Sacituzumab tirumotecan

作者：琉璃韵 前言    双靶ADC正在成为下一代ADC开发的重要方向。其设计初衷并不只是简单叠加两个靶点，而是希望通过双靶识别提升肿瘤选择性、覆盖抗原异质性，并改善内吞递送效率和治疗窗口。 从全球重点项目看，EGFR/HER3、HER3/TROP2、EGFR/c-Met、PSMA/STEAP1、CEACAM5/CEACAM6、B7-H3/EGFR等组合已陆续进入临床验证。百利的EGFR/HER3双靶ADC iza-bren已获批治疗鼻咽癌。 从已披露剂量看，剂量探索范围大部分项目在0.6–6.0 mg/kg；JSKN-016、JS212、TQB6411、ABBV-969、DM005等项目在不同实体瘤队列中披露了约30%–60%不等的ORR/uORR数据，适应症覆盖TNBC、NSCLC、mCRPC、胃食管腺癌等方向。 具体项目数据    1. JSKN-016（康宁杰瑞） 药物机制：JSKN-016 是一款靶向HER3/TROP2的双特异性 ADC，其载荷为Top1i。ASCO 会议披露了针对标准治疗失败、既往接受过系统性治疗且伴有高比例内脏转移的晚期乳腺癌患者的临床数据： 实验设计： TNBC（N=50）组：中位年龄50岁，100% 的患者既往接受过基础标准治疗（紫杉类化疗），且有28.0%的患者已经历过 ≥3 线的系统性抗肿瘤治疗。 HR+/HER2- BC （N=32）组：中位年龄52岁，100% 的患者已对内分泌治疗及目前的核心靶向治疗（CDK4/6 抑制剂）产生耐药，且超过半数（53.1%）接受过 ≥2 线治疗。 临床疗效：JSKN-016在后线TNBC乳腺癌患者中显示出强大的抗肿瘤活性。在剂量6 mg/kg Q3W中，后线TNBC组的cORR达到58.1%，DCR为83.9%。该组的mPFS为8.5个月， mDoR为8.3个月，且12个月的OS生存率达到了73%。 在HR+/HER2- BC组中，针对已对CDK4/6抑制剂产生耐药的患者，同样取得了优异的疗效，cORR为48.3%，DCR达到100%，12个月的OS生存率高达92.4%。 JSKN-016在乳腺癌中的初步疗效显示出优于目前针对乳腺癌治疗的其他同类药物的趋势（如SKB264、SG和Dato DXd）。 安全性：JSKN-016在后线TNBC乳腺癌患者中展现出了良好的安全性。与SKB264相比，JSKN-016在乳腺癌治疗中表现出更优的安全性特征，尤其是血液毒性更低。 2. JS212 (君实生物) 药物机制：JS212 是一款靶向 EGFR/HER3 的双特异性 ADC。AACR 会议公布了其在晚期实体瘤中开展的首次人体（FIH）I/II 期临床研究结果： 实验设计：该研究包括剂量递增与扩展（I期）以及临床扩展阶段（II期）。剂量递增阶段首先采用加速滴定法（0.6 mg/kg，Q3W），随后采用贝叶斯最优区间（BOIN）设计进行剂量递增（范围覆盖1.2至4.8 mg/kg，Q3W）。研究共入组N=63例患者，其中包括32例非小细胞肺癌（NSCLC）、9例乳腺癌（BC）以及22例食管鳞状细胞癌（ESCC）。 临床疗效：在接受了≥1次肿瘤评估的57例患者中，总体ORR为33.3%（19/57），DCR为93.0%（53/57）。在≥1.8 mg/kg剂量组中均观察到了肿瘤缓解。在较高的≥4.2 mg/kg剂量区间中，ORR达到了40.0%（8/20）；其中，4.2 mg/kg和4.6 mg/kg剂量组的ORR分别高达44.4%和50.0%，且DCR均为100.0%。目前mDOR尚未达到。在具体的瘤种亚组中，BC和ESCC患者的ORR分别为50.0%和38.9%。 安全性：整体耐受性良好，尚未达到MTD。研究中共观察到4例DLT。TRAE≥3级的发生率为31.7%，并未出现导致死亡的TRAE。常见的≥3级TRAE（发生率≥5%）主要为血液学毒性，包括中性粒细胞减少症（19.0%）、白细胞减少症（14.3%）和血小板减少症（7.9%）。 3. TQB6411（正大天晴） 药物机制：TQB6411 是一款靶向EGFR/c-Met 的新型双抗 ADC。该分子采用了1:2 的非对称价态设计，研发策略旨在增强对 c-Met 的亲和力，同时相对降低 EGFR 结合力，以规避 EGFR 相关的皮肤毒性。ASCO 会议披露了其在实体瘤中的 I 期临床数据： 实验设计：该 I 期临床共入组 26 例晚期实体瘤患者，中位年龄 60 岁，女性占 46.2%。受试者均为至少 1 线全身系统性治疗失败或不耐受人群，涵盖 NSCLC（21例）、食管癌（3例）和结直肠癌（2例）。试验设立 5 个给药队列，剂量从0.8 mg/kg 爬坡至 6.6 mg/kg，给药频率为 Q3W。 临床疗效：在≥4 mg/kg剂量组中，共有9例受试者接受了至少一次影像学评估，其中4例达到了PR，ORR为44.4%，DCR达到了100%。具体来看，在5.3 mg/kg剂量组中，有1例经过2线治疗的NSCLC患者，其靶病灶较基线显著缩小了55.2%。在4.0 mg/kg剂量组中，有2例接受过≥3线治疗的NSCLC患者，其靶病灶分别缩小了30.4%和48.1%。表明其在多线难治性患者中具备突破潜力。 安全性：针对随访时间至少达到21天的23例患者数据表明，TRAE≥3级的发生率为21.7%。在全组患者中，均未观察到≥4级的TRAE，且未出现ILD事件，整体安全性表现良好。 4. ABBV969（AbbVie） 药物机制：ABBV-969 基于 DVD-Ig 结构平台开发，同时靶向PSMA 和 STEAP1，载荷为Top1i。ASCO 会议公布了其在转移性去势抵抗性前列腺癌（mCRPC）中开展的I 期 FIH 剂量递增研究初步结果： 实验设计：共纳入49 例前列腺腺癌受试者，入组前未进行生物标志物（Biomarker）筛选。试验采用Q3W、IV 给药，剂量爬坡范围为 1 mg/kg - 12.5 mg/kg，该人群基线显示为高度重度经治状态。 临床疗效：在包含既往接受紫杉类和 PSMA-RLT 治疗后进展的患者中，展示出深度且持久的生化响应。在≥3 mg/kg 剂量组中，confirmed PSA50 达 67.4%（29/43），confirmed PSA90 达 30.2%（13/43）。PSA 响应的中位持续时间为 10.8 个月，中位至 PSA 响应时间为 3.0 个月 影像学方面，RECIST 可评估患者的cORR 达到 44.8%（13/29，含 5 例 CR 和 8 例 PR），未观察到疾病进展（PD），mDOR 达 11.0 个月。影像学缓解可见于伴有肝脏、肺部及淋巴结转移病灶的受试者。全体 49 例患者的中位影像学无进展生存期（rPFS）为 15.3 个月。 安全性：最常见的血液学TRAE为贫血；TRAE≥3级发生率为46.9%，严重相关AE发生率为8.2%；因TRAE导致给药中断、剂量降低和治疗终止的比例分别为36.7%、32.7%和4.1%。治疗相关DLT发生率为6.1%，均为贫血；治疗相关死亡1例，为12.5mg/kg剂量下发生的肺炎，另有2例因肺炎导致停药。 TRAE≥3级整体呈剂量相关性，主要集中在血液学毒性，且多发生于较高剂量组。贫血、中性粒细胞减少和血小板减少的≥3级发生率分别为44.9%、28.6%和14.3%，在8mg/kg、10mg/kg和12.5mg/kg剂量组更为集中；其中贫血在8mg/kg以上剂量组发生率明显升高，但未报告4/5级贫血事件。非血液学≥3级TRAE较少，乏力发生率为4.1%，ILD/肺炎发生率为4.1%，且ILD/肺炎仅发生于 12.5 mg/kg 最高剂量组。 5. DM005（多玛医药） 药物机制：DM005采用全人源化双特异性抗体靶向EGFR和c-MET，载荷为Top1i，此次在ASCO会议中公布I期剂量递增数据： 实验设计：入组人群来自中国、美国和澳大利亚N= 45，并在 8 个剂量队列中接受了至少 1 剂 DM005 治疗。中位年龄为 59 岁（范围 40–76）。基线 ECOG 评分：0 分（7 例），1 分（38 例）。所有患者既往均接受过平均 3 线（范围 1–7）的标准治疗且出现进展。招募患有晚期实体瘤的患者，剂量范围为0.5 ~ 6.5 mg/kg，Q3W。 临床疗效：在 32 名可评估患者中，有 8 例患者达到PR（25%），14 例患者达到SD（43.75%）。在 3.3/4.2/5.2 mg/kg 剂量组中，接受了影像学肿瘤评估的NSCLCm 患者有13 名，其中 6 名达到 PR，5 名达到 SD。uORR为 46.2%，DCR为 84.6%。 安全性：在最高 6.5 mg/kg 剂量下，未观察到DLT，未达到 MTD。TRAE 发生率为80%。最常见的 TRAE（发生率≥10%）包括：恶心（28.9%）、贫血（28.9%）、乏力（26.7%）、食欲下降（26.7%）、白细胞减少（20%）、天门冬氨酸氨基转移酶升高（15.6%）、淋巴细胞减少（13.3%）和便秘（11.1%）。大多数 TRAE 为 1–2 级； TRAE≥3 级为22.2%（包含 2 例淋巴细胞减少，以及各 1 例中性粒细胞减少、贫血、白细胞减少、恶心、口腔炎、呕吐、乏力、疼痛、尿路感染、缺氧和低血压）。未观察到ILD或输液反应。 小结     总体来看，双靶ADC已经不再只是早期概念验证，而是进入更系统的临床数据积累和注册转化阶段。iza-bren的获批上市，说明双靶ADC已经开始从临床开发走向实际治疗应用；JSKN-016、ABBV-969、EBC-129、DM005等项目也在不同实体瘤中显示出初步疗效信号。 不过，双靶ADC的核心竞争力仍需要回到具体产品本身：靶点组合是否真正解决肿瘤异质性问题，双靶结合是否带来更好的内吞和递送效率，载荷和DAR设计能否维持安全窗，以及临床人群选择是否足够清晰。 欢迎大家加入BioPlus Partners微信交流群。 入群申请联系人 ：Lisa 邮箱：lisa.li@bp-bioplus.com 电话：18662346610（同微信） 入群申请，请先添加Lisa微信，并分享名片 入群画像 ：Biotech/药厂研发/BD、投资机构、临床医生等 入群福利：不定时行业资料包分享

— The study shows that EGFR-TKIs induce TROP2 upregulation in DTP cells, providing a mechanistic basis for combining sac-TMT with EGFR-TKI. — The Company is conducting a Phase III registrational study of sac-TMT plus osimertinib as first-line treatment for advanced EGFR-mutant NSCLC (enrollment completed; follow‑up phase) and a Phase II study of the same combination as neoadjuvant treatment for EGFR-mutant resectable NSCLC. — Sac-TMT has been approved in China for advanced EGFR-mutant NSCLC following progression on TKI therapy or TKI therapy and platinum-based chemotherapy, and has demonstrated significant PFS and OS benefits in TKI-resistant settings. June 22, 2026 -- Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. ("Kelun-Biotech" or the "Company") announced that translational research results on its sacituzumab tirumotecan (sac-TMT, also known as SKB264/MK-2870)(佳泰莱®) in combination with osimertinib as first-line treatment for advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) have been published online in Cancer Cell, an international academic journal. The paper, titled "Targeting TROP2 in drug-tolerant persister cells delays EGFR tyrosine kinase inhibitor resistance in non-small-cell lung cancer," was led by Professor Li Zhang and Professor Wenfeng Fang from the Sun Yat-sen University Cancer Center. The study shows that trophoblast cell-surface antigen 2 (TROP2) expression is upregulated in residual drug-tolerant persister (DTP) cells after EGFR tyrosine kinase inhibitor (TKI) treatment; in preclinical models, sac-TMT combined with osimertinib inhibited DTP cell formation and delayed tumor recurrence. These findings provide translational medicine evidence for the combination of TROP2-directed antibody drug conjugate (ADC) and EGFR‑TKI in delaying drug resistance, and further underscore the differentiated value of sac-TMT as a key combination partner for EGFR-TKIs. Building on the above research and clinical development plans, the Company is advancing a Phase III registrational study (NCT06670196) of sac-TMT in combination with osimertinib versus osimertinib monotherapy as first-line treatment for locally advanced or metastatic EGFR-mutant non-squamous NSCLC. The study is designed to evaluate the efficacy and safety of sac-TMT (4 mg/kg, Q2W) plus osimertinib compared with osimertinib monotherapy in this indication. Patient enrollment in China has been completed, and the study is currently in the follow-up and data maturity phase. In addition, the Company is advancing clinical exploration of sac-TMT for earlier-stage EGFR-mutant NSCLC. A Phase II study (NCT07329322) is ongoing to evaluate sac-TMT in combination with osimertinib or as monotherapy in the neoadjuvant setting for EGFR-mutant resectable NSCLC, further exploring the potential value of sac-TMT in perioperative treatment. This publication in Cancer Cell reinforces the scientific foundation for combining sac-TMT with EGFR-TKIs as first-line treatment for EGFR-mutant NSCLC. The Company will continue to explore the potential of this combination regimen in earlier-line treatment, resistance delay, and long-term benefit, building on the approved indications and clinical development plan of sac-TMT in EGFR-mutant NSCLC. Kelun-Biotech remains committed to driving innovation in treatment paradigms for EGFR-mutant NSCLC and expanding therapeutic options for patients. Sac-TMT, a core product of the Company, is a novel human TROP2 ADC in which the Company has proprietary intellectual property rights, targeting advanced solid tumors such as NSCLC, breast cancer (BC), gastric cancer (GC), gynecological tumors and genitourinary tumors, among others. Sac-TMT is developed with a unique, bifunctional linker that maximizes payload delivery to tumor cells both through its irreversible connection with the anti-TROP2 monoclonal antibody sacituzumab and its pH-sensitive cleavage from a belotecan-derivative topoisomerase I inhibitor payload in the lysosome, with a drug-to-antibody-ratio (DAR) of 7.4. Sac-TMT specifically recognizes TROP2 on the surface of tumor cells by recombinant anti-TROP2 humanized monoclonal antibodies, which is then endocytosed by tumor cells and releases the payload KL610023 intracellularly. KL610023, as a topoisomerase I inhibitor, induces DNA damage to tumor cells, which in turn leads to cell-cycle arrest and apoptosis. In addition, it also releases KL610023 in the tumor microenvironment. Given that KL610023 is membrane permeable, it can enable a bystander effect, or in other words kill adjacent tumor cells. In May 2022, the Company licensed the exclusive rights to MSD (the tradename of Merck & Co., Inc, Rahway, NJ, USA) to develop, use, manufacture and commercialize sac-TMT in all territories outside of Greater China (which includes Mainland China, Hong Kong, Macao and Taiwan). To date, four indications for sac-TMT have been approved and marketed in China for: 1) unresectable locally advanced or metastatic triple‑negative breast cancer (TNBC) who have received at least two prior systemic therapies (at least one of them for advanced or metastatic setting); 2) EGFR mutant-positive locally advanced or metastatic non-squamous NSCLC following progression on EGFR-TKI therapy and platinum-based chemotherapy; 3) EGFR mutant-positive locally advanced or metastatic non-squamous NSCLC who progressed after treatment with EGFR-TKI therapy; 4) unresectable or metastatic hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) (Immunohistochemistry (IHC) 0, IHC 1+ or IHC 2+/In Situ Hybridization (ISH)-) BC who have received prior endocrine therapy and at least one line of chemotherapy in advanced setting. The first two indications above have been included in China's National Reimbursement Drug List (NRDL). This inclusion is expected to bring clinically meaningful benefits to a greater number of patients with BC and NSCLC. Additionally, sac-TMT has been granted six Breakthrough Therapy Designations (BTDs) by the National Medical Products Administration (NMPA). Sac-TMT is the world's first TROP2 ADC drug approved for marketing in lung cancer. A new indication application for sac-TMT in combination with pembrolizumab (KEYTRUDA®[1]) as first‑line treatment for locally advanced or metastatic NSCLC who have programmed death ligand 1 (PD-L1) tumor proportion score (TPS)≥1% and are EGFR-negative and anaplastic lymphoma kinase (ALK)-negative has been accepted for review by the NMPA, and has entered the priority review and approval process. As of today, Kelun-Biotech has initiated 9 registrational clinical studies in China. MSD is evaluating 17 ongoing global Phase III clinical studies of sac-TMT as a monotherapy or in combination with pembrolizumab or other anti-cancer agents for several types of cancer. These studies are sponsored and led by MSD. Kelun-Biotech (6990.HK) is a holding subsidiary of Kelun Pharmaceutical, which focuses on the R&D, manufacturing, commercialization and global collaboration of innovative biological drugs and small molecule drugs. Kelun-Biotech focuses on major disease areas such as solid tumors, autoimmune, and metabolic diseases, and in establishing a globalized drug development and industrialization platform to address the unmet medical needs in China and the rest of world. Kelun-Biotech is committed to becoming a leading global enterprise in the field of innovative drugs. At present, Kelun-Biotech has more than 30 ongoing key innovative drug projects, of which 4 projects with 8 indications have been approved for marketing, 1 project is in the NDA stage and more than 10 projects are in the clinical stage. Kelun-Biotech has established one of the world's leading proprietary ADC and novel DC platforms, OptiDC™, and has 2 ADC projects with 5 indications approved for marketing, and multiple ADC and novel DC assets in clinical or preclinical research stage. The content above comes from the network. if any infringement, please contact us to modify.