PO.CT01.01 · 临床试验
Pharmacodynamic (PD) characterization of BGB-24714, a second mitochondrial-derived activator of caspases (SMAC) mimetic, in a first-in-human study in solid tumors
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摘要 Abstract
Background: Inhibitor of apoptosis proteins (IAPs) are key regulators that suppress programmed cell death and are frequently overexpressed in cancer, contributing to tumor survival, drug resistance, and poor prognosis. Inhibition of IAPs restores apoptotic sensitivity and activates the NF-κB pathway, leading to induction of inflammatory cytokines and chemokines. SMACs, when released from mitochondria, naturally antagonize IAPs. BGB-24714 is a potent and selective SMAC mimetic that binds and inhibits IAPs, demonstrating robust antitumor activity across multiple xenograft models. This study presents the first translational PD biomarker evaluation of BGB-24714 in patients with solid tumors; safety and efficacy outcomes are reported separately.
Methods: PD biomarkers were developed and validated in preclinical models to assess target engagement and downstream pathway modulation. In the monotherapy dose escalation cohorts of BGB-24714 first-in-human study (NCT05381909), blood samples were collected at baseline (pre-dose on cycle 1 day 1) and at serial post-dose timepoints. Cellular IAP1 (cIAP1) levels in PBMCs were quantified to assess target engagement. Caspase-cleaved cytokeratin-18 (ccCK18) was measured as a circulating marker of apoptosis, and cytokine/chemokine profiles were analyzed to evaluate inflammatory signaling.
Results: In a human breast cancer xenograft model, BGB-24714 induced dose-dependent antitumor activity accompanied by rapid and sustained degradation of cIAP1, with maximal effects at 100 mg/kg. cIAP1 inhibition occurred within 1 hour post-dose and persisted at least for 24 hours, indicating that rapid and durable cIAP1 degradation is required for optimal efficacy. Similar levels and kinetics of cIAP1 degradation were observed in PBMCs and tumor tissue in mice at a clinically relevant dose, validating PBMCs as a suitable surrogate for PD assessment. In the phase 1 study, BGB-24714 induced rapid, sustained, and dose-dependent cIAP1 degradation in PBMCs. Approximately 50% degradation was observed on Day 2 at the 60 mg dose, near complete cIAP1 degradation was achieved by Day 2 and maintained thereafter at doses ≥ 200 mg. Dose-dependent increases in ccCK18 at Day 15 from 200 mg onward indicated apoptosis induction, while dose-dependent elevations in circulating cytokines and chemokines at Day 15 from doses 200 mg or 300 mg, with a more pronounced trend at 450 mg and above, were consistent with NF-κB pathway activation. Collectively, these PD findings confirm the on-mechanism biological activity of BGB-24714.
Conclusion: BGB-24714 demonstrated potent, sustained target engagement, apoptosis induction, and immune-inflammatory modulation consistent with its SMAC mimetic mechanism of action. These translational PD results support the biological activity of BGB-24714 in patients with solid tumors.
利益披露 Disclosure
J. Zhang,
BeOne Medicines Employment, Stock.
M. Deng,
BeOne Medicines Employment.
B. Jiang,
BeOne Medicines Employment.
J. Li,
BeOne Medicines Employment.
J. 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 ).
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.
H. Gao,
BeOne Medicines Employment, Stock, Patent.
X. Song,
BeOne Medicines Employment.
Z. Shen,
BeOne Medicines Employment.
W. Jin,
BeOne Medicines Employment.
F. Doñate,
BeOne Medicines Employment.