## 4 Discussion  
This study provides real-world data on treatment patterns and clinical outcomes in US patients with aUC and offers insight into the clinical benefit of treatments in a patient population not well represented in clinical trials. Among this group of 214 patients that received avelumab 1 LM after PBC, most (84%, n = 179) either received 2L therapy or remained on 1 LM through the end of the study period, with 19% (n = 40) receiving 3L therapy. EV was the most common 2L treatment (n = 53, 55%), as reported in similar real-world studies [21, 22] and in agreement with NCCN Guidelines as a preferred therapy following avelumab 1 LM [4]. Although PBC combination was the sole established 1L therapy for aUC for decades, treatment options are rapidly expanding, reflected in the most recent NCCN Guidelines [4]. New frontline options include the Category 1, 'preferred' treatment of pembrolizumab plus EV based on the results of the EV-302 trial (NCT04223856) [23] and the Category 1, 'other recommended' treatment of nivolumab, gemcitabine, and cisplatin followed by nivolumab maintenance based on the results of the CheckMate-901 trial substudy (NCT03036098) [24]. Considering these recent additions, this study highlights the role the JAVELIN paradigm of PBC followed by avelumab 1 LM continues to play. Despite the emergence of multiple treatment options over the past few years, it is important to remember that the vast majority of patients with aUC are still not cured. There remains an opportunity to further improve the survival outcomes in patients by ensuring that the frontline treatment strategy chosen considers subsequent LOTs and is supported by evidence-based recommendations. It is often suspected there is a discordance between clinical trials and real-world outcomes in part due to strict eligibility criteria that limit the external generalizability or validity of the study results. It is widely believed patients in clinical trials are usually healthier with superior performance status, and real-world data provide an opportunity to validate the outcomes seen in clinical trials. This was seen in our study; compared with patients receiving avelumab 1 LM in the JB100 trial [6], patients in this study were slightly older (68.0 vs. 70.0 years) and had poorer performance status--a higher proportion of patients in JB100 had a baseline ECOG PS of 0 (n = 213, 60.9%) vs. in this study (n = 69, 32.2%). Meanwhile, this study also included patients with an ECOG PS of \(\geq\)2 (n = 21, 9.8%), who would not have met the strict eligibility criteria of ECOG PS of 0 or 1 required by the JB100 trial to receive treatment. Additionally, the best response to 1L PBC differed between the studies. In the JB100 trial, 25.7% (n = 90) had a CR, 46.6% (n = 163) had a PR, and 27.7% (n = 97) had SD. In contrast, among the 202 patients in this study with a recorded response to 1L PBC, most had rwPR (n = 159, 78.7%), with fewer patients having rwCR (n = 14, 6.9%) or rwSD (n = 29, 14.4%). Differences in study design (clinical trial vs. real-world study), study populations (global vs. US only), and clinicians' determination and interpretation of  
Figure 5: rwOS and rwPFS from 2L EV initiation. Abbreviations: 2L, second line; EV, enfortumab vedotin; NE, not estimable; rwOS, real-world overall survival; rwPFS, real-world progression-free survival. response, which was verified by blinded centralized review in JB100, may have contributed to these differences in response between the two studies. It is satisfying to see that despite the differences in these study populations, outcomes from welumab 1 LM initiation in this study align with those observed in JB100 [6]. Although this study had a shorter median treatment duration vs. JB100, possibly due to shorter follow-up (8.7 vs. 38.0 months) and differences in the characteristics of study populations, OS and PFS were comparable [6].