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

827 Background: Nectin-4 is widely expressed in UC tumors, although protein expression levels vary between patients. Prior analyses have suggested that low overall Nectin-4 expression based on immunohistochemistry may be associated with worse outcomes in patients with advanced UC irrespective of treatment. 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 switch-maintenance treatment in subgroups defined by tumor NECTIN4 RNA expression. Methods: In JAVELIN Bladder 100 (NCT02603432), patients with unresectable la/mUC without progression after 4-6 cycles of 1L PBC were randomized to receive avelumab 1L maintenance + best supportive care (BSC) or BSC alone. Whole-transcriptome profiles in tumor samples (primary tumors in ≈75%) were generated using RNA sequencing, and transcript levels were quantified using Personalis ACE technology. NECTIN4 RNA expression was assessed as a continuous variable for subgroups defined by response to 1L PBC, and as a dichotomous variable (median split) for survival analyses. Results: In biomarker-assessable patients enrolled in JAVELIN Bladder 100, no significant differences were observed in tumor NECTIN4 RNA expression in patients who had complete response (n=149), partial response (n=261), or stable disease (n=150) to 1L PBC (Kruskal-Wallis p=0.192). In subgroups with high or low NECTIN4 RNA expression, overall survival (OS) and progression-free survival (PFS) improvements with avelumab + BSC vs BSC alone were consistent with improvements observed in the overall study population (Table). No significant differences in OS and PFS were observed between subgroups with high or low NECTIN4 RNA expression within the avelumab + BSC (p=0.26 and 0.89) and BSC alone (p=0.34 and 0.94) arms. Limitations include ad hoc exploratory analysis and potential selection bias. Conclusions: Exploratory analyses from JAVELIN Bladder 100 suggest that NECTIN4 RNA expression was not prognostic or predictive of level of response to 1L PBC or survival with avelumab 1L maintenance treatment in patients with la/mUC without progression after 1L PBC. Clinical trial information: NCT02603432 . Avelumab + BSC BSC alone High NECTIN4 RNA expression n=139 n=140 Median OS (95% CI), months 22.0 (18.2-30.9) 14.8 (12.9-19.4) Median PFS (95% CI), months 5.65 (4.60-9.00) 3.29 (1.97-3.75) Low NECTIN4 RNA expression n=145 n=136 Median OS (95% CI), months 30.0 (21.4-35.2) 18.7 (13.7-25.5) Median PFS (95% CI), months 5.65 (3.81-9.95) 2.20 (1.91-3.71)