First results of SURE-02: A phase 2 study of neoadjuvant sacituzumab govitecan (SG) plus pembrolizumab (Pembro), followed by response-adapted bladder sparing and adjuvant pembro, in patients with muscle-invasive bladder cancer (MIBC).

4518 Background: Standard of care for MIBC is radical cystectomy (RC) with neoadjuvant chemotherapy (CT), but ~50% of patients (pts) are ineligible for/refuse CT and survival for RC alone is dismal. Neoadjuvant Pembro and SG monotherapies showed activity in MIBC within PURE-01 and SURE-01 studies. SURE-02 (NCT05535218) is a phase 2 study of neoadjuvant SG+Pembro and adjuvant Pembro, including a bladder-sparing approach depending on clinical response. We report results of a prespecified interim analysis. Methods: Pts age ≥18 y, ECOG PS 0-1, with histologically confirmed cT2-T4N0M0 MIBC, ineligible/refusing CT, and scheduled for RC received 4 cycles of Pembro 200 mg on D1 and SG 7.5 mg/Kg on D1 and D8, Q3W, followed by postsurgical Pembro x 13 cycles, Q3W. A reTURBT is allowed instead of RC, followed by Pembro x 13 cycles, for pts achieving a clinical complete response (cCR), stringently defined as a negative magnetic resonance imaging (MRI) and no residual viable tumor at reTURBT (ypT0). Primary outcome measure is cCR rate: H0≤30%, H1≥45%. Other outcomes: ypT≤1N0-x rate including pts undergoing RC, safety (CTCAE v.5.0), survival. The total sample size is 48 pts in a 2-stage design, with 23 pts enrolled at first stage (≥7 cCR needed). Decipher Bladder (Veracyte, San Diego, CA) was used for transcriptome-wide analyses of primary TURBT tissue. Results: From 10/23 to 01/25, 40 pts were treated and 31 were efficacy evaluable. 20 (64.5%) had a cT2 stage, 12 (38.7%) had a centrally confirmed variant histology. The cCR-rate was 38.7% (N = 12; 95%CI: 21.8-57.8); all these pts underwent a reTURBT; ypT≤1N0-x rate was 51.6% (N = 16). Grade ≥3 treatment-related adverse-events occurred in 4 pts (12.9%), 2 dose omissions of SG and one dose delay (1W) were recorded. No SG dose-reduction was needed. cCR varied by molecular subtype. Transcriptome results were available for 23 pts: complete pathologic (ypT0) responses varied by Genomic Subtyping Classifier (GSC) groups with luminal tumors showing higher ypT0 rates vs non-luminal (73 vs 25%, p = 0.04). Similarly, based on Lund subtypes, genomically unstable (GU) tumors had ypT0 response in 67%, vs 57% for urothelial-like, 20% for basal/squamous and 0% for neuroendocrine-like. Higher stromal signature (> median) was associated with non-ypT0 response (p = 0.004), while neither Trop2 (p = 0.15) nor TOP1 (p = 0.79) gene expression were associated with ypT0 response. Conclusions: Perioperative SG+Pembro revealed a compelling cCR rate, with a manageable safety profile, allowing a bladder preservation in ~40% of pts. Pre-treatment molecular biomarker analyses suggest a unique tumor profile associated with cCR. Overall, SURE-02 interim results support the completion of study accrual and further investigation of SG+Pembro in pts with MIBC. Clinical trial information: NCT05535218 .