全球研發 | 有望覆蓋NSCLC全人羣，復宏漢霖PD-L1 ADC HLX43完...

2025年6月10日，復宏漢霖（2696.HK）宣佈，公司基於與宜聯生物的合作開發的靶向程序性死亡-配體1（PD-L1）的新型抗體偶聯藥物（ADC）注射用HLX43在晚期非小細胞肺癌（NSCLC）患者中開展的國際多中心II期臨牀研究（HLX43-NSCLC201）於中國完成首例受試者給藥。在剛剛召開的2025 美國臨牀腫瘤學會（ASCO）年會上，HLX43的I期臨牀數據首次發佈，顯示出令人鼓舞的初步療效和安全性，對鱗狀/非鱗狀NSCLC，有無EGFR突變、有無腦/肝轉移、PD-L1陽性/陰性的NSCLC患者都展現了優異的治療潛力。目前，全球尚無同類靶向PD-L1的ADC產品獲批上市，HLX43為全球首個進入臨牀II期的PD-L1 ADC。

廣譜抗腫瘤ADC，

劍指實體瘤全人羣生存突破

近年來，以抗PD-(L)1抗體為代表的免疫檢查點抑制劑（ICI）促進了腫瘤免疫治療的高速發展，成為腫瘤患者各線治療的主要手段之一。然而，部分患者對該療法無響應，或者出現耐藥^[1]。對於免疫治療耐藥或經免疫治療等標準治療失敗后的患者人羣，尚缺少有效的后線治療方案。ADC作為當下腫瘤治療中療效最突出的新型療法，已在乳腺癌、肺癌、食管癌、胃癌等多項實體瘤中展現出令人振奮的治療潛力，成為重要的探索方向^[2]。而PD-L1作為一個泛腫瘤靶點，在非小細胞肺癌、頭頸鱗癌、結直腸癌、三陰性乳腺癌、黑色素瘤等癌種中均有表達，部分瘤種陽性率（高表達+中低表達）超過50%，在肺癌上更高達70%，且在正常組織中表達有限，使其成為開發ADC藥物的潛力靶點，為腫瘤治療帶來新的途徑^[3]。

據GLOBOCAN最新數據顯示，肺癌是全球發病率和死亡率最高的癌症，2022年全球約有超過248萬新發肺癌病例，佔癌症新發病例的12.4%^[4]，其中非小細胞肺癌（NSCLC）是最常見的肺癌類型（約85%）。大部分肺癌患者確診時已處於疾病晚期階段^[5]，存在巨大的尚未滿足的臨牀需求。根據病理類型，NSCLC又可分為鱗狀細胞癌（約30%）、肺腺癌（約50%）等，儘管針對EGFR等驅動基因突變（AGA）的靶向治療方案已經趨於成熟，但在全部NSCLC患者中，EGFR野生型佔比高達70%-85%，涵蓋幾乎所有的鱗癌患者和50-55%的肺腺癌患者^[6]。當前療效優異的產品仍較少，特別在2L+人等后線人羣治療上，仍主要依賴於多西他賽為基礎的化療方案，后線治療的效果有限^[7,8]。

NSCLC療效顯著，

全球首款進入II期臨牀的PD-L1 ADC

HLX43是一款靶向程序性死亡-配體1（PD-L1）的新型ADC候選藥物，由全人源IgG1抗PD-L1抗體與創新連接子-拓撲異構酶抑制劑荷載偶聯而成，藥物抗體比（drug-to-antibody ratio, DAR）約為8。HLX43兼具毒素精準殺傷和腫瘤免疫作用的複合功能：其毒素不僅能夠藉靶點內吞進入腫瘤細胞后進行釋放，並在腫瘤微環境中釋放后藉助旁觀者效應進入腫瘤細胞，阻斷DNA複製，從而導致腫瘤細胞凋亡；此外，HLX43的PD-L1靶向抗體可激活免疫調節機制，發揮協同抗腫瘤效應。臨牀前及I期臨牀研究顯示，HLX43具有顯著的抗腫瘤療效，且安全性良好。2.0 mg/kg每三周輸注一次HLX43時，晚期NSCLC患者經研究者評估的ORR為38.1%，對於四線及更后線治療的難治NSCLC患者，ORR仍可達38.5%。 其中鱗狀非小細胞肺癌sqNSCLC（n=15）和非鱗狀非小細胞肺癌nsqNSCLC（n=6）患者的客觀緩解率（ORR）分別為40%和33.3%，並實現了73.3%和100%的疾病控制。值得關注的是，腦轉移NSCLC患者全部得到疾病控制（DCR=100%）。相關臨牀前及I期臨牀研究數據分別於2023歐洲腫瘤內科學會（ESMO）大會和2025 美國臨牀腫瘤學會 （ASCO）年會上發佈。

作為全球率先進入臨牀階段的靶向PD-L1的ADC產品，HLX43於2023年相繼獲得中國藥品監督管理局（NMPA）、美國食品藥品監督管理局（FDA）的臨牀試驗許可，目前已進入II期臨牀開發階段，廣泛覆蓋非小細胞肺癌、胸腺鱗癌、肝細胞癌、食管鱗癌、頭頸鱗癌、宮頸癌、鼻咽癌等實體瘤的治療。單藥之外，HLX43聯用復宏漢霖自研斯魯利單抗（H藥漢斯狀，抗PD-1單抗）治療實體瘤的 Ib/II 期臨牀試驗也正在進行中，進一步探索「ADC+IO」的協同抗腫瘤療效。HLX43不僅可能克服PD-1/L1免疫療法不響應或耐藥問題，並對化療、TKI治療失敗的患者都具有潛在療效，有望為更多晚期/轉移性實體瘤患者帶來新的治療選擇。

未來，復宏漢霖將持續立足於未滿足的臨牀需求，充分發揮公司在抗體藥物和抗體偶聯藥物領域的一體化平臺優勢，加速推動更多前沿治療方案的研究和開發，為全球患者帶來更多高質量、可負擔的創新治療方案。

HLX43-NSCLC201

本研究為一項評估HLX43在晚期非小細胞肺癌（NSCLC）患者的開放、國際多中心II期臨牀試驗，旨在評估HLX43在晚期NSCLC患者中的有效性和安全性。研究分為兩個階段：第一階段將進行劑量探索，以選擇合適的HLX43劑量進行第二階段研究。第二階段為單臂、多中心II期臨牀研究。本研究的主要研究目的為評估HLX43在晚期非小細胞肺癌（NSCLC）中的臨牀療效，次要研究目的為安全性、耐受性、藥代動力學特徵、免疫原性，以及探索潛在預測性或耐藥性生物標誌物。主要研究終點為由盲態獨立中心審查委員會根據RECIST v1.1標準評估的客觀緩解率。

關於復宏漢霖

復宏漢霖（2696.HK）是一家國際化的創新生物製藥公司，致力於為全球患者提供可負擔的高品質生物藥，產品覆蓋腫瘤、自身免疫疾病、眼科疾病等領域，已有6款產品在中國獲批上市，4款產品在國際獲批上市，5個上市申請分別獲中國藥監局、美國FDA和歐盟EMA受理。自2010年成立以來，復宏漢霖已建成一體化生物製藥平臺，高效及創新的自主核心能力貫穿研發、生產及商業運營全產業鏈。公司已建立完善高效的全球創新中心，按照國際藥品生產質量管理規範（GMP）標準進行生產和質量管控，不斷夯實一體化綜合生產平臺，其中，公司商業化生產基地已相繼獲得中國、歐盟和美國GMP認證。

復宏漢霖前瞻性佈局了一個多元化、高質量的產品管線，涵蓋約50個分子，並全面推進基於自有抗PD-1單抗H藥漢斯狀的腫瘤免疫聯合療法。截至目前，公司已獲批上市產品包括國內首個生物類似藥漢利康（利妥昔單抗）、自主研發的中美歐三地獲批單抗生物類似藥漢曲優（曲妥珠單抗，美國商品名：HERCESSI，歐洲商品名：Zercepac）、漢達遠（阿達木單抗）、漢貝泰（貝伐珠單抗）、全球首個獲批一線治療小細胞肺癌的抗PD-1單抗漢斯狀（斯魯利單抗，歐洲商品名：Hetronifly）以及漢奈佳（奈拉替尼）。公司亦同步就19個產品在全球範圍內開展30多項臨牀試驗，對外授權全面覆蓋歐美主流生物藥市場和眾多新興市場。

First Subject Dosed for a Phase 2 MRCT of Henlius’ PD-L1-Targeting ADC HLX43 for the Treatment of NSCLC

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.

About Henlius

Henlius (2696.HK) is a global biopharmaceutical company with the vision to offer high-quality, affordable and innovative biologic medicines for patients worldwide with a focus on oncology, autoimmune diseases and ophthalmic diseases. Up to date, 6 products have been launched in China, 4 have been approved for marketing in overseas markets, and 5 marketing applications have been accepted for review in China, the U.S. and the EU, respectively. Since its inception in 2010, Henlius has built an integrated biopharmaceutical platform with core capabilities of high-efficiency and innovation embedded throughout the whole product life cycle including R&D, manufacturing and commercialization. It has established global innovation centre and Shanghai-based commercial manufacturing facilities certificated by China, the EU and U.S. GMP.

Henlius has pro-actively built a diversified and high-quality product pipeline covering about 50 molecules and has continued to explore immuno-oncology combination therapies with proprietary HANSIZHUANG (anti-PD-1 mAb) as the backbone. To date, the company's launched products include HANLIKANG (rituximab), the first China-developed biosimilar, HANQUYOU (trastuzumab, trade name: HERCESSI in the U.S., Zercepac in Europe), a China-developed mAb biosimilar approved in China, Europe and U.S., HANDAYUAN (adalimumab), HANBEITAI (bevacizumab), HANSIZHUANG (serplulimab, trade name: Hetronifly in Europe), the world’s first anti-PD-1 mAb for the first-line treatment of SCLC, and HANNAIJIA (neratinib). What’s more, Henlius has conducted over 30 clinical studies for 19 products, expanding its presence in major markets as well as emerging markets.

References

[1] Attili I, et al. Strategies to overcome resistance to immune checkpoint blockade in lung cancer[J]. Lung cancer: Journal of the International Association for the Study of Lung Cancer, 2021(154-):154.

[2] He J, et al. Antibody-drug conjugates in cancer therapy: mechanisms and clinical studies. MedComm (2020). 2024 Jul 28;5(8):e671.

[3] O'Malley DP, et al. Immunohistochemical detection of PD-L1 among diverse human neoplasms in a reference laboratory: observations based upon 62,896 cases. Mod Pathol. 2019 Jul;32(7):929-942.

[4] 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.

[5] 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.

[6] 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. 

[7] 中國臨牀腫瘤學會 中國臨牀腫瘤學會(CSCO).(2024)非小細胞肺癌診療指南

[8] NCCN Guidelines Version 3. 2025, Non-Small Cell Lung Cancer.

(復星醫藥)