PO.CT01.02 · 临床试验
靶向EphA2的Bicycle药物偶联物（BDC）BT5528联合nivolumab治疗晚期实体瘤患者（pts）：一项1/2期研究结果
An EphA2-targeting Bicycle Drug Conjugate (BDC), BT5528, in combination with nivolumab in patients (pts) with advanced solid tumors: Results from a Phase 1/2 study
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：BT5528是一种BDC®，由靶向EphA2的双环肽通过可裂解连接子与MMAE偶联而成。EphA2在多种实体瘤中过表达，并与不良临床结局相关。既往靶向EphA2的疗法伴有显著毒性，限制了疗效分析。由于分子量低且选择性高，BDC具有通过减少非肿瘤暴露来限制毒性的潜力。BT5528单药治疗的剂量递增（DE）安全性数据良好，支持启动本项BT5528在晚期实体瘤患者中安全性和有效性研究中的BT5528+nivolumab（nivo）剂量递增部分（A-2）（NCT04180371）。
方法：入组的成人患者为复发性转移性实体瘤，有可用组织进行EphA2表达检测，且已用尽所有适当的治疗选择。患者接受BT5528静脉给药（2.2或4.4 mg/m²每周一次，或6.5 mg/m²每2周（wks）一次）+nivo静脉给药（480 mg每4周一次）。主要目的：安全性/耐受性。次要目的：初步抗肿瘤活性/药代动力学（PK）参数。EphA2免疫组化为回顾性分析，采用肿瘤比例评分>1判定为阳性。
结果：截至2025年11月10日，21例患者接受治疗。中位年龄65岁；57%为ECOG PS 1；既往治疗线数中位数为2（范围1-7）；11/18（61%）肿瘤样本为EphA2+。6.5 mg/m²队列的全部14例患者均为转移性尿路上皮癌（mUC），此前均在检查点抑制剂治疗中进展，其中10例在enfortumab vedotin治疗中进展。全部患者BT5528治疗持续时间中位数为58.0天；6.5 mg/m²队列为81.5天；5例患者仍在治疗中。最常见的BT5528相关不良事件（TRAE）为乏力（29%）、恶心（24%）、腹泻（19%）和呕吐（14%）。≥3级TRAE为乏力（10%）和ALT/AST升高（各5%）。临床关注的TRAE为皮肤反应（24%）和外周神经病变（10%），均为1/2级。未发生出血相关TRAE。6.5 mg/m²队列中出现1例乏力的剂量限制性毒性。全部患者的客观缓解率为14%。在6.5 mg/m²队列中，10例EphA2+ mUC患者中有3例达到确认的部分缓解（cPR）；3例EphA2+且MMAE初治的患者中，2例达到cPR。全部患者的临床获益率（完全缓解+PR+疾病稳定≥4个月）为24%，6.5 mg/m²队列中3例EphA2+ MMAE初治患者为100%。BT5528和MMAE的PK在联合或不联合nivo时相似，表明无明显PK相互作用。
结论：与既往靶向EphA2的尝试不同，BT5528+nivo在各剂量下总体表现出良好的耐受性安全性特征，无新的安全性信号，无PK药物-药物相互作用。在BT5528 6.5 mg/m²每2周一次+nivo 480 mg每4周一次的剂量下，mUC患者中显示出初步抗肿瘤活性，尤其是在EphA2+肿瘤的MMAE初治患者中。
查看英文原文 English abstract
Background: BT5528 is a BDC® comprising a bicyclic peptide targeting EphA2 linked to MMAE via a cleavable linker. EphA2 is overexpressed in various solid tumors and is correlated with poor clinical outcomes. Earlier EphA2-targeted therapies were associated with significant toxicity which limited efficacy analysis. BDCs have potential to limit toxicity by reducing non-tumor exposure due to low molecular weight and high selectivity. Favorable dose escalation (DE) safety data for BT5528 monotherapy supported initiating the BT5528 + nivolumab (nivo) DE part (A-2) of the safety and efficacy study of BT5528 in pts with advanced solid tumors (NCT04180371).
Methods: Eligible adults had recurrent metastatic solid tumors with tissue available for EphA2 expression testing and had exhausted all appropriate treatment options. Pts received BT5528 IV (2.2 or 4.4 mg/m 2 once weekly, or 6.5 mg/m 2 once every 2 weeks (wks) + nivo IV (480 mg once every 4 wks). Primary objectives: safety/tolerability. Secondary objectives: preliminary anti-tumor activity/pharmacokinetic (PK) parameters. EphA2 immunohistochemistry was retrospective using Tumor Proportion Score >1 to determine positivity.
Results: As of November 10, 2025, 21 pts were treated. Median age was 65 years; 57% had ECOG PS 1; median prior lines of therapy was 2 (range 1-7); 11/18 (61%) tumor samples were EphA2+. All 14 pts in the 6.5 mg/m 2 cohort had metastatic urothelial carcinoma (mUC) and had previously progressed on a checkpoint inhibitor and 10 while on enfortumab vedotin. Median BT5528 treatment duration was 58.0 days in all pts; 81.5 days in the 6.5 mg/m 2 cohort; 5 pts remain on treatment. The most common BT5528-related adverse events (TRAEs) were fatigue (29%), nausea (24%), diarrhea (19%), and vomiting (14%). Grade ≥3 TRAEs were fatigue (10%) and ALT/AST increase (5% each). TRAEs of clinical interest were skin reactions (24%) and peripheral neuropathy (10%), all Grade 1/2. No TRAEs of hemorrhage occurred. There was one dose-limiting toxicity of fatigue in the 6.5 mg/m 2 cohort. The objective response rate in all pts was 14%. In the 6.5 mg/m 2 cohort, 3/10 pts who had EphA2+ mUC achieved a confirmed partial response (cPR); of 3 pts who were EphA2+ and MMAE-naïve, 2 achieved a cPR. The clinical benefit rate (complete response + PR + stable disease ≥4 months) for all pts was 24% and 100% for the 3 EphA2+ MMAE-naïve pts in the 6.5 mg/m 2 cohort. PK of BT5528 and MMAE are similar +/- nivo, indicating no apparent PK interaction.
Conclusions: BT5528 + nivo demonstrated a generally well-tolerated safety profile across doses, with no new safety signals, in contrast to prior attempts to target EphA2, with no PK drug-drug interactions. Preliminary anti-tumor activity was demonstrated in pts with mUC at a dose of BT5528 6.5 mg/m 2 once every 2 wks + nivo 480 mg once every 4 wks, especially in MMAE-naive pts with EphA2+ tumors.
利益披露 Disclosure
B. Bashir,
Merck/Eisai Other, Consulting or Advisory Role.
Boehringer Ingelheim ).
Ikena Oncology ).
Bicycle Therapeutics ).
Syros Pharmaceuticals ).
KAHR Medical ).
Tarveda Therapeutics ).
Amgen ).
RasCal ).
Merck ).
Artios ).
Daiichi Sankyo/Lilly ).
Pionyr ).
Lyell Immunopharma ).
Elucida Oncology ).
Gritstone Bio ).
Jazz Pharmaceuticals ).
J. Martin-Liberal,
Astellas Other, Personal fees.
Bristol-Myers Squibb Other, Personal fees.
MSD Other, Personal fees.
Novartis Other, Personal fees.
Pierre Fabre Other, Personal fees.
Pfizer Other, Personal fees.
Roche Other, Personal fees.
Sanofi Other, Personal fees.
Highlight Therapeutics Other, Personal fees.
J. S. Wang,
Kelun/Klus ).
MSD ).
R. Aljumaily, None..
B. Doger de Spéville, None..
E. Garralda, None.
M. McKean,
AbbVie Other, Consulting feeds.
Bristol-Myers Squibb ), Other, Consulting fees.
Castle Biosciences Other, Consulting fees.
Daiichi Sankyo ), Other, Consulting fees.
Ideaya Biosciences ), Other, Consulting fees.
IQVIA Other, Consulting Fees.
Merck Other, Consulting fees.
Moderna ), Other, Consulting fees.
Pfizer ), Other, Consulting fees.
Pierre Fabre Other, Consulting fees.
Regeneron ), Other, Consulting fees.
Revolution Medicine Other, Consulting fees.
Aadi Biosciences ).
Alpine Immune Sciences ).
Arcus Biosciences ).
Arvinas ).
Ascentage Pharma Group ).
ASCO ).
Astellas ).
Bicycle Therapeutics ).
E. Fontana,
HCA/Sarah Cannon Employment.
Repare Therapeutics ), Travel.
Bicycle Therapeutics ), Travel, Other, Consulting or Advisory Role.
Artios ).
Seagen ), Travel.
Amgen ).
Nurix ).
BioNTech SE ).
Relay Therapeutics ).
Taiho Pharmaceutical ).
Pfizer ).
Roche ).
Daiichi Sankyo ).
Gilead Sciences ).
Basilea ).
Jiangsu Hengrui Medicine ).
Mereo Biopharma ).
HUTCHMED ).
Merus ).
Crescendo Biologics ).
H. Prenen,
Amgen Other, Honoraria.
AstraZeneca Other, Honoraria; Consulting or Advisory Role.
Merck Other, Honoraria.
Biocartis Other, Consulting or Advisory Role.
D. A. Peterson,
Bicycle Therapeutics Employment, Stock, Stock Option.
V. Reichert,
Bicycle Therapeutics Employment, Stock, Stock Option.
X. Gu,
Bicycle Therapeutics Employment, Stock, Stock Option.
M. Li,
Bicycle Therapeutics Employment, Stock, Stock Option.
A. De Rienzo,
Bicycle Therapeutics Employment, Stock, Stock Option, Patent, Other Intellectual Property.
A. Greystoke,
AstraZeneca ), Other, Consultancy and speaker fees.
Amgen Other, Consultancy and speaker fees.
Boehringer Ingelheim Other, Consultancy and speaker fees.
Bristol-Myers Squibb Other, Consultancy and speaker fees.
Janssen/ J and J Other, Consultancy and speaker fees.
MSD Other, Consultancy and speaker fees.
Novartis Other, Consultancy and speaker fees.
Pfizer Other, Consultancy and speaker fees.
Lilly Other, Consultancy and speaker fees.
Takeda Other, Consultancy and speaker fees.
Roche Other, Consultancy and speaker fees.