Editor’s Note: The 2025 American Society of Clinical Oncology (ASCO) Annual Meeting was held from May 30 to June 3 in Chicago. As the world’s leading oncology conference, this year’s ASCO saw a strong presence from Chinese researchers whose impactful findings contributed meaningfully to the global fight against cancer. Among the most notable advances were those related to antibody-drug conjugates (ADCs) in solid tumors. Dr. Jie Wang from the Cancer Hospital Chinese Academy of Medical Sciences, presented key findings from China’s first-in-human phase I trial of HLX43, a PD-L1–targeting ADC (study code HLX43-FIH101). The results demonstrated promising antitumor activity and a manageable safety profile, particularly in patients with non-small cell lung cancer (NSCLC) and thymic squamous cell carcinoma (TSCC). Oncology Frontier interviewed Dr. Jie Wang, the leading principal investigator, to gain deeper insight into the study’s results, underlying mechanisms, and potential impact on future cancer therapies.Oncology Frontier: At ASCO 2025, you presented the phase I clinical results of HLX43, China’s first PD-L1–targeted ADC. Compared to traditional ADCs, what are the key innovations in HLX43’s target selection and drug design? From a mechanistic perspective, what advantages does HLX43 bring to cancer therapy?
Dr. Jie Wang: HLX43 is the world’s first PD-L1–targeted ADC to advance into phase II clinical trials. It consists of HLX20—an anti-PD-L1 human IgG1 monoclonal antibody—conjugated via a cleavable tripeptide linker to the topoisomerase I inhibitor C24. This design achieves important breakthroughs by optimizing both target selection and the linker-toxin system, offering unique therapeutic potential for cancer treatment.
First, HLX43’s target selection marks a bold and innovative decision. PD-L1 is a key immune checkpoint target broadly expressed across multiple solid tumors. However, PD-L1–targeted ADCs remain rare due to two major concerns: potential off-target effects on immune cells expressing PD-L1, and inadequate internalization of the antibody-drug complex, limiting toxin delivery. HLX43 addresses both issues with its optimized HLX20 antibody. Preclinical data have shown that HLX20 exhibits low cytotoxicity toward immune cells, while maintaining strong affinity for PD-L1 on tumor cells and significantly enhancing internalization efficiency. This enables HLX43 to simultaneously block PD-1/PD-L1 signaling and deliver the cytotoxic payload precisely into tumor cells.
Second, in terms of drug design, HLX43 uses a cleavable linker that not only enables traditional intracellular release via endocytosis but also facilitates extracellular release within the tumor microenvironment. This dual-release mechanism enhances the “bystander effect,” a key feature that allows the drug to affect neighboring tumor cells that may not express the target antigen.
Third, HLX43 is conjugated with C24, an optimized and highly potent topoisomerase I inhibitor, offering several advantages:
- Shorter plasma half-life, which lowers systemic toxicity and improves the overall safety profile.
- Enhanced tissue penetration, enabling better diffusion into adjacent tumor cells and strengthening the bystander killing effect.
- High stability of the linker-toxin complex in circulation, minimizing off-target toxicity.
In summary, HLX43 represents a sophisticated and innovative ADC design that integrates precise targeting, efficient internalization, dual release, a powerful bystander effect, and an improved safety profile. Its mechanism of action and clinical potential mark an exciting step forward in the field of immuno-oncology.
Oncology Frontier: Could you walk us through the design of the phase I clinical trial for HLX43? What key findings have been observed so far regarding safety and tolerability?
Dr. Jie Wang: The phase I trial of HLX43 was designed to assess its safety, tolerability, and preliminary efficacy in patients with advanced or metastatic solid tumors. This is an open-label, first-in-human (FIH), single-arm study comprising two parts: a dose-escalation phase (Part Ia) and a dose-expansion phase (Part Ib). Eligible participants were between 18 and 75 years old with an ECOG performance status of 0 or 1. Notably, the study included patients with resistance to prior immunotherapy to explore HLX43’s dual mechanism of action—direct cytotoxicity and immune modulation.
In Part Ia, six dose levels were evaluated (0.5, 1, 2, 2.5, 3, and 4 mg/kg, administered every 3 weeks) using a classical 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). The primary endpoints were dose-limiting toxicity (DLT) within the first 3 weeks of treatment and identification of the MTD. Part Ib focused on patients with advanced/metastatic non-small cell lung cancer (NSCLC) who had failed standard therapies. It evaluated the safety and efficacy of HLX43 at 2.0, 2.5, and 3.0 mg/kg doses. The primary objectives were to determine the recommended phase II dose (RP2D) and objective response rate (ORR).
As of March 28, 2025, Part Ia had completed enrollment of 21 patients. One patient in the 4 mg/kg cohort experienced a DLT (febrile neutropenia with leukopenia), establishing the MTD at 4 mg/kg. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 28.6% of patients in Part Ia and 42.9% in Part Ib. The most common AEs included hematologic toxicities, hyponatremia, and nausea. In Part Ib, patients treated with 2 mg/kg HLX43 experienced relatively mild hematologic toxicity: grade ≥3 anemia and lymphopenia each occurred in 14.3% of patients, while no grade ≥3 thrombocytopenia or neutropenia was reported. These findings support HLX43’s overall manageable safety and tolerability, laying the groundwork for its future development in first-line and combination regimens.
Oncology Frontier: Based on the phase I data so far, in which patient populations has HLX43 shown the most promising signals of clinical benefit? What insights do these findings offer for future development?
Dr. Jie Wang: In terms of efficacy, median follow-up in Part Ia was 9.7 months, with an investigator-assessed ORR of 36.8% and a median progression-free survival (mPFS) of 4.2 months. Part Ib is ongoing, and current data reflect outcomes only from the 2.0 mg/kg cohort. With a median follow-up of 7.0 months, NSCLC patients in this group had an ORR of 38.1%, and mPFS extended to 5.4 months; overall survival (OS) data remain immature.
From the current phase I findings, HLX43 appears to offer clear clinical benefit in the following patient subgroups:
1. Patients with refractory disease: All patients in the 2 mg/kg Part Ib cohort had previously received both immunotherapy and platinum-based chemotherapy, with a median of three prior lines of treatment. Despite this heavily pretreated background, HLX43 achieved an ORR of 38.1% and an mPFS of 5.4 months. Notably, among NSCLC patients with brain metastases, the disease control rate (DCR) reached 100%.
2. Patients with thymic squamous cell carcinoma (TSCC): In Part Ia, HLX43 achieved an ORR of 75% in TSCC patients (3 out of 4 achieved partial response), substantially higher than the historical ORR of approximately 25%. This suggests that HLX43 may provide a breakthrough option for TSCC, a tumor type that typically shows high PD-L1 expression but limited treatment choices.
3. Efficacy independent of PD-L1 expression: In subgroup analyses from Part Ib, patients with PD-L1 CPS ≥1 and CPS <1 had ORRs of 37.5% and 40%, respectively—demonstrating no significant difference in efficacy based on PD-L1 levels. This supports the hypothesis that HLX43’s therapeutic activity may be driven by its payload’s direct cytotoxic effect or the ADC’s bystander effect, rather than PD-L1 expression alone. These findings suggest that HLX43 could potentially benefit a broader patient population regardless of PD-L1 status.
Given HLX43’s favorable efficacy, safety, and mechanistic profile, future clinical development should prioritize both monotherapy and combination strategies. Focused exploration in tumors with active PD-L1 pathways and limited treatment options—such as TSCC, advanced NSCLC, and other PD-L1–expressing solid tumors—may uncover the greatest opportunities for clinical impact.
Oncology Frontier: PD-L1–targeted ADCs are still in the exploratory stage globally. In your view, what is the future clinical value of HLX43?
Dr. Jie Wang: As a pioneer in the global PD-L1–targeted ADC landscape, HLX43 holds significant clinical potential. Its breakthrough design fills a key gap in PD-L1–directed ADC therapeutics and embodies the innovative “pipeline-in-a-pill” development philosophy—positioning it to target multiple tumor types across a wide range of indications.
Mechanistically, HLX43 integrates both the functionalities of ADCs and immunotherapy, offering precision tumor cell killing along with durable immune modulation. This dual capability provides a novel treatment strategy for patients with advanced solid tumors. From a drug development perspective, HLX43’s rapid clinical advancement sets a benchmark for innovative drug R&D in China and accelerates the country’s leadership in next-generation ADC development on the global stage.
To date, no PD-L1–targeted ADC has been approved anywhere in the world. HLX43 represents the forefront of innovation in this space and possesses strong potential to become a best-in-class therapy. We look forward to seeing results from upcoming pivotal trials to further validate its efficacy and safety, with the ultimate goal of securing regulatory approval. HLX43 may well become a landmark therapy in the treatment of solid tumors.
Looking ahead, as more clinical data are generated, HLX43 has the potential to emerge as a new therapeutic option for patients who are resistant or unresponsive to PD-1/PD-L1 checkpoint inhibitors. It may also move into earlier lines of therapy and be combined with other modalities to benefit an even broader patient population.
Director, Department of Medical Oncology Cancer Hospital, Chinese Academy of Medical Sciences
- Tenured Professor, Peking Union Medical College
- Assistant President, Cancer Hospital, Chinese Academy of Medical Sciences
- President, Shanxi Branch, Cancer Hospital, Chinese Academy of Medical Sciences
- Chief Physician and Doctoral Supervisor
- Recipient of the 2021 Ho Leung Ho Lee Science and Technology Progress Award
- Recipient of the National Science Fund for Distinguished Young Scholars
- Vice President, Chinese Society of Clinical Oncology (CSCO)
- Chair, Multidisciplinary Oncology Committee, Chinese Medical Doctor Association
- Chair, CSCO NSCLC Expert Committee
- Vice Chair, CSCO SCLC Expert Committee
- Vice Chair, Non-Small Cell Lung Cancer Committee, Chinese Anti-Cancer Association
- Lead Recipient, National Science and Technology Progress Award (Second Class)
- Winner of the Wu Jieping Medical Innovation Award, National Innovation Pioneer Award, and the China Young Women Scientist Award
