Recently, Shanghai Henlius Biotech, Inc. (2696.HK) announced that the company has initiated a Phase 2/3 international multi-regional clinical trial (HLX43-NSCLC302) of HLX43, the company's innovative PD-L1-targeting antibody-drug conjugate (ADC) in patients with advanced or metastatic squamous non-small cell lung cancer (sqNSCLC) in the US. The study is planned to proceed to the subsequent Phase 3 stage following the completion of the Phase 2 stage and further discussions with the FDA. The Phase 3 stage is expected to serve as the first pivotal registration study for HLX43 and represents a significant milestone for HLX43 in the field of NSCLC, poised to offer a new therapeutic option for refractory sqNSCLC patients who have progressed on prior standard therapies.
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 2022.1 Non-small cell lung cancer (NSCLC) is the predominant type of lung cancer (approximately 85%). By histology, NSCLC can be classified into squamous cell carcinoma (approximately 30%), adenocarcinoma (approximately 50%) and other subtypes, with a generally poorer prognosis for sqNSCLC.2 While immune checkpoint inhibitors (ICIs) combined with chemotherapy have significantly improved survival in advanced/metastatic sqNSCLC, effective options remain limited for patients progressing after first-line therapy. The current second-line and later-line treatment landscape is dominated by docetaxel-based regimens, with few agents demonstrating superior efficacy, highlighting a substantial unmet medical need.3-4 In recent years, antibody-drug conjugates (ADCs) have demonstrated favorable clinical efficacy in oncology, with promising activity observed in the later-line treatment of sqNSCLC.5-6 Separately, anti-EGFR monoclonal antibodies combined with chemotherapy have achieved progress in sqNSCLC, albeit primarily in EGFR-high expressing populations.7-9 The efficacy of novel therapeutic regimens incorporating anti-EGFR monoclonal antibodies in patients with low EGFR expression remains an area requiring further exploration.
HLX43 is a potentially best-in-class pan-tumor ADC candidate targeting PD-L1, which exhibits dual mechanisms integrating immune checkpoint blockade and payload-mediated cytotoxicity. Currently, it has demonstrated a manageable safety profile and encouraging efficacy in various solid tumors, with notable anti-tumor activity observed in multiple NSCLC patient subgroups. According to updated data presented at the 2025 WCLC, in the later-line treatment of sqNSCLC, HLX43 has demonstrated preliminary encouraging efficacy. Among patients receiving HLX43 at 2.0 mg/kg , the objective response rate (ORR) reached 40.0%, with a disease control rate (DCR) of 73.3%. Notably, in patients who had received prior docetaxel treatment, the ORR reached 30.0% with a DCR of 80.0%. HLX07 is an innovative anti-EGFR mAb developed by Henlius. Compared with cetuximab, HLX07 demonstrates lower immunogenicity and higher target affinity. According to updated results from the 2025 WCLC, the combination of HLX07 with serplulimab and chemotherapy demonstrated remarkable antitumor activity and durable efficacy in patients with EGFR-overexpressing sqNSCLC. At a median follow-up of 18.6 months, both dose groups achieved an objective response rate (ORR) of approximately 70% and a disease control rate (DCR) of over 90%. The median progression-free survival (PFS) reached 17.4 months in the high-dose group. HLX43 is expected to synergize with the anti-EGFR monoclonal antibody HLX07. This combination has the potential for superior efficacy compared to HLX43 monotherapy or an anti-EGFR antibody combined with chemotherapy, thereby offering greater clinical benefit to patients with advanced solid tumors such as sqNSCLC.
The company is currently accelerating the clinical development of HLX43. To date, over 700 patients have been enrolled globally in HLX43 studies, including more than 400 patients with NSCLC (over 60%). Among them, a multi-regional Phase 2 trial (HLX43-NSCLC201) is currently underway in China, the US, Australia, and Japan. Henlius has initiated over 10 clinical studies of HLX43, covering non-small cell lung cancer (NSCLC), cervical cancer (CC), esophageal squamous cell carcinoma (ESCC), head and neck squamous cell carcinoma (HNSCC), nasopharyngeal carcinoma (NPC), metastatic colorectal cancer (mCRC), gastric/gastroesophageal junction cancer (G/GEJ), pancreatic ductal adenocarcinoma (PDAC) and breast cancer (BC). Proof-of-concept (PoC) data in CC, ESCC, NPC, and HNSCC have been or will be presented at international conferences including ESMO Asia, ASCO GI, ASCO, and ESMO. Building on its intrinsic immuno-oncology (IO) activity, Henlius is exploring combination therapies, such as with the in-house anti-EGFR antibody HLX07 and anti-PD-1 mAb serplulimab, to maximize HLX43's clinical value.
Guided by its commitment to address unmet medical needs, Henlius will continue to advance its core pipeline including HLX43 to deepen the differentiated therapeutic potential of our products, accelerate the delivery of greater clinical value, and ultimately deliver more breakthrough treatment options to patients worldwide.
About HLX43-NSCLC302
This study is a randomized, open‑label, multi-center, global Phase 2/3 clinical study designed to evaluate the efficacy and safety of HLX43 (anti-PD‑L1 ADC) as monotherapy or in combination with HLX07 (a recombinant anti‑EGFR humanized monoclonal antibody injection) compared with docetaxel in patients with advanced or metastatic squamous non‑small cell lung cancer (NSCLC) who have failed prior therapy.
The study consists of two stages. Stage 1 is an open-label, randomized, multi-center phase 2 study, eligible subjects will be randomized in a 1:1:1 ratio to one of the following treatment arms: Group A (HLX43 monotherapy), Group B (HLX43 in combination with HLX07) or Group C (Docetaxel). Stage 2 is an open‑label, randomized, multi-center phase 3 study. Based on the results from Stage 1, either HLX43 monotherapy or HLX43 in combination with HLX07 will be selected as the investigational group. Approximately 566 subjects will be randomized in a 1:1 ratio to Investigational group (HLX43 monotherapy or HLX43 + HLX07) or Control group (Docetaxel).
The primary objective of this study is to evaluate the clinical efficacy of HLX43 monotherapy or HLX43 combined with HLX07 in the treatment of advanced squamous NSCLC after failure of first-line treatment, and the study adopts overall survival (OS) and progression‑free survival (PFS) as dual primary endpoints. Secondary objectives of this study include evaluation of safety of HLX43 monotherapy or HLX43 in combination with HLX07 vs. docetaxel, pharmacokinetic (PK) characteristics and immunogenicity of HLX43 and HLX07, and exploration of potential predictive or resistance biomarkers.
References
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2. Wang, Y., et al. Immunotherapy for advanced-stage squamous cell lung cancer: the state of the art and outstanding questions. Nat Rev Clin Oncol 22, 200–214 (2025).
3. 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
4. NCCN Guidelines Version 3. 2025, Non-Small Cell Lung Cancer.
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7. Pirker R, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol. 2012 Jan;13(1):33-42.8.
8. Thatcher N, et al. Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2015 Jul;16(7):763-74.
9. Becotatug (JMT101, Beco) combined with docetaxel (albumin-bound, HB1801) for the treatment of patients (pts) with locally advanced squamous cell non-small cell lung cancer (sqNSCLC): A randomized control phase II study (BATTLE study). ESMO Asia 2025|2025-12-05.