PO.CT01.01 · 临床试验

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 🕑 4/20 02:00–05:00 📍 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

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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