PO.CT01.03 · 临床试验

ZL-1310（一种 DLL3 靶向 ADC）在既往接受过治疗且有基线脑转移的广泛期小细胞肺癌患者中的颅内活性：一项 1 期试验的分析

Intracranial activity of ZL-1310, a DLL3-targeted ADC, in patients with previously treated extensive-stage small cell lung cancer and baseline brain metastasis: Analysis of a phase 1 trial

编号 CT193 展板 15 时间 4/21 09:00–12:00 区域 Section 50 主讲 Pingkuan Zhang, MD

分会场 Phase I Clinical Trials

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作者与单位 Authors & Affiliations

Pedro Rocha¹, Manish Patel², Yi-Long Wu³, Jun Zhao⁴, Grace Dy⁵, María Eugenia Olmedo García⁶, Qiming Wang⁷, Valentina Gambardella⁸, Oscar Juan-Vidal⁹, Afshin Dowlati¹⁰, David Vicente Baz¹¹, Alexander Spira¹², Anne C. Chiang¹³, Yingying Du¹⁴, Martin Gutierrez¹⁵, Xiaorong Dong¹⁶, Jie Hu¹⁷, Mariam Alexander¹⁸, Haiyong Wang¹⁹, Wenxiu Yao²⁰, Liza Villaruz²¹, Zhen Wang³, Pingkuan Zhang²², Renke Zhou²², Xiao Wang²², Luis Paz-Ares²³

¹Instituto de Investigacion Oncologica Vall d’Hebron (VHIO), Barcelona, Spain,²Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL,³Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China,⁴Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China,⁵Roswell Park Comprehensive Cancer Center, Buffalo, NY,⁶Hospital Universitario Ramón y Cajal, Madrid, Spain,⁷Henan Cancer Hospital, Zhengzhou, China,⁸Hospital Clínico Universitario de Valencia, INCLIVA, Valencia, Spain,⁹Hospital Universitari i Politècnic La Fe, Valencia, Spain,¹⁰University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH,¹¹Hospital Universitario Virgen Macarena, Sevilla, Spain,¹²NEXT Oncology Virginia, Fairfax, VA,¹³Yale Cancer Center, Yale School of Medicine, New Haven, CT,¹⁴The First Affiliated Hospital of Anhui Medical University, Hefei, China,¹⁵Hackensack University Medical Center, Hackensack, NJ,¹⁶Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,¹⁷Zhongshan Hospital, Fudan University, Shanghai, China,¹⁸Medical University of South Carolina, Charleston, SC,¹⁹Cancer Hospital of Shandong First Medical University, Jinan, China,²⁰Sichuan Cancer Hospital, Chengdu, China,²¹UPMC Hillman Cancer Center, Pittsburgh, PA,²²Zai Lab (US) LLC, Cambridge, MA,²³Hospital Universitario 12 de Octubre, Madrid, Spain

摘要 Abstract

中文摘要

背景：脑转移（BM）在广泛期小细胞肺癌（ES-SCLC）中很常见，也是治疗失败的常见原因。BM 仍然是一项未满足的需求，可用的治疗选择有限，如姑息性放疗。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-载荷）平台，即一种抗 DLL3 单克隆抗体通过蛋白酶可切割连接子与拓扑异构酶 I 抑制剂载荷相连。ZL-1310 在经过大量预处理的 ES-SCLC 中已显示出令人鼓舞的全身疗效。我们报告一项 1 期研究中 ZL-1310 的初步颅内疗效。方法：这项多国 1 期研究（NCT06179069）入组了在 ≥1 次铂类化疗后进展的 ES-SCLC 成人。稳定或无症状 BM 者（包括既往未接受脑放疗者）符合入选条件。ZL-1310 每 3 周静脉给药一次，直至疾病进展或不可接受的毒性。全身疗效由研究者使用实体瘤疗效评价标准（RECIST）v1.1 评估。颅内疗效由盲态独立放射科医生使用神经肿瘤学放射学疗效评估修订标准（mRANO）评估。结果：截至 2025 年 8 月 1 日，104 例患者接受了跨越 6 个剂量水平（0.8-2.8 mg/kg）的 ZL-1310。中位年龄为 65 岁（范围：36，80）；42.3% 的患者为女性，28.8% 为亚裔。54 例（51.9%）有 1 线既往治疗，其余 50 例（48.1%）有 2 线或更多线既往治疗。共 94 例（90.4%）接受过既往抗 PD-L1，13 例（12.5%）接受过既往 lurbinectedin，10 例（9.6%）接受过既往 DLL3 靶向治疗。基线时 33 例（31.7%）患者存在脑转移（包括 11 例未经治疗的 BM）。24 例患者有经独立评审的颅内疗效结果，包括 15 例既往接受过放疗和 9 例未经治疗者。确认的颅内缓解为 58.3%（14/24，95% CI：36.6，77.9%），包括 5 例 CR 和 9 例 PR。既往未接受脑放疗患者的颅内缓解率为 66.7%（6/9），既往接受脑放疗患者为 53.3%（8/15）。颅内疾病控制率为 95.8%（23/24）。颅内缓解起效的中位时间为 5.6 周（最小 5.1，最大 8.7 周）。在 33 例有 BM 且全身疗效可评估的患者中，确认 ORR 为 61%，包括 1 例确认 CR。整体上 22/104（21.2%）例患者报告了 ≥3 级治疗相关不良事件，1.6 mg/kg 剂量水平的 5/39（12.8%）例患者报告；1.6 mg/kg 剂量水平中 ≥2 例患者报告的包括贫血和中性粒细胞减少（各 2 例）。独立 mRANO 评估正在进行中，将提供更新数据。结论：ZL-1310 耐受性良好，在经过大量预处理且伴 BM 的 ES-SCLC 中显示出令人鼓舞的全身疗效。初步独立评估还表明 ZL-1310 具有高颅内疗效，包括在未经治疗的 BM 患者中。

查看英文原文 English abstract

Background: Brain metastasis (BM) is prevalent in extensive-stage small-cell lung cancer (ES-SCLC) and also a common cause for treatment failure. BM remains as an unmet need with limited treatment options available such as palliative radiotherapy. 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 protease-cleavable linker. ZL-1310 has demonstrated encouraging systemic efficacy in heavily pre-treated ES-SCLC. We report the initial intracranial efficacy of ZL-1310 from a phase 1 study. Methods: This multi-country Phase 1 study (NCT06179069) enrolled adults with ES-SCLC who have progressed following ≥1 platinum-based chemotherapy. Those with stable or asymptomatic BM are eligible (including those with no prior brain radiotherapy). ZL-1310 is given intravenously every 3 weeks until disease progression or unacceptable toxicity. Systemic efficacy was assessed by investigators using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Intracranial efficacy was assessed by blinded independent radiologists using Modified Criteria for Radiographic Response Assessment in NeuroOncology (mRANO). Results: As of 1 Aug 2025, 104 pts received ZL-1310 across 6 dose levels (0.8-2.8 mg/kg). The median age was 65 years (range: 36, 80); 42.3% of pts were female, and 28.8% were Asian. Fifty-four (51.9%) had 1 prior line and the remaining 50 (48.1%) had 2 or more lines of prior therapies. A total of 94 (90.4%) received a prior anti-PD‑L1, 13 (12.5%) had prior lurbinectedin, and 10 (9.6%) had prior DLL3-targeted therapy. Brain metastases were present in 33 (31.7%) pts (including 11 pts with untreated BM) at baseline. Independently reviewed intracranial efficacy results were available for 24 pts, including 15 pretreated with radiation and 9 untreated. Confirmed intracranial response was 58.3% (14/24, 95% CI: 36.6, 77.9%), including 5 CR and 9 PR. The intracranial response rate in pts without prior brain radiation was 66.7% (6/9) and 53.3% (8/15) in pts with prior brain radiation. Intracranial disease control rate was 95.8% (23/24). The median time to onset of intracranial response was 5.6 weeks (min 5.1, max 8.7 weeks). Of the 33 pts with BM and systemic efficacy evaluable, confirmed ORR was 61%, including 1 confirmed CR. Grade ≥3 treatment-related adverse events were reported for 22/104 (21.2%) pts overall and 5/39 (12.8%) pts in the 1.6 mg/kg dose level; those reported in ≥2 pts at the 1.6 mg/kg dose level included anemia and neutropenia (2 pts each). Independent mRANO evaluation is ongoing and updated data will be provided. Conclusions: ZL-1310 is well tolerated and demonstrated encouraging systemic efficacy in heavily pretreated ES-SCLC with BM. The preliminary independent assessment also showed ZL-1310 has high intracranial efficacy including in patients with untreated BM.

利益披露 Disclosure

P. Rocha, Amgen Other, Honoraria. Daiichi Sankyo Other, Consulting or advisory role. IGES Pharma Consulting or advisory role. AstraZeneca Travel. Bristol Myers Squibb Travel. Daiichi Sankyo Travel. Kyowa Kirin Travel. MSD Travel. PharmaMar Travel. Roche Travel. M. Patel, ION Pharma Other Business Ownership. Daiichi Sankyo Other, Consulting or Advisory Role. UCB Japan Other, Consulting or Advisory Role. Kura Oncology Other, Consulting or Advisory Role. Accutar Biotech Other, Consulting or Advisory Role. Mitsubishi Tanabe Pharma Other, Consulting or Advisory Role. Shivanka Research Other, Consulting or Advisory Role. Johnson & Johnson/Janssen Consulting or Advisory Role. Agenus ). Boehringer Ingelheim ). Cyteir Therapeutics ). Daiichi Sankyo ). Genentech/Roche ). Janssen ). Loxo ). Macrogenics ). Merck ). Moderna Therapeutics ). Pfizer ). Prelude Therapeutics ). Y. Wu, None.. J. Zhao, None. G. Dy, Amgen Other, Consulting fee and/or Honoraria. AstraZeneca Consulting fee and/or Honoraria. Bayer Consulting fee and/or Honoraria. Bristol Myers Squibb Consulting fee and/or Honoraria. Janssen Consulting fee and/or Honoraria. Novartis Consulting fee and/or Honoraria. Regeneron Consulting fee and/or Honoraria. Whitehawk Therapeutics Consulting fee and/or Honoraria. M. Olmedo García, None.. Q. Wang, None.. V. Gambardella, None.. O. Juan-Vidal, None.. A. Dowlati, None.. D. Vicente Baz, 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. Bristol Myers Squibb Other, Honoraria. Bayer Other, Honoraria. Prelude Therapeutics Other, Honoraria. Abbvie Other, Honoraria. Astellas Pharma 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. A. C. Chiang, Amgen Other, Advisory board/consulting. Abbvie Other, Advisory board/consulting. AstraZeneca Other, Advisory board/consulting. BI Other, Advisory board/consulting. Daichi Other, Advisory board/consulting. Fosun Other, Advisory board/consulting. Genentech Other, Advisory board/consulting. Janssen Other, Advisory board/consulting. Merck Other, Advisory board/consulting. Zai Lab Other, Advisory board/consulting. Amgen ). AbbVie ). AstraZeneca ). Genentech ). BMS ). Zai Lab ). Jazz ). AstraZeneca Other, Member of the data and safety monitoring board. . Y. Du, None. M. Gutierrez, Merck Other, Advisory Board/Consultant. Incyte Biosciences Other, Advisory Board/Consultant. Outcomes Matter Innovations LLC Stock. Genomic Testing Cooperative Stock. COTA Stock. Lisata Therapeutics Inc. ). Georgetown University ). Constellation Pharmaceuticals Inc. ). Bristol Meyers Squibb ). AstraZeneca ). Incyte Corporation ). Memorial Sloan Kettering Cancer Center ). Prelude Therapeutics Inc ). Zai Lab ). Boehringer Ingelheim ). Johns & Johnson ). BeiGene ). Novartis ). Merck & Co. ). Seagen Inc. ). X. Dong, None.. J. Hu, None. M. Alexander, Abbvie Other, Consultant or Advisory Board. Amgen Other, Consultant or Advisory Board. Daiichi Sankyo Other, Consultant or Advisory Board. Janssen Other, Consultant or Advisory Board. Regeneron Other, Consultant or Advisory Board. CHEST Other, Consultant or Advisory Board. IDEOlogy Health Other, Speaker Honoraria. MedStar Other, Speaker Honoraria. H. Wang, None.. W. Yao, None.. L. Villaruz, None.. Z. Wang, None. P. Zhang, Zai Lab Employment, Stock. R. Zhou, Zai Lab Employment, Stock. X. Wang, Zai Lab Employment, Stock. L. Paz-Ares, Zai Lab Employment, Stock.

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