Background: In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), patients (pts) with aUC without progression after 1L platinum-based chemotherapy had significantly prolonged overall survival and progression-free survival with avelumab 1L maintenance + best supportive care (BSC) vs BSC alone. The safety profile of avelumab 1L maintenance was consistent with prior avelumab monotherapy studies, with no new safety signals identified and no detrimental impact on quality of life. Results led to the adoption of avelumab 1L maintenance into international guidelines as standard of care. We report post hoc safety analyses after a minimum 2 years of follow-up. Methods: Eligible pts had unresectable locally advanced or metastatic UC without progression after 1L platinum-based chemotherapy. Here, pts who received treatment in the avelumab + BSC arm were analyzed. Trial treatment continued until confirmed progression, unacceptable toxicity, or withdrawal of consent. Results: At data cutoff (June 4, 2021), median follow-up in the avelumab arm was 38.0 months. In 344 pts who received ≥1 dose of avelumab, median treatment duration was 5.8 months (range, 0.5-49.7) and median number of infusions was 11.5 (range, 1.0-106.0). Treatment-related adverse events (TRAEs) of any grade occurred in 269 pts (78.2%). Grade ≥3 TRAEs occurred in 67 pts (19.5%); the most common (>2%) were lipase increased (n=12; 3.5%) and amylase increased (n=8; 2.3%). 40 pts (11.6%) had a TRAE that led to avelumab discontinuation. Immune-related AEs (irAEs) occurred at any grade in 111 pts (32.3%) and at grade ≥3 in 26 (7.6%). The most common categories of irAEs (any grade in >5%) were thyroid disorders (n=44; 12.8%) and immune-related rash (n=37; 10.8%); the most common categories of grade ≥3 irAEs (>1%) were immune-related rash and hepatitis (each n=5; 1.5%). Serious irAEs occurred in 18 pts (5.2%), of which immune-related nephritis/renal dysfunction (n=4; 1.2%) was the most common category. 21 pts (6.1%) had an irAE that led to avelumab discontinuation; the most common categories (>1%) were immune-related hepatitis and nephritis/renal dysfunction (each n=4; 1.2%). Among 118 pts treated with avelumab for ≥12 months, irAEs occurred after 12 months in 27 pts (22.9%), including grade ≥3 irAEs in 5 (4.2%). The most common category of irAEs occurring after 12 months (any grade in >5%) was immune-related rash (n=12; 10.2%). No category of grade ≥3 irAEs occurred after 12 months in >1 pt. Conclusions: Post hoc analyses from JAVELIN Bladder 100 confirm the acceptable long-term safety profile of avelumab 1L maintenance. Grade ≥3 TRAEs or irAEs occurred in relatively low proportions of pts, and no new safety signals were identified with longer treatment. These results further support the use of avelumab 1L maintenance until progression as standard of care for pts with aUC without progression after 1L platinum-based chemotherapy. Clinical trial information: NCT02603432.