Molecular subtypes,
NECTIN4/HER2
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: Eckstein Markus , Klümper Niklas , Grivas Petros , Grande Enrique , Brägelmann Johannes , Hoffman Jason , Mazur Johanna , Bogatyrova Olga , Grünwald Viktor 
Published: February 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.