海报库PosterKeep
PO.CT01.01 · 临床试验

BGB-24714（一种第二线粒体来源的半胱天冬酶激活剂（SMAC）模拟物）作为单药或与化疗或同步放化疗联合治疗实体瘤的1期研究

A phase 1 study of BGB-24714, a second mitochondrial-derived activator of caspases (SMAC) mimetic, as monotherapy or in combination with chemotherapy or concurrent chemoradiotherapy in solid tumors

编号 CT120 展板 12 时间 4/20 02:00–05:00 区域 Section 51 主讲 Hua-Xin Gao
分会场 Phase 0 and First-in-Human Phase I Clinical Trials
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作者与单位 Authors & Affiliations

Andreas Varkaris1, Erika Hamilton2, Jermaine Coward3, Rafael Santana-Davila4, Jinming Yu5, Byoung Chul Cho6, Jung Yun Lee6, Yongsheng Li7, Sanjeev Deva8, Youngjoo Lee9, Huai Liu10, Yuping Sun5, Zhe Yang11, Wen Xu12, Sook Ryun Park13, Se-Hoon Lee14, Andrew Z. Wang15, Hui Shao16, Jinhui Zhang17, Zhaoyin Zhu18, Runzhe Chen18, Hua-Xin Gao18, Judy S. Wang19

1Massachusetts General Hospital, Boston, MA,2Sarah Cannon Research Institute, Nashville, TN,3ICON Cancer Centre, South Brisbane, QLD, Australia,4Fred Hutch Cancer Center, Seattle, WA,5Shandong Cancer Hospital, Jinan, Shandong, China,6Severance Hospital, Yonsei University Health System, Seoul, Korea, Republic of,7Chongqing Cancer Hospital, Shapingba District, Chongqing, China,8Auckland City Hospital, Grafton, Auckland, New Zealand,9National Cancer Center, Goyang-si, Gyeonggi-do, Korea, Republic of,10Hunan Cancer Hospital, Changsha, Hunan, China,11Shandong Provincial Hospital, Jinan, Shandong, China,12Princess Alexandra Hospital, Woolloongabba, QLD, Australia,13Asan Medical Center, Seoul, Korea, Republic of,14Samsung Medical Center, Seoul, Korea, Republic of,15University of Texas Southwestern Medical Center, Dallas, TX,16BeOne Medicines Ltd, Beijing, China,17BeOne Medicines Ltd, Shanghai, China,18BeOne Medicines Ltd, San Carlos, CA,19Florida Cancer Specialists and Sarah Cannon Research Institute, Sarasota, FL

摘要 Abstract

中文摘要
背景：调节凋亡可能增强实体瘤中标准治疗化疗（CT）和同步放化疗（cCRT）的疗效。BGB-24714是一种拮抗凋亡蛋白抑制因子（IAP）的选择性SMAC模拟物，已展现出有前景的临床前抗肿瘤活性。这项开放标签、多中心、首次人体的1期（Ph）研究评估了BGB-24714作为单药或与CT或cCRT联合治疗晚期或转移性实体瘤患者（pts）的疗效（NCT05381909）。 方法：该研究包括剂量递增（1a）和剂量扩展（1b）阶段。Ph1a A部分评估BGB-24714单药治疗；B部分：BGB-24714+每周紫杉醇；C/D部分：BGB-24714+cCRT分别用于NSCLC和食管鳞状细胞癌（ESCC）。Ph1b纳入二线或以上转移性NSCLC和铂耐药卵巢癌（PROC）患者，分别接受BGB-24714+多西他赛或紫杉醇。主要终点为安全性/耐受性（Ph1a）和初步抗肿瘤活性（Ph1b）。 结果：截至2025年7月25日，共入组并治疗157例患者（Ph1a 132例；Ph1b 25例[11例NSCLC；14例PROC]）。在Ph1a A部分评估了BGB-24714的9个剂量水平（DL；30 mg至900 mg QD）（n=68），在Ph1a B至D部分评估了7个DL（60 mg至650 mg QD）（n=64）。Ph1a单药或联合剂量递增均未达到MTD。最常见的BGB-24714相关TEAE因研究部分而异，且以低级别为主：Ph1a A部分为恶心（33.8%），B部分为腹泻（25%），C/D部分为中性粒细胞计数下降（43.8%），Ph1b-NSCLC为腹泻和疲乏（各45.5%），Ph1b-PROC为口腔炎、ALT/AST升高（各28.6%）。最常见的≥3级BGB-24714相关TEAE为Ph1a A部分的ALT升高（5.9%），B部分的脂肪酶升高和疲乏（各6.3%），C/D部分的中性粒细胞计数下降（31.3%），Ph1b-NSCLC的贫血（27.3%），以及Ph1b-PROC的中性粒细胞计数下降（28.6%）。最常见的严重BGB-24714相关TEAE（≥5%）为Ph1a B部分的肺炎（6.3%），Ph1b-NSCLC的腹泻（18.2%），以及Ph1b-PROC的发热性中性粒细胞减少症和疲乏（各7.1%）。因BGB-24714相关TEAE导致的治疗中止发生于12.1%的Ph1a患者和24.0%的Ph1b患者。Ph1a的确认ORR分别为0%（A部分）、12.8%（B部分）、54.5%（C部分）和66.7%（D部分）；DCR分别为40.0%、59.6%、81.8%和100.0%。在Ph1b中，NSCLC和PROC的确认ORR分别为0%和28.6%；DCR分别为70.0%和85.7%；NSCLC和PROC的中位PFS均为162天。药效动力学显示cIAP1以剂量依赖方式快速且持续降解，表明凋亡调控通路存在强烈的靶点结合。 结论：BGB-24714在晚期或转移性实体瘤患者中展现出抗肿瘤活性和可管理的安全性特征。
查看英文原文 English abstract
Background: Apoptosis modulation may enhance the efficacy of standard-of-care chemotherapy (CT) and concurrent chemoradiotherapy (cCRT) in solid tumors. BGB-24714, a selective SMAC mimetic that antagonizes Inhibitor of Apoptosis Proteins (IAPs), has demonstrated promising preclinical antitumor activity. This open-label, multicenter, first-in-human Phase (Ph) 1 study evaluated BGB-24714 as monotherapy or in combination with CT or cCRT in patients (pts) with advanced or metastatic solid tumors (NCT05381909). Methods: The study included dose-escalation (1a) and -expansion (1b) Phs. Ph1a Part A assessed BGB-24714 monotherapy; Part B: BGB-24714 + weekly paclitaxel; Parts C/D: BGB-24714 + cCRT in NSCLC and esophageal squamous cell carcinoma (ESCC), respectively. Ph1b enrolled pts with second-line or later metastatic NSCLC and platinum-resistant ovarian cancer (PROC) to receive BGB-24714 + docetaxel or paclitaxel, respectively. Primary endpoints were safety/tolerability (Ph1a) and preliminary antitumor activity (Ph1b). Results: As of July 25, 2025, 157 pts were enrolled and treated (132 in Ph1a; 25 in Ph1b [11 NSCLC; 14 PROC]). 9 dose levels (DLs; 30 mg to 900 mg QD) of BGB-24714 were assessed (n=68) in Ph1a Part A and 7 DLs (60 mg to 650 mg QD) in Ph1a Parts B to D (n=64). No MTD was reached in Ph1a monotherapy or combination dose escalation.The most common BGB-24714-related TEAEs varied by study part and were predominantly low grade: nausea (33.8%) in Ph1a Part A, diarrhea (25%) in Part B, neutrophil count decreased (43.8%) in Parts C/D, diarrhea and fatigue (45.5% each) in Ph1b-NSCLC, and stomatitis, ALT/AST increased (28.6% each) in Ph1b-PROC. The most common Grade ≥3 BGB-24714-related TEAEs were ALT increased (5.9%) in Ph1a Part A, lipase increased and fatigue (6.3% each) in Part B, neutrophil count decreased (31.3%) in Parts C/D, anemia (27.3%) in Ph1b-NSCLC, and neutrophil count decreased (28.6%) in Ph1b-PROC. The most common serious BGB-24714-related TEAEs (≥5%) were pneumonitis (6.3%) in Ph1a Part B, diarrhea (18.2%) in Ph1b-NSCLC, and febrile neutropenia and fatigue (7.1% each) in Ph1b-PROC. Treatment discontinuation due to BGB-24714-related TEAEs occurred in 12.1% of Ph1a and 24.0% of Ph1b pts. Confirmed ORRs in Ph1a were 0% (Part A), 12.8% (Part B), 54.5% (Part C), and 66.7% (Part D); DCRs were 40.0%, 59.6%, 81.8%, and 100.0%, respectively. In Ph1b, confirmed ORRs were 0% in NSCLC and 28.6% in PROC; DCRs were 70.0% and 85.7%, respectively; median PFS was 162 days for both NSCLC and PROC. Pharmacodynamics showed rapid and sustained cIAP1 degradation in a dose-dependent manner, demonstrating strong target engagement in apoptosis regulatory pathway. Conclusion: BGB-24714 demonstrated antitumor activity with a manageable safety profile in pts with advanced or metastatic solid tumors.
利益披露 Disclosure
A. Varkaris, None. E. Hamilton, AbbVie; Accutar Biotechnology; Artios; Arvinas; AstraZeneca; AtlasMedx; BeiGene; BeOne Medicines; Bicycle Therapeutics; Biohaven Pharmaceuticals; BioNTech ). Compugen; Cullinan; Daiichi Sankyo; Dantari; Bay One Biopharmaceuticals; Duality Biologics; Ellipses Pharma; Elucida Oncology; Exelixis; FujiFilm; Genmab; Gilead Sciences; H3 Biomedicine ). Iambic Therapeutics; Immunogen; Inspirna; InventisBio; Jacobio; Jazz Pharmaceuticals; K-Group Beta; Kind Pharmaceuticals; Lilly; Loxo Oncology; Mabspace Biosciences; Mabwell Bioscience ). Marengo Therapeutics; MediLink Therapeutics; Merck; Mersana; Novartis; Olema; Orinove; Orum Therapeutics; Pfizer; Pionyr Immunotherapeutics; Prelude Therapeutics; Profound Bio; Regeneron; ). Relay Therapeutics; Rgenix; Roche/Genentech; SeaGen; Shattuck Labs; Simcha Therapeutics; Stemline Therapeutics; Sutro; Systimmune; Taiho; Tesaro; TheRas; Treadwell Therapeutics; Verastem ). Xadcera Biopharmaceutical; Zymeworks ). Arvinas; AstraZeneca; BeOne Medicines; BioNTech; Boehringer Ingelheim; Boundless Bio; Bristol-Myers Squibb; Circle Pharma; Daiichi Sankyo; Gilead Sciences; Halda Therapeutics; Incyclix Bio; IQVIA Other, Consulting paid to institution. Janssen; Jazz Pharmaceuticals; Jefferies LLC; Johnson and Johnson; Lilly; Mersana Therapeutics; Novartis; Pfizer; Precede Biosciences; Pyxis Oncology; Roche/Genentech; Samsung Bioepis; Shorla Pharma Other, Consulting paid to institution. Stemline Therapeutics; Tempus Labs Other, Consulting paid to institution. J. Coward, None. R. Santana-Davila, Fosum Pharma Other, Advisory Board. Amgen Advisory Board. AstraZeneca Other, Advisory Board. Boehringer Ingleheim Other, Advisory board. Bristol Myers Squibb Company Other, Advisory board. Coherus Other, Advisory board. Daiichi Sankyo Other, Advisory board. Gilead Sciences Other, Advisory Board. Regeneron Other, Advisory Board. Rigel Pharma Other, Advisory board. Takeda Other, Advisory board. J. Yu, None. B. Cho, Champions Oncology; Crown Bioscience; Imagen; PearlRiver Bio GmbH; GIInnovation Other Intellectual Property. GIInnovation; AstraZeneca; Champions Onoclogy; CJ bioscience; Cyrus; Janssen; MSD; Dong-A; ST; Yuhan; ImmuneOncia; Therapex; JINTSbio; Vertical Bio AG ). BeiGene; Novartis; AstraZeneca; Boehringer-Ingelheim; Roche; BMS; CJ; Cyrus therapeutics; Ono; Yuhan; Pfizer; Eli Lilly; Janssen; Takeda; MSD; Gilead; Amgen; Daiichi Sankyo; Regeneron; Sanofi Other, Consultant. AnHeart; Therapeutics; Seagen; Harpoon Therapeutics; GSK; ArriVent Other, Consultant. Yonsei University Health System Employment. KANAPH Therapeutic Inc; Bridgebio Therapeutics; Cyrus Therapeutics; Guardant Health; J INTS Bio; Therapex Co., Ltd Other, Advisory Board. ASCO; AstraZeneca; Guardant; Roche; ESMO; IASLC; Korean Cancer Association; Korean Society of Medical Onoclogy; Korean Society of Thyroid-Head and Neck Surgery; Korean Cancer Study Group; Novartis Other, Invited speaker. MSD; The Chinese Thoracic Oncology Society; Pfizer; Zailab Other, Invited speaker. TheraCanVac Inc; Gencurix Inc; Bridgebio therapeutics; KANAPH Therapeutic Inc; Cyrus Therapeutics; Interpark Bio Convergence Corp.; J INTS BIO Stock. DAAN Biotherapeutics Other, Founder. J INTS BIO g., Board of Directors, non-salaried role). J. Lee, AstraZeneca Independent Contractor. Eisai Independent Contractor. MSD Independent Contractor. Roche Independent Contractor. Takeda Independent Contractor. CanariaBio Independent Contractor. DS Independent Contractor. Genmab Independent Contractor. GII Independent Contractor. ImmunoGen Independent Contractor. Seagen Independent Contractor. Sutro Independent Contractor. Regeneron Independent Contractor. Novartis ). Janssen ). BMS ). GSK ). Daiichi Sankyo ). AbbVie ). ONO ). Y. Li, None. S. Deva, Roche Travel. Y. Lee, None.. H. Liu, None.. Y. Sun, None.. Z. Yang, None. W. Xu, Merck ), Travel, Other, Advisory board, speakers honoraria. MSD Other, Advisory board, speakers honoraria. BMS Travel, Advisory board. AZD Other, Speakers honorarium. S. Park, Incyte ). ONO Pharmaceutical ). ImmuneOncia Therapeutics ). BeOne Medicines Independent Contractor. S. Lee, None. A. Z. Wang, Johnson and Johnson Other, Consulting. Fosun Pharma USA/Archimmune Therapeutics Stock, Patent, Other, Cofounder. Capio Biosciences g., Board of Directors, non-salaried role), Stock, Patent, Other, Cofounder. H. Shao, BeOne Medicines Employment. J. Zhang, BeOne Medicines Employment, Stock. Z. Zhu, BeOne Medicines Employment, Stock. R. Chen, BeOne Medicines Employment, Stock Option. H. Gao, BeOne Medicines Employment, Stock. J. S. Wang, Boehringer Ingelheim Travel. NGM Bio Travel. AbbVie; Abdera Therapeutics; Accent Therapeutics; Accutar Biotech; Acrivon Therapeutics; Adagene; Allorion Therapeutics; Alterome Therapeutics; Apollo; Artios; Astellas Pharma; Avenzo; BeiGene ). Bicycle Therapeutics; BioNTech SE; Biostar; Blueprint Medicines; BMS GmbH & Co. KG; Boehringer Ingelheim; C4 Therapeutics; Celgene/Bristol-Myers Squibb; Circle Pharma; Compass Therapeutics; Compugen; ). Cullinan Oncology; Conjupro Biotherapeutics; D3 Bio; Daiichi Sankyo/UCB Japan; Day One Bio; Dren Bio; DualityBio; Edgewood Oncology; Eli Lilly; Ellipses Pharma; Erasca; Inc; Genentech; Genmab ). Georgiamune; GlaxoSmithKline; Halda Therapeutics; Hotspot Therapeutics; IgM Biosciences; Immunitas; Immunogen; Incyte; ITeos Therapeutics; Janssen; Jazz Pharmaceuticals; Kineta; Klus Pharma; Kumquat; ). Kura Oncology; Loxo/Lilly; MabSpace Biosciences; Macrogenics; MBQ Pharma; Medikine; MediLink Therapeutics; Stemline/Menarini; Merck KGaA; Mersana; Moderna Therapeutics; NGM Biopharmaceuticals; NiKang ). Novartis; Nurix; Olema Oncology; OnCusp Therapeutics; Pfizer; Pyxis; Quanta Therapeutics; Relay Therapeutics; Revolution Medicines; Roche; Sanofi; Step Pharma; Syndax; Systimmune; Tango Therapeutics ). Vividion Therapeutics; Xencor; Zai Lab; Zymeworks ).

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