Abstract

LBA4517 Background: SG is an antibody-drug conjugate composed of an anti-trophoblast cell surface antigen 2 (Trop-2) antibody coupled to SN-38 (a topoisomerase-I inhibitor) with US FDA-accelerated approval for locally advanced or metastatic urothelial carcinoma (mUC). A multi-cohort, open-label, phase 2 SURE study is evaluating neoadjuvant SG (SURE-01, NCT05226117) or neoadjuvant SG+pembrolizumab followed by adjuvant pembrolizumab (SURE-02, NCT05535218) in MIBC in a flexible design allowing a bladder-sparing approach. We report interim results from SURE-01. Methods: Pts with cT2-4N0M0 MIBC who were ineligible for or refused cisplatin-based neoadjuvant chemotherapy were planned to receive 4 cycles of neoadjuvant SG 10 mg/kg intravenously (IV) on days 1 and 8, Q3W, followed by radical cystectomy (RC). The trial included pre-post MRI imaging of the pelvis and ctDNA analysis. Pts with clinical complete response (cCR, defined with negative MRI, cystoscopy and ctDNA assays) refusing RC were offered redo transurethral resection of the bladder tumor (reTURBT) followed by observation in case no viable high-grade tumor in the bladder was found. The primary endpoint of the study is to assess the proportion of ypT0N0. The assumptions include a ypT0N0≤20% as H0 and ≥45% as H1 in a single-stage A’Hern’s design. Secondary end points include event-free survival (EFS), cCR rate and OS. Treatment-related adverse events (TRAEs) and safety are assessed using standard criteria (CTCAE v5). Tumor samples underwent comprehensive genomic profiling assay. Results: From 03/22 to 11/23, 21 pts were enrolled. After the initial 8 pts the study was amended with SG at 7.5 mg/Kg dose due to a Grade 5 TRAE. Median age was 71y, 7 pts (33.3%) had a cT3-4N0. Ten pts (47.6%) had a mixed variant histology. All pts received at least 1 cycle of SG: Grade ≥3 TRAE occurred in 9 pts (42.5%), including one Grade 5 event (at 10mg/Kg dose). Toxicity was unrelated to UGT1A1 polymorphism. Ten pts (47.6%) achieved a cCR. Sixteen pts are evaluable for final response at treatment completion: one pt had a disease progression and started palliative therapy, two did not undergo RC due to TRAE. Thirteen pts have undergone surgery (RC: N=10; reTURBT: N=3). ypT0N0-x response was achieved in 6/16 pts (37.5%), 7 (43.7%) an ypT≤1N0-x response. All pts with a residual disease revealed a ctDNA-negative test post-RC. Tumor samples from pts with cCR were enriched in ARID1A and BRCA1/2 mutations vs nonCR: 40 vs 9%, 30 vs 18%; nonCR were enriched in ERBB2 mutations vs cCR: 44 vs 10%. Conclusions: Observed ypT0N0-x responses after neoadjuvant SG showed promising activity in MIBC who have a high unmet need, with a potential to avoid RC. Reduced dose of SG was feasible and the data support the ongoing SURE studies in MIBC. Clinical trial information: NCT05226117 ; NCT05535218 .