Outcomes with first-line (1L) platinum-based chemotherapy (PBC) and avelumab 1L maintenance in locally advanced or metastatic urothelial carcinoma (la/mUC) by NECTIN4 and HER2 RNA expression: Exploratory analyses from JAVELIN Bladder 100.

4575 Background: Nectin-4 and HER2 are relevant therapeutic targets and potential biomarkers for the treatment of la/mUC. NECTIN4 and HER2 RNA expression are heterogeneous in UC tumors, with highest expression observed in luminal molecular subtypes. We report exploratory biomarker analyses from the JAVELIN Bladder 100 phase 3 trial evaluating response to 1L PBC and survival outcomes with avelumab administered as 1L maintenance treatment in subgroups defined by tumor NECTIN4 and HER2 RNA expression. Methods: In JAVELIN Bladder 100 (NCT02603432), patients (pts) with unresectable la/mUC without progression after 4-6 cycles of 1L PBC were randomized 1:1 to receive avelumab + best supportive care (BSC) or BSC alone. Biomarker analyses were performed using existing whole transcriptome profiles generated using RNA sequencing, and transcript levels were quantified using Personalis ACE technology. NECTIN4 and HER2 RNA expression were assessed as continuous variables for subgroups defined by response to 1L PBC and as dichotomous variables (median and lower quartile split) for stratified survival analyses. Results: In biomarker-assessable pts (n=560) who had complete response (CR; n=149), partial response (n=261), or stable disease (SD; n=150) to 1L PBC, no significant differences in tumor NECTIN4 RNA expression were observed, whereas slightly higher tumor HER2 RNA expression was observed in pts who had CR vs SD. Overall, when defined by median split, 201 pts (35.9%) had high NECTIN4 /high HER2 RNA expression, 202 (36.1%) had low NECTIN4 /low HER2 , 78 (13.9%) had high NECTIN4 /low HER2 , and 79 (14.1%) had low NECTIN4 /high HER2 . Molecular subtype was non-luminal in 20.4%, 87.1%, 55.1%, and 50.6%, respectively. The table shows overall survival (OS) with avelumab + BSC vs BSC alone in subgroups defined by combined high or low NECTIN4 / HER2 expression. OS improvements with avelumab + BSC vs BSC alone were observed across subgroups defined by high or low NECTIN4 / HER2 RNA expression alone. Conclusions: Exploratory analyses from JAVELIN Bladder 100 showed that pts with low NECTIN4 and low or high HER2 RNA expression had pronounced OS with avelumab 1L maintenance vs BSC alone. Results are hypothesis generating. Clinical trial information: NCT02603432 . Avelumab + BSC BSC High NECTIN4 /high HER2 n=100 n=101 Median OS (95% CI), mo 23.0 (17.8-30.9) 14.3 (10.8-21.3) HR (95% CI) 0.73 (0.52-1.02) Low NECTIN4 /low HER2 n=105 n=97 Median OS (95% CI), mo 29.8 (20.1-46.9) 18.8 (13.9-29.4) HR (95% CI) 0.78 (0.55-1.11) High NECTIN4 /low HER2 n=39 n=39 Median OS (95% CI), mo 18.4 (13.0-NE) 17.4 (14.0-NE) HR (95% CI) 0.84 (0.47-1.50) Low NECTIN4 /high HER2 n=40 n=39