Abstract CT063: 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

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/m2 once weekly, or 6.5 mg/m2 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/m2 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/m2 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/m2 cohort. The objective response rate in all pts was 14%. In the 6.5 mg/m2 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/m2 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/m2 once every 2 wks + nivo 480 mg once every 4 wks, especially in MMAE-naive pts with EphA2+ tumors. Citation Format: Babar Bashir, Juan Martin-Liberal, Judy S. Wang, Raid Aljumaily, Bernard Doger de Spéville, Elena Garralda, Meredith McKean, Elisa Fontana, Hans Prenen, Daniel A. Peterson, Vienna Reichert, Xuemin Gu, Mengyao Li, Assunta De Rienzo, Alastair Greystoke. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT063.