PO.CT01.02 · 临床试验
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
摘要 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.