tumor efficacy, ADCs have shown preliminary therapeutic potential in the treatment of multiple advanced solid tumors, such as breast cancer (BC), lung cancer (LC), esophageal cancer (EC) and gastric cancer (GC), making it a promising therapeutic in solid tumors [2]. PD-L1 is expressed in patients across a broad spectrum of tumor types including NSCLC, colorectal cancer (CRC), triple negative breast cancer (TNBC), head and neck squamous cell carcinoma. The prevalence of PD-L1 expression is over 50% in multiple tumor types, with lung cancer up to 70%. And it displays limited expression on normal tissues, highlighting the potential of PD-L1 as a target for ADCs, which may bring new options for cancer treatment [3].
Lung cancer is the most common cancer worldwide in terms of incidence and mortality. According to GLOBOCAN 2022, there were over 2.48 million new cases of lung cancer globally in 2022, accounting for 12.4% of all new cancer cases [4]. Most lung cancer patients are diagnosed at advanced stages [5], indicating a significant unmet clinical need. By histology, NSCLC can be classified into squamous cell carcinoma (approximately 30%), adenocarcinoma (approximately 50%) and other subtypes including large cell carcinoma. While targeted therapies for driver gene mutations, such as EGFR, have become well-established, EGFR wild-type cases account for 70%-85% of all NSCLC patients, including nearly all squamous cell carcinoma cases and 50-55% of adenocarcinoma cases [6]. Currently, the treatment landscape of EGFR wild-type NSCLC remains limited by a scarcity of highly effective options, particularly in second-line and later (2L+) therapy, where docetaxel-based chemotherapy continues to serve as the standard of care despite its suboptimal efficacy [7,8].
HLX43 is a novel PD-L1 directed ADC, composed of a fully humanized anti-PD-L1 IgG1 antibody, a novel tripeptide linker and topoisomerase inhibitor payload. The drug-to-antibody ratio (DAR) is around 8. Its mechanisms of action integrate targeted cytotoxic delivery and immune checkpoint activation through PD-L1/PD-1 blockade. Upon binding to tumor cells with PD-L1 expression, the cytotoxic payload of HLX43 will be delivered into tumor cells via dual mechanisms. HLX43 will undergo receptor-mediated endocytosis, releasing the cytotoxic payload intracellularly via linker cleavage, and the payload further diffuses into neighboring tumor cells via bystander effect, thereby blocking DNA replication and triggering tumor cell apoptosis. Meanwhile, the anti-PD-L1 antibody of HLX43 activates immune modulation and blocks immune checkpoints, driving synergistic anti-tumor efficacy. Preclinical and phase 1 studies have demonstrated that, HLX43 has a favorable safety profile and exhibited potent anti-tumor activity. Investigator-evaluated ORR for the phase 1b 2.0 mg/kg cohort was 38.1%, and ORR reached 38.5% in heavily pre-treated NSCLC patients (≥ 4L). ORRs in the sqNSCLC (n=15) and nsqNSCLC (n=6) patients reached 40% and 33.3%, with 73.3% and 100% for the DCRs of the two subgroups of patients, respectively. Notably, the DCR in NSCLC patients with brain metastasis reached 100%. The results of the pre-clinical studies and phase 1 clinical trial were published at the 2023 ESMO Congress as well as the 2025 ASCO Annual Meeting.
HLX43 is the leading ADC targeting PD-L1 that is progressing to phase 2 clinical development globally. It has received investigational new drug (IND) approvals from the China National Medical Products Administration (NMPA) and the U.S. Food and Drug Administration (FDA). Currently, HLX43 is being investigated in phase 2 clinical trials for a variety of solid tumor indications including NSCLC, thymic squamous cell carcinoma (TSCC) , hepatocellular carcinoma (HCC), esophageal squamous cell carcinoma (ESCC), head and neck squamous cell carcinoma (HNSCC), cervical cancer (CC) and nasopharynx cancer (NPC). Both monotherapy studies and a phase 1b/2 trial combining HLX43 with serplulimab (HANSIZHUANG, Henlius’ proprietary anti-PD-1 monoclonal antibody) are ongoing simultaneously to further exploit the synergistic effects of ADC-mediated cytotoxicity and immunotherapy-induced immune activation. HLX43 may benefit more patients with advanced or metastatic solid tumors by providing a novel treatment option for those who are unresponsive or have developed resistance to PD-1/PD-L1-targeted therapies, as well as the patients who have failed prior chemotherapy or TKI therapies.
With a particular focus on addressing the unmet medical needs, Henlius will further take efforts to accelerate the R&D of more cutting-edge therapeutic options and promote the layout of our innovative portfolio based on the company’s competitive edge of an integrated antibody drug R&D platform, bringing more high-quality and affordable therapeutics for patients worldwide.
About HLX43-NSCLC201
This is an open-label, multi-center, global phase 2 clinical study to evaluate HLX43 in patients with advanced non-small cell lung cancer (NSCLC). This study aims to evaluate the efficacy and safety of HLX43 in advanced NSCLCpatients. It consists of two parts: Part 1, which focuses on dose exploration to identify the optimal HLX43 dosage for Part 2, and Part 2, which is a single arm, multi-center phase 2 clinical trial. The primary objective of this study is to evaluate the clinical efficacy of HLX43 in advanced NSCLCpatients. The secondary objectives are to assess safety, tolerability, pharmacokinetics, immunogenicity, and to explore potential predictive or resistance biomarkers. The primary endpoint of the study is objective response rate evaluated by the Blinded Independent Central Review (BICR) according to RECIST v1.1.
