Neoadjuvant sacituzumab govitecan (SG) plus pembrolizumab (Pembro), followed by response-adapted bladder sparing and adjuvant pembro, in patients with muscle-invasive bladder cancer (MIBC): SURE-02 primary analysis and biomarker results.

769 Background: Standard-of-care treatment 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 poor. 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 primary analysis and final biomarker analyses. 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 was 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 was cCR rate with 19 cCR required to meet the endpoint in a 2-stage design. Transcriptome-wide analyses (Decipher Bladder, Veracyte, Inc) and comprehensive genomic profiling (CGP, Foundation Medicine, Inc) assays were performed on baseline tumor samples. Results: From 10/23 to 02/25, 49 pts were treated and efficacy evaluable. 33 (67.3%) had a cT2 stage, 19 (38.8%) had a centrally confirmed variant histology. The cCR-rate was 38.8% (N = 19; 95%CI: 25.2-53.8); all these pts underwent a reTURBT; ypT≤1N0-x rate was 51% (N = 25). 12m Event-free survival (EFS: defined as any high-grade relapse, progression, further therapy to the bladder or death) was 71% (95%CI: 56.7-88.8); 12m-EFS in cCR was 90.9% vs 59.6% in non-cCR. All cCR pts were metastases-free after a median follow-up of 14 months; 2 pts developed an intravesical relapse. Grade ≥3 treatment-related adverse-events (TRAE) occurred in 8 pts (16.3%). No Grade 5 TRAE occurred. CGP revealed ERBB2 mutations/amplifications in 42.1% of cCR vs 13.7% non-cCR pts. Median TMB was 12.1 in cCR vs 7.9 in non-cCR pts. Variance by subtype showed that Luminal tumors had higher TROP2 and ERBB2 expression, as well as higher KEGG mismatch repair deficiency (MMR) signature. Molecular subtyping revealed higher cCR rates for Luminal subtypes (62% vs 31% in non-Luminal). Higher MMR KEGG signature was significantly associated with longer EFS (100% at 12 months). Conclusions: Perioperative SG+Pembro revealed a compelling cCR rate, with a manageable safety profile, allowing a bladder preservation with sustained remission in ~40% of pts. Pre-treatment biomarker analyses revealed an enrichment of putative biomarkers of response and outcome in Luminal subtypes. Clinical trial information: NCT05535218 .