Molecular subtypes, <i>NECTIN4/HER2</i> expression, and clinical outcomes in patients (pts) with advanced urothelial carcinoma (aUC) or muscle invasive bladder cancer (MIBC): Exploratory analyses from JAVELIN Bladder 100 and the Tempus database.
Authors: Markus Eckstein, Niklas Klümper, Petros Grivas, Enrique Grande, Johannes Brägelmann, Jason Hoffman, Johanna Mazur, Olga Bogatyrova, Viktor Grünwald
Journal: Journal of Clinical Oncology (2025)

828 Background: Consensus molecular subtypes of UC/BC include basal/squamous (Ba/Sq), stroma-rich (SR), luminal unstable (lumU), luminal papillary (lumP), luminal nonspecified (lumNS), and neuroendocrine (NE)-like. Nectin-4 and HER2 are targets for novel antibody-drug conjugates. We report exploratory analyses of molecular subtypes, including NECTIN4 and HER2 RNA expression, in pts with aUC or MIBC from the JAVELIN Bladder 100 phase 3 trial and Tempus real-world database. Methods: JAVELIN Bladder 100 (NCT02603432) enrolled pts with aUC without progression after first-line platinum-based chemotherapy. Pts with MIBC or aUC were identified in the Tempus database of deidentified pt data from US clinical practice. Whole-transcriptome profiles in tumor samples were generated using RNA sequencing. NECTIN4 and HER2 transcript levels were quantified using Personalis ACE technology (JAVELIN Bladder 100) or kallisto (Tempus). Results: In evaluable aUC tumors from the JAVELIN cohort (n=560), NECTIN4 and HER2 RNA expression was heterogenous across molecular subtypes and was highest in lumU/lumP/lumNS subtypes and lowest in the NE-like subtype (Table); 57% of tumors had high (≥ median) expression of both NECTIN4 and HER2 RNA. Variations in NECTIN4 / HER2 RNA expression across molecular subtypes were similar in MIBC/aUC tumors from the Tempus cohort (n=501); 39% of tumors had high NECTIN4/HER2 RNA expression. In both cohorts, a strong correlation between NECTIN4 and HER2 RNA expression was observed overall (R=0.6-0.655), although correlation was not observed within all subtypes. In pts treated with avelumab in JAVELIN Bladder 100 (n=283; excluding NE-like [n=1]), no significant difference in overall survival was noted by molecular subtype (median [95% CI], mo: Ba/Sq, 27.2 [18.2-not estimable (NE)]; LumNS, 34.4 [20.8-NE]; LumP, 20.8 [18.2-31.4]; LumU, 24.9 [18.6-43.1]; SR, 28.8 [19.3-NE]). Limitations include exploratory analyses and potential selection bias. Conclusions: In these analyses, including the first analysis of consensus molecular subtypes in a phase 3 trial in aUC, NECTIN4 and HER2 RNA expression was heterogeneous across molecular subtypes of aUC and MIBC tumors and was highest in luminal subtypes. No significant difference in overall survival was noted across subtypes in pts treated with avelumab first-line maintenance. Clinical trial information: NCT02603432 . Subtype JAVELIN (n=560) Tempus (n=501) n (%) Expression level* n (%) Expression level* NECTIN4 HER2 NECTIN4 HER2 Ba/Sq 95 (17.0) 0.812 0.779 177 (35.3) 0.828 0.769 LumNS 30 (5.4) 1.029 0.905 30 (6.0) 0.990 0.926 LumP 135 (24.1) 0.984 0.888 89 (17.8) 0.962 0.925 LumU 95 (17.0) – – 99 (19.8) – – NE-like 3 (0.5) 0.152 0.460 37 (7.4) 0.311 0.613 SR 202 (36.1) 0.833 0.862 69 (13.8) 0.884 0.879 *Fold difference in transcripts per million vs LumU.