Recently, Henlius has achieved significant advancement in the global development of HLX43, its innovative programmed death-ligand 1 (PD-L1) targeting antibody-drug conjugate (ADC), which has already been approved by the China National Medical Products Administration (NMPA), the U.S. Food and Drug Administration (FDA), Australia Therapeutic Goods Administration (TGA) and Japan`s Pharmaceuticals and Medical Devices Agency (PMDA) to initiate phase 2 multi-regional clinical trial in patients with advanced non-small cell lung cancer (NSCLC). Additionally, the first patient dosing has been completed in China. To date, 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.
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 [1]. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer (approximately 85%).The majority of lung cancer patients are are diagnosed at advanced stages [2], 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 [3]. 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 [4,5].
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.
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 in various solid tumors especially in patients with 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. 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%. In addition, 75% patients with thymic squamous cell carcinoma (TSCC) achieved partial response (ORR=75%, 3/4).
The company is currently accelerating the clinical development of HLX43 and actively exploring its therapeutic potential in various solid tumors, including NSCLC, TSCC, hepatocellular carcinoma (HCC), esophageal squamous cell carcinoma (ESCC), head and neck squamous cell carcinoma (HNSCC), cervical cancer (CC) and nasopharyngeal cancer (NPC). Both monotherapy studies and a phase 1b/2 trial combining HLX43 with serplulimab (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.
Looking forward, Henlius will accelerate the global development of HLX43, continuously strengthening the differentiated layout of more innovative molecules to bring high-quality, affordable innovative treatment options to tumor patients worldwide.
Reference
[1] Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263.
[2] Robinson CG, et al. Postoperative Radiotherapy for Pathologic N2 Non–Small-Cell Lung Cancer Treated with Adjuvant Chemotherapy: A Review of the National Cancer Data Base. Journal of Clinical Oncology 2015, 33(8): 870-876.
[3] Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res. 2015 Feb;4(1):36-54.
[4] 中国临床肿瘤学会 中国临床肿瘤学会(CSCO).(2024)非小细胞肺癌诊疗指南
[5] NCCN Guidelines Version 3. 2025, Non-Small Cell Lung Cancer.