Shanghai Henlius Biotech has dosed the first patient in HLX43-NSCLC201, a global Phase 2 trial of HLX43, marking a significant milestone as the world's first PD-L1-targeting antibody-drug conjugate (ADC) to advance to Phase 2 clinical development. The novel therapeutic addresses a critical gap in treating patients with advanced non-small cell lung cancer (NSCLC) who have exhausted standard treatment options.
Promising Phase 1 Results Drive Phase 2 Advancement
Results from HLX43's Phase 1 clinical trial, first presented at the 2025 ASCO Annual Meeting, demonstrated a manageable safety profile and encouraging efficacy across multiple tumor types. The investigator-evaluated objective response rate (ORR) for the Phase 1b 2.0 mg/kg cohort reached 38.1%, with particularly notable activity in heavily pretreated NSCLC patients where ORR reached 38.5% in patients who had received four or more prior lines of therapy.
The drug showed consistent activity across NSCLC subtypes, with ORRs of 40% in squamous NSCLC patients (n=15) and 33.3% in non-squamous NSCLC patients (n=6). Disease control rates reached 73.3% and 100% in these respective subgroups. Notably, the disease control rate in NSCLC patients with brain metastases reached 100%, highlighting the drug's potential in treating challenging patient populations.
Addressing Critical Unmet Medical Needs
Lung cancer represents the most common cancer worldwide, with over 2.48 million new cases globally in 2022, accounting for 12.4% of all new cancer cases according to GLOBOCAN 2022. Most patients are diagnosed at advanced stages, creating significant unmet clinical needs.
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. Currently, the treatment landscape for EGFR wild-type NSCLC remains limited, particularly in second-line and later therapy, where docetaxel-based chemotherapy continues as the standard of care despite suboptimal efficacy.
Many patients with positive PD-L1 expression do not respond to or develop resistance to PD-1/PD-L1-targeted therapy, with no established subsequent-line treatment for patients resistant to PD-1/L1 immunotherapy or those who failed to benefit from standard treatments including immunotherapy.
Novel Mechanism of Action
HLX43 is composed of a fully humanized anti-PD-L1 IgG1 antibody, a novel tripeptide linker, and a topoisomerase inhibitor payload, with a drug-to-antibody ratio (DAR) of around 8. The drug's 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, HLX43 undergoes receptor-mediated endocytosis, releasing the cytotoxic payload intracellularly via linker cleavage. The payload further diffuses into neighboring tumor cells via bystander effect, blocking DNA replication and triggering tumor cell apoptosis. Simultaneously, the anti-PD-L1 antibody activates immune modulation and blocks immune checkpoints, driving synergistic anti-tumor efficacy.
The cytotoxic payload is a novel DNA topoisomerase-I inhibitor known for potent anti-tumor activity, shorter half-life in the bloodstream, and improved safety profile, allowing HLX43 to possess a higher therapeutic index and potency for solid tumor treatment.
Comprehensive Development Program
HLX43 has received investigational new drug (IND) approvals from both the China National Medical Products Administration (NMPA) and the U.S. Food and Drug Administration (FDA). The drug is currently being investigated in Phase 2 clinical trials for various solid tumor indications including NSCLC, thymic squamous cell carcinoma, hepatocellular carcinoma, esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, cervical cancer, and nasopharynx cancer.
The HLX43-NSCLC201 study is an open-label, multi-center, global Phase 2 clinical trial consisting of two parts: Part 1 focuses on dose exploration to identify the optimal HLX43 dosage, while Part 2 is a single-arm, multi-center Phase 2 trial. The primary endpoint is objective response rate evaluated by Blinded Independent Central Review according to RECIST v1.1.
Combination Therapy Exploration
Henlius is simultaneously conducting both monotherapy studies and a Phase 1b/2 trial combining HLX43 with serplulimab (HANSIZHUANG), the company's proprietary anti-PD-1 monoclonal antibody. This combination approach aims to exploit the synergistic effects of ADC-mediated cytotoxicity and immunotherapy-induced immune activation, representing the next wave of "IO+ADC" innovation.
The combination study aims to evaluate safety, tolerability, and efficacy in patients with advanced/metastatic solid tumors, with primary endpoints including dose-limiting toxicity events, maximum tolerated dose, and objective response rate assessed by Independent Radiological Review Committee.
Global Leadership in PD-L1 ADC Development
At present, no PD-L1 targeting ADC has been approved for marketing globally, with only Pfizer's SGN-PDL1V about to initiate Phase 3 clinical trials. HLX43 represents the world's second and China's first PD-L1-targeting ADC to progress to clinical research, and notably, the first globally to advance to Phase 2 development.
PD-L1 expression prevalence exceeds 50% in multiple tumor types, with lung cancer reaching up to 70%, while displaying limited expression on normal tissues. This expression pattern highlights PD-L1's potential as an ADC target, potentially bringing new treatment options for cancer patients who have exhausted current therapeutic approaches.
