Association between non-luminal molecular subtypes and complete response rates after neoadjuvant chemo-immune therapy for muscle-invasive bladder cancer: Biomarker analyses of NURE-combo and BLASST-01 phase 2 clinical trials.

845 Background: The BLASST-01 (NCT03294304) and NURE-combo (NCT04876313) clinical trials evaluated the use of neoadjuvant chemo-immune therapy before radical cystectomy (RC) in cT2-T4aN≤1M0 muscle invasive bladder cancer (MIBC) patients. Here, we evaluated associations between transcriptome-based molecular subtypes and outcomes in BLASST-01 and NURE-combo. Methods: BLASST-1 was a phase 2 trial evaluating neoadjuvant nivolumab + gemcitabine-cisplatin followed by radical cystectomy surgery (RC). NURE was a phase 2 trial evaluating neoadjuvant nivolumab + nab-paclitaxel followed by RC and 12 months of adjuvant nivolumab. Available TURBT specimens were analyzed with the Decipher Bladder Genomic Subtyping Classifier (GSC), a clinical-grade transcriptome-wide assay (Veracyte, San Diego, CA). Pathological complete response (PCR, ypT0N0) at RC was the primary endpoint and overall survival (OS) was the secondary endpoint. Multivariable logistic regression analyses for PCR were adjusted for patient age and sex and log-rank tests were performed for overall survival comparison. Results: Transcriptome-wide data were available for 37/43 (86%) of BLASST1 and 24/31 (77%) of NURE-combo patients. Median ages were 64 and 65 years, and male sex rates were 59% and 75% in BLASST-1 and NURE-combo, respectively. BLASST-1 was primarily cT2N0 (89% vs 25%), while NURE had more variant histology (48% vs 0%). Non-luminal subtypes were found in 77% (47/61) at a similar frequency in both trials. PCR rate was 65% in BLASST-1 and 58% in NURE-combo. We found higher PCR rate for non-luminal subtypes (47%, versus 14% for luminal subtype, X 2 p=0.058). From non-luminal subtypes, we found highest PCR rate among claudin-low subtype (62%) and multivariable analysis revealed a significant association between claudin-low MIBC and PCR (p=0.04). Two-year overall survival was 84% in patients with non-luminal MIBC vs. 100% in patients with luminal MIBC (Log-Rank p=0.18). Conclusions: Non-luminal MIBC is associated with highest PCR rates after neoadjuvant chemo-immunotherapy for MIBC. These results support clinical decision-making using Decipher Bladder in the neoadjuvant setting for MIBC. Clinical trial information: NCT03294304 & NCT04876313 .