PO.CT01.03 · 临床试验

ZL-1310(一种DLL3靶向ADC)治疗神经内分泌癌及其他选定实体瘤患者的1b/2期、开放标签、多中心研究的初步结果

Preliminary results from the phase 1b/2, open-label, multi-center study of ZL-1310, a DLL3-targeted ADC, in patients with neuroendocrine carcinomas and other selected solid tumors

编号 CT189 展板 11 时间 4/21 09:00–12:00 区域 Section 50 主讲 Rohit Thummalapalli, MD

分会场 Phase I Clinical Trials

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作者与单位 Authors & Affiliations

Rohit Thummalapalli¹, Ming Lu², Alexander Spira³, Amr Mohamed⁴, Rahul Aggarwal⁵, Yu Wang⁶, Namrata Vijayvergia⁷, Jordi Rodon⁸, Andrew Scott Paulson⁹, Pingkuan Zhang¹⁰, Hui Yang¹¹, Yuan Xin¹¹, Jingmin Wen¹¹, Jie Chen¹²

¹Memorial Sloan Kettering Cancer Center, New York, NY,²Digestive Oncology Department, Peking University Cancer Hospital and Institute; Digestive Oncology Department, Beijing GoBroad Hospital, Beijing, China,³Virginia Cancer Specialists, Fairfax, VA,⁴Department of Medicine, Division of Hematology and Medical Oncology, UH Seidman Cancer Center. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH,⁵University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA,⁶Interventional Oncology Department, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China,⁷Fox Chase Cancer Center, Philadelphia, PA,⁸MD Anderson Cancer Center, Houston, TX,⁹Texas Oncology, Dallas, TX,¹⁰Zai Lab (US) LLC, Cambridge, MA,¹¹Zai Lab (Shanghai) Co., Ltd, Shanghai, China,¹²Neuroendocrine Oncology Department, Fudan University Shanghai Cancer Center, Shanghai, China

摘要 Abstract

中文摘要

背景：神经内分泌癌(NEC)患者在一线治疗后治疗选择有限，对新型有效疗法存在高度未满足的临床需求。Delta样配体3(DLL3)在NEC中广泛表达。ZL-1310是一种新型抗体-药物偶联物(ADC)，采用TMALIN®(肿瘤微环境可激活连接子-载药)平台，由抗DLL3单克隆抗体通过稳定的蛋白酶可裂解连接子与拓扑异构酶I抑制剂载药相连。我们报告ZL-1310-002(NCT06885281)试验1b期评估ZL-1310单药治疗NEC患者(pts)的初步安全性和疗效数据。方法：患者为晚期/转移性原发NEC(不包括小细胞肺癌)，且在含铂化疗期间或之后进展。ZL-1310以1.6 mg/kg起始剂量每3周静脉给药，直至疾病进展或不可接受的毒性。抗肿瘤活性按RECIST v1.1评估(研究者评估)。结果：截至2025年11月11日，28例NEC患者接受治疗(胃肠胰(GEP)-NEC：50%，宫颈/子宫：14%，原发不明14%，神经内分泌前列腺癌(NEPC)7%，膀胱7%，肺大细胞神经内分泌癌(LCNEC-L)4%，纵隔4%)；中位年龄53岁(范围：27，76)，ECOG PS：0/1(32%/68%)；男性：18例(64%)；亚裔：64%；5例(18%)患者接受过2线既往治疗。DLL3免疫组化表达在中心实验室回顾性完成，26例患者可获得数据，80%(21/26)患者阳性(临界值：H评分≥1)。中位H评分为123(范围：0-288)。中位随访2.9个月(范围：0.2-6.0)；患者接受中位3.2个治疗周期(范围：1，9)。17例(61%)患者仍在接受治疗；疾病进展是治疗中止的最常见原因。共25例(89%)患者发生治疗中出现的不良事件(TEAE)，4例(14.3%)发生3级及以上TEAE。最常见的TEAE(>20%，所有级别)包括贫血(39%)、恶心(36%)和呕吐(29%)。1例(3.6%)患者因AE(3级中性粒细胞计数下降)减少ZL-1310剂量；1例(3.6%)患者发生2级间质性肺病导致治疗中止。未报告5级AE。客观缓解率(ORR)为48%，在21例可评价患者中有8例确认应答和2例未确认应答，包括1例既往接受DLL3靶向双特异性抗体治疗且获得确认PR的患者。结论：ZL-1310以1.6 mg/kg每3周给药耐受性良好。NEC患者中观察到的AE特征总体上与一项更大规模研究中SCLC的特征一致。在含铂化疗后存在高度未满足需求的该患者群体中，初步疗效结果令人鼓舞。NEC的2期扩展正在进行，以进一步评估ZL-1310的安全性和疗效，届时将呈现更新数据。

查看英文原文 English abstract

Background: Patients with neuroendocrine carcinomas (NECs) have limited treatment options after front-line therapy, and have a high unmet clinical need for new effective therapies. Delta-like ligand 3 (DLL3) is broadly expressed in NECs. ZL-1310 is a novel antibody-drug conjugate (ADC) that employs the TMALIN ® ( T umor M icroenvironment A ctivable LIN ker-payload) platform, an anti-DLL3 monoclonal antibody linked to a topoisomerase I inhibitor payload via a stable protease-cleavable linker. We report initial safety and efficacy data from Phase 1b of the ZL-1310-002 (NCT06885281) trial assessing ZL-1310 monotherapy in patients (pts) with NECs. Methods: Patients had advanced/metastatic de novo NECs (excluding small cell lung cancer) and had progressed on or after platinum-based chemotherapy. ZL-1310 was given via IV at a starting dose of 1.6 mg/kg every 3 weeks until disease progression or unacceptable toxicity. Antitumor activity was assessed by RECIST v1.1 (investigator-assessed). Results: As of 11 Nov 2025, 28 pts with NECs were treated (GastroEnteroPancreatic (GEP)-NEC: 50%, cervical/uterine: 14%, unknown primary 14%, neuroendocrine prostate carcinoma (NEPC) 7%, bladder 7%, large cell neuroendocrine carcinoma of the lung (LCNEC-L) 4%, mediastinal 4%); median age was 53 years (range: 27, 76), ECOG PS: 0/1 (32%/68%); male: 18 (64%); Asian: 64%; 5 (18%) of the pts had 2 lines of prior therapy. DLL3 expression by immunohistochemistry was performed retrospectively in central laboratory and was available for 26 pts and 80% (21/26) patients were positive (cutoff: H-score ≥ 1). The median H-score was 123 (range: 0-288). Median follow-up was 2.9 months (range: 0.2-6.0); pts received a median of 3.2 treatment cycles (range: 1, 9). Seventeen (61%) of pts remain on treatment; disease progression was the most common reason for treatment discontinuation. A total of 25 pts (89%) had treatment-emergent adverse events (TEAEs), and 4 (14.3%) had Grade 3+ TEAEs. Most common TEAEs (>20%, all grade) include anemia (39%), nausea (36%) and vomiting (29%). One pt (3.6%) decreased the dose of ZL-1310 due to AE (G3 neutrophil count decreased); one pt (3.6%) experienced G2 interstitial lung disease leading to treatment discontinuation. No Grade 5 AE was reported. Objective response rate (ORR) was 48% with 8 confirmed and 2 unconfirmed responses in 21 evaluable pts, including one pt with prior DLL3-targeted bispecific antibody treatment who achieved confirmed PR. Conclusions: ZL-1310 dosed at 1.6mg/kg Q3W is well tolerated. The AE profile observed in pts with NEC is generally consistent with that of SCLC from a larger study. The preliminary efficacy results are encouraging in this patient population with a high unmet need following platinum-based chemotherapy. Phase 2 expansion in NEC is ongoing to further evaluate the safety and efficacy of ZL-1310 and updated data will be presented.

利益披露 Disclosure

R. Thummalapalli, Boehringer Ingelheim Other, Consulting or Advisory Role. Zai Lab ). M. Lu, None. A. Spira, NEXT Oncology Virginia Other, Leadership. CytomX Therapeutics Other, Honoraria. AstraZeneca/MedImmune Other, Honoraria. Merck Other, Honoraria. Takeda Other, Honoraria. Amgen Other, Honoraria. Janssen Oncology Other, Honoraria. Novartis Other, Honoraria. Incyte Other, Consulting or Advisory Role. Amgen Other, Consulting or Advisory Role. Novartis Other, Consulting or Advisory Role. Mirati Therapeutics Other, Consulting or Advisory Role. Gritstone Oncology Other, Consulting or Advisory Role. Jazz Pharmaceuticals Other, Consulting or Advisory Role. Takeda Other, Consulting or Advisory Role. LAM Therapeutics ). Roche ). AstraZeneca ). Boehringer Ingelheim ). Astellas Pharma ). A. Mohamed, None.. R. Aggarwal, None.. Y. Wang, None.. N. Vijayvergia, None.. J. Rodon, None.. A. Paulson, None. P. Zhang, Zai Lab Employment, Stock. H. Yang, Zai Lab Employment, Stock. Y. Xin, Zai Lab Employment, Stock. J. Wen, Zai Lab Employment, Stock. J. Chen, None.

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