BACKGROUND:In the ongoing EV-302 trial, first-line enfortumab vedotin plus pembrolizumab improved progression-free survival and overall survival versus platinum-based chemotherapy in patients with locally advanced or metastatic urothelial cancer. Patient-reported outcomes (PROs) from EV-302 are reported here. METHODS:EV-302 was a phase 3, open-label, two-group, randomised global study to evaluate the combination of enfortumab vedotin plus pembrolizumab versus standard-of-care platinum-based chemotherapy (gemcitabine with cisplatin or carboplatin) in patients with previously untreated locally advanced or metastatic urothelial cancer. The study was done at 185 clinical sites in 25 countries. Eligible patients were aged 18 years and older with unresectable untreated locally advanced or metastatic urothelial cancer, were eligible for platinum-based chemotherapy, and had an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were randomly assigned (1:1) to receive either enfortumab vedotin (1·25 mg/kg, intravenously) on days 1 and 8 of 3-week cycles plus pembrolizumab (200 mg, intravenously) on day 1 of each cycle; or platinum-based chemotherapy consisting of gemcitabine (1000 mg/m2, intravenously) on days 1 and 8 of each cycle plus either cisplatin (70 mg/m2) or carboplatin (area under the curve [AUC] 4·5 or 5·0 according to local guidelines) on day 1 of each 3-week cycle for up to six cycles using interactive response technology. Randomisation was stratified by cisplatin eligibility, PD-L1 expression status, and presence or absence of liver metastases. The dual primary endpoints of progression-free survival and overall survival in patients with locally advanced or metastatic urothelial cancer have been reported previously. Here, we report additional, protocol-prespecified secondary endpoint data, and statistical analysis plan-prespecified descriptive endpoints assessing patient quality of life (QOL). These endpoints related to patient functioning and symptoms and were assessed using two PRO questionnaires: the Brief Pain Inventory-Short Form (BPI-SF) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). The PRO full analysis set comprised patients who received study treatment and completed at least one baseline PRO questionnaire. The BPI-SF and the EORTC QLQ-C30 were completed at baseline, weekly for 12 weeks, at week 14, then every 3 weeks during follow-up. Time to pain progression and mean change from baseline in BPI-SF worst pain at week 26 were protocol-prespecified secondary endpoints tested by the hierarchical gatekeeping strategy. Mean change from baseline to week 26 in EORTC QLQ-C30 and BPI-SF scale scores were analysed descriptively. The trial is registered with ClinicalTrials.gov, NCT04223856. FINDINGS:At data cutoff on Aug 8, 2023, 886 patients were enrolled in the study, with a median duration of follow-up for survival of 17·2 months (IQR 12·5-21·7). 731 (83%) of 886 patients completed at least one PRO questionnaire at baseline and were included in the PRO full analysis set, with 376 patients treated with enfortumab vedotin plus pembrolizumab and 355 with platinum-based chemotherapy. 570 (78%) of 731 patients were male, 161 (22%) were female, and 479 (66%) patients were White. There was no significant difference in time to pain progression between treatments; hence differences in least squares mean change in BPI-SF worst pain score from baseline to week 26 with enfortumab vedotin plus pembrolizumab versus platinum-based chemotherapy were not formally tested. However, a numerical improvement from baseline up to week 26 was observed (least squares mean -0·74, SE 0·12 vs -0·36, 0·12; least squares mean difference -0·38, SE 0·13; 95% CI -0·64 to -0·12; nominal two-sided p value 0·0037). Overall least squares mean change in EORTC QLQ-C30 Global Health Status (GHS)/QOL from baseline up to week 26 favoured enfortumab vedotin plus pembrolizumab (least squares mean difference 2·54, 95% CI 0·41-4·67). In patients with moderate to severe baseline pain (worst pain score ≥5) receiving enfortumab vedotin plus pembrolizumab, there were clinically meaningful improvements from baseline up to week 26 in worst pain (least squares mean change: enfortumab vedotin plus pembrolizumab -2·96 [SE 0·22], platinum-based chemotherapy -2·43 [0·21]; least squares mean difference -0·53, 95% CI -1·03 to -0·02; nominal p=0·041) and in EORTC QLQ-C30 GHS/QOL (least squares mean change: enfortumab vedotin plus pembrolizumab 8·88 [1·53], platinum-based chemotherapy 4·11 [1·45]; least squares mean difference 4·77, 95% CI 1·24-8·29; nominal p=0·0083). INTERPRETATION:Enfortumab vedotin plus pembrolizumab significantly improved survival outcomes versus platinum-based chemotherapy without detriment to GHS/QOL, pain, or functioning. Patients with moderate to severe baseline pain had clinically meaningful improvements in worst pain and GHS/QOL with enfortumab vedotin plus pembrolizumab. These data provide further evidence to support the use of enfortumab vedotin plus pembrolizumab as a preferred treatment option for patients with previously untreated locally advanced or metastatic urothelial cancer. FUNDING:Seagen (acquired by Pfizer in December, 2023), Astellas Pharma, and Merck Sharp & Dohme.

Background Given the changing treatment landscape for locally advanced or metastatic urothelial carcinoma (la/mUC), this study aimed to describe real-world treatments, overall survival (OS), health care resource utilization (HCRU), and costs among US patients with la/mUC receiving first-line therapy. Methods This retrospective study was conducted using 100% Medicare claims data (2015-2020). Patients with la/mUC were selected; initiation of first-line therapy was the index date. Treatments and OS were assessed during follow-up (index date to the earliest of end of data availability, health plan coverage, or death). All-cause HCRU and costs (2021 USD) were assessed during the first-line treatment period (index date to the earliest of first-line discontinuation, switch to second-line therapy, end of follow-up, or death). Outpatient pharmacy costs were not included. All-cause OS from start of first-line therapy was estimated using the Kaplan-Meier approach. The HCRU, cost, and OS analyses were stratified by 3 index treatment groups-platinum-based chemotherapy, non-platinum-based chemotherapy, and programmed cell death protein 1/ligand 1 (PD-1/L1) inhibitor monotherapy-and adjusted for baseline characteristics. Results Of 9,939 patients included, 77.1% were men and mean age was 76 years. In total, 5,050 (50.8%) received platinum-based chemotherapy, 1,361 (13.7%) received non-platinum-based chemotherapy, and 3,242 (32.6%) received PD-1/L1 inhibitor monotherapy for first-line la/mUC. Median OS was 12.9, 12.9 (P = 0.960), and 9.0 months (P < 0.001) with platinum-based chemotherapy (reference), non-platinum-based chemotherapy, and PD-1/L1 inhibitor monotherapy, respectively. Most (> 99%) patients had >= 1 outpatient visit during the treatment period; mean number of visits per patient was 13.1 with platinum-based chemotherapy, 10.5 with non-platinum-based chemotherapy, and 18.3 with PD-1/L1 inhibitor monotherapy. In general, HCRU was significantly lower for patients receiving PD-1/L1 inhibitor monotherapy versus platinum-based chemotherapy. However, costs were significantly higher with PD-1/L1 inhibitor monotherapy versus platinum-based chemotherapy. Mean total monthly cost per patient was $10,285 for platinum-based chemotherapy, $8,982 for non-platinum-based chemotherapy, and $18,147 for PD-1/L1 inhibitor monotherapy. Conclusions From 2015 to 2020, patients with la/mUC had substantial HCRU and costs and short survival, regardless of first-line treatment. More effective therapies were needed to prolong survival and reduce the economic burden of la/mUC. (c) 2024 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

PURPOSE:Locally advanced/metastatic urothelial cancer (la/mUC) affects patients' quality of life (QOL) and functioning. We describe the impact of first-line (1L) enfortumab vedotin (EV) alone or with pembrolizumab (P) on QOL/functioning/symptoms in patients with la/mUC who were cisplatin-ineligible from EV-103 Cohort K. METHODS:In this phase Ib/II trial, patients were randomly assigned 1:1 to EV + P or EV monotherapy (mono). Exploratory patient-reported outcomes (PROs) were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire (EORTC QLQ-C30) and Brief Pain Inventory Short Form (BPI-SF) at baseline, once per week for cycles 1-3, and then in every cycle through the end of treatment. Changes in scores from baseline to week 24, reported as least squares mean (standard error), were assessed by mixed models for repeated measures. There were no formal statistical comparisons between treatment arms. RESULTS:Of 149 patients treated, 65 (EV + P) and 63 (EV mono) comprised the PRO analysis set. For EV + P, EORTC QLQ-C30 QOL was maintained through week 24 with improvements in emotional functioning, pain, and insomnia. Clinically meaningful improvements were seen in EORTC QLQ-C30 pain after EV + P at weeks 12 (-14.41 [3.14]) and 24 (-14.99 [3.56]) and BPI-SF worst pain at week 24 (-2.07 [0.37]). For EV mono, EORTC QLQ-C30 QOL remained stable with clinically meaningful improvements in EORTC QLQ-C30 pain (-12.55 [4.27]), insomnia (-14.46 [4.69]), and constipation (-10.09 [4.35]) at week 24. There were small-to-moderate improvements in BPI-SF worst pain at week 24. CONCLUSION:EV + P in patients with la/mUC who were cisplatin-ineligible was associated with preservation or improvement of QOL/functioning/symptoms. Improvement in pain was seen in both PRO instruments and treatment arms. These data complement clinical outcomes of 1L EV + P.

Introduction First-line (1L) platinum-based chemotherapy (PBT) is recommended for patients with locally advanced or metastatic urothelial carcinoma (la/mUC). Among patients without disease progression following 1L PBT, avelumab maintenance (maintA) is recommended based on a survival benefit versus best supportive care in the JAVELIN Bladder 100 trial. However, there are limited data on the proportion of patients who are eligible for maintA in clinical practice. This study assessed the proportion of patients with la/mUC who are eligible for and who received maintA in US clinical practice. Methods This retrospective, observational study used the US nationwide Flatiron Health longitudinal electronic health record-derived database comprising de-identified patient-level structured and unstructured data. Adults diagnosed with la/mUC who received ≥1 dose of 1L PBT between April 2020 to January 2022 were included. MaintA eligibility and utilization and patient disposition were assessed. MaintA eligibility was defined as complete response, partial response, or stable disease following 1L PBT. Results In total, 336 patients with la/mUC were included in the analysis. Mean age (SD) was 70.1 (9.3) years and 72.6% were male. 186 (55.4%) received a cisplatin-based regimen and the remainder a carboplatin-based regimen; 181 patients (53.9%) were eligible for maintA. Of 138 evaluable maintA-ineligible patients, the primary reason for maintA ineligibility was disease progression (71.7% of patients, 99/138), followed by death during/post 1L PBT (28.3%, 39/138). Of maintA-eligible patients, 37.0% (67/181) received maintA, representing 19.9% (67/336) of the 1L PBT-treated population. Among patients who initiated maintA, mean (SD) time to initiation from end of 1L PBT was 1.0 (0.74) month and duration of maintenance was 5.5 (3.9) months. Conclusions Of patients initiating 1L PBT, almost half were not eligible for maintA, primarily due to disease progression (71.7%) or death (28.3%) and >80% of the overall 1L PBT-treated population did not receive maintA. These data highlight the need for novel 1L treatments for patients with la/mUC.

Patients with locally advanced/metastatic urothelial carcinoma (la/mUC) were historically treated at first-line (1L) with platinum-based chemotherapy (PBC) followed by maintenance avelumab for eligible patients. In real- world practice about half of patients with la/mUC were eligible for maintenance avelumab, one-fifth received it, and overall survival remained short for the overall 1L PBC-treated la/mUC population, despite availability of maintenance avelumab. Introduction: 1L PBC has historically been recommended for patients with la/mUC. Maintenance avelumab is recommended for patients without disease progression following 1L PBC. Real-world data on the proportion of patients eligible for maintenance avelumab are limited, and outcomes among patients ineligible for maintenance avelumab are uncertain. This study assessed the proportion of patients with la/mUC initiating 1L PBC who were maintenanceavelumab eligible and real-world outcomes following 1L PBC by maintenance-avelumab eligibility. Methods: A retrospective, observational study was conducted using a longitudinal electronic health record-derived database comprising de-identified patient-level structured and unstructured data including adults with Ia/mUC who received >= 1 dose of 1L PBC (April 2020-January 2022). The proportion of patients eligible for maintenance avelumab (real-world stable disease, partial response, or complete response following 1L PBC) was estimated and median overall survival (mOS) assessed for maintenance avelumab-eligible and -ineligible patients. Results: Of 336 patients with Ia/mUC treated with 1L PBC (55.4% received cisplatin-based treatment 44.6% carboplatin-based treatment); 181 (54%) were maintenanceavelumab eligible; and 138 (41%) maintenance-avelumab ineligible (17 [5%] were nonevaluable). Of 181 maintenanceavelumab-eligible patients, 67 (37.0%; 19.9% of all 1L PBC-treated patients) received maintenance avelumab. mOS (95% CI) among all 1L PBC-treated patients was 15.0 (12.2-19.6) months and among maintenance-avelumab-ineligible patients was 8.0 (6.7-10.3) months; whereas among maintenance-avelumab-eligible patients (including 37% who received maintenance avelumab), mOS was 27.6 (23.4-not reached) months. Conclusions: In this study, approximately half of 1L PBC-treated patients were maintenance-avelumab eligible, and one-fifth received it. Real-world OS remains short for the overall 1L PBC-treated population. These results support the use of treatment-guideline preferred 1L treatment options that demonstrate survival benefit for all patients with la/mUC, and are available to patients irrespective of their eligibility for cisplatin, or response to PBC.

e23287 Background: Historically, cisplatin-containing chemotherapy has been the recommended first-line (1L) treatment for locally advanced or metastatic urothelial carcinoma (la/mUC). For those ineligible for cisplatin due to poor performance status, impaired renal function, or comorbidities, alternative choices include carboplatin-based chemotherapy and PD-1/L1 inhibitors. This study aimed to describe real-world treatment patterns and overall survival (OS) among US Medicare patients with la/mUC receiving 1L therapy. Methods: This retrospective study used Medicare fee-for-service claims data from 2015 through 2022 to identify patients diagnosed with la/mUC who received systemic treatment. Initiation of 1L therapy was the index date for study inclusion; treatment patterns and OS were assessed until end of data availability, discontinuation of health plan enrollment, or death. OS was estimated using the Kaplan–Meier approach, and a log-rank test was used to compare OS across the following 1L treatment groups: platinum-based chemotherapy (PBC; cisplatin- and carboplatin-based), non-PBC monotherapy, and PD-1/L1 inhibitor monotherapy. Hazard ratios (HRs) were estimated across groups using Cox proportional hazards models adjusting for baseline characteristics. Results: Of 13,104 patients included in this analysis, 77.5% were male, and mean (SD) age was 76.2 (7.5) years. The most commonly observed 1L treatment categories were PBC (cisplatin-based, 19.7%; carboplatin-based, 28.4%), PD-1/L1 inhibitors (34.8%), non-PBC (13.7%), and other combination therapies (2.9%). Common comorbidities included renal disease (39.9%), chronic obstructive pulmonary disease (36.1%), and diabetes (32.2%). Compared with patients in the cisplatin cohort, patients in other cohorts had higher NCI Comorbidity Index scores. Median duration of 1L treatment was 3.5 months for PD-1/L1 inhibitors, 3.2 months for carboplatin, 3.0 months for cisplatin, and 2.0 months for non-PBC. Median OS was longest with cisplatin (17.0 months; IQR: 7.8–51.9), followed by non-PBC (14.7; 5.5–39.7), carboplatin (10.5; 4.9–25.1), and PD-1/L1 inhibitors (9.4; 2.8–27.9). In the adjusted Cox model, all treatment groups had statistically significantly higher hazards of death compared with cisplatin, with an HR (95% CI) of 1.50 (1.41, 1.59; P< 0.001) for PD-1/L1 inhibitors, 1.38 (1.30, 1.46; P< 0.001) for carboplatin, and 1.11 (1.03, 1.19; P= 0.007) for non-PBC. Conclusions: In this large retrospective study of US Medicare patients from 2015–2022 with la/mUC, PBC was the most common 1L treatment, followed by PD-1/L1 inhibitors and non-PBC. While cisplatin-treated patients had longer OS than patients in other groups, treatment durations were short, and OS was generally poor across regimens. These findings highlight an unmet need for more effective 1L therapies in la/mUC.

e16547 Background: Platinum-based chemotherapy (PBC) has been the standard of care for first-line (1L) locally advanced/metastatic urothelial carcinoma (la/mUC). This systematic literature review (SLR) and network meta-analysis (NMA) analyzed the latest 1L clinical trial data to assess the comparative efficacy of the novel regimen enfortumab vedotin in combination with pembrolizumab (EV+P) against PBC and other approved and investigational 1L regimens for patients with la/mUC. Methods: English language publications (1/2000-10/2023) and congress presentations (1/2015-10/2023) of Phase 2 and 3 clinical trials assessing efficacy and safety of 1L therapies in la/mUC were identified in the SLR. Studies were categorized as: mixed eligibility (cisplatin [cis]-eligible and -ineligible), cis-eligible, and cis-ineligible. An NMA assessed comparative efficacy of EV+P to guideline-recommended therapies and emerging therapies with demonstrated survival benefit. 1L switch maintenance therapies were not included due to differences in study design. Comparative efficacy for overall survival (OS) was assessed under a Bayesian framework assuming constant hazard ratio (HR). Results: The SLR identified 69 unique studies, 2 of which demonstrated survival benefit over PBC (EV-302 and CheckMate-901 substudy). Across all mixed eligibility studies, median OS for PBC ranged from 12.1-16.1 months. Five studies were included in the NMA (3 mixed eligibility, 4 cis-eligible, 3 cis-ineligible). NMA results for the mixed eligibility network showed that EV+P improved OS over all comparator regimens (HR 0.47-0.51; Table). In the cis-eligible network, EV+P subgroup analysis showed improved OS over nivolumab+PBC (HR 0.68 [95% CI 0.47, 0.98]) and PBC (HR 0.53 [95% CI 0.39, 0.72]) and numerically improved OS over ddMVAC (HR 0.76 [95% CI 0.48, 1.20]). In the cis-ineligible network, EV+P subgroup analysis showed improved OS over all comparator regimens (HR range 0.43-0.52). Limitations include few studies contributing to the networks and heterogeneity in patient populations. Conclusions: EV+P is the only regimen shown to improve survival compared with PBC regardless of cisplatin eligibility. This indirect comparison suggests that EV+P has a favorable survival benefit compared with other approved and investigational 1L regimens in patients with previously untreated la/mUC. [Table: see text]

PURPOSE:Categorizing patients with cancer by their disease stage can be an important tool when conducting administrative claims-based studies. As claims databases frequently do not capture this information, algorithms are increasingly used to define disease stage. To our knowledge, to date, no study has used an algorithm to categorize patients with bladder cancer (BC) by disease stage (non-muscle-invasive BC [NMIBC], muscle-invasive BC [MIBC], or locally advanced/metastatic urothelial carcinoma [la/mUC]) in a US-based health care claims database. METHODS:A claims-based algorithm was developed to categorize patients by disease stage on the basis of the administrative claims portion of the SEER-Medicare linked data. The algorithm was validated against a reference SEER registry, and the algorithm's parameters were iteratively modified to improve its performance. Patients were included if they had an initial diagnosis of BC between January 2016 and December 2017 recorded in SEER registry data. Medicare claims data were available for these patients until December 31, 2019. The algorithm was evaluated by assessing percentage agreement, Cohen's kappa (κ), specificity, positive predictive value (PPV), and negative predictive value (NPV) against the SEER categorization. RESULTS:A total of 15,484 patients with SEER-confirmed BC were included: 10,991 (71.0%) with NMIBC, 3,645 (23.5%) with MIBC, and 848 (5.5%) with la/mUC. After multiple rounds of algorithm optimization, the final algorithm had an agreement of 82.5% with SEER, with a κ of 0.58, a PPV of 87.0% for NMIBC, and 76.8% for MIBC and a high NPV for la/mUC of 98.0%. CONCLUSION:This claims-based algorithm could be a useful approach for researchers conducting claims-based studies categorizing patients with BC at diagnosis.

108 Background: EV+P nearly doubled median progression-free survival and overall survival vs PBC in patients (pts) with previously untreated la/mUC in the phase 3 EV-302 trial. PROs are reported here. Methods: In EV-302 (NCT04223856) pts were randomized 1:1 to EV+P or PBC (gemcitabine with cisplatin or carboplatin). PRO assessments included the EORTC Quality of Life Questionnaire (EORTC QLQ-C30), and the Brief Pain Inventory Short Form (BPI-SF) completed at baseline, weekly for 12 weeks (wks), then every 3 wks through survival follow-up, inclusive of the time post-progression. Time to pain progression (TTPP) and mean change from baseline in worst pain at wk 26 using the BPI-SF were prespecified analyses statistically tested using a gatekeeping strategy. Mean change from baseline through wk 26 and time to confirmed deterioration (TTCD) of EORTC-QLQ-C30 and BPI-SF domains were prespecified descriptive analyses. TTPP and TTCD were assessed using Kaplan-Meier methods. Results: Of 886 pts randomized, 731 (376 received EV+P; 355 PBC) completed baseline PRO questionnaires. Compliance rates differed between arms and remained >70% through wk 29 for EV+P and through only wk 17 for PBC. Median TTPP was 14.2 months (mos) with EV+P and 10.0 mos with PBC (hazard ratio [HR]=0.92; 95% CI=0.72, 1.17; 2-sided p-value=0.48). The least squares (LS) mean reduction in worst pain at wk 26 was numerically greater with EV+P vs PBC (-0.61 vs -0.03, LS mean difference [95% CI]: -0.58 [-1.05, -0.11] [nominal 2-sided P = 0.015]). Pts with moderate to severe pain at baseline who were treated with EV+P (n=128, 34%) had a meaningful (>2 pt) improvement from baseline in BPI worst pain from wk 3 through 26. In EORTC QLQ-C30 Global Health Status/Quality of Life [GHS/QoL], EV+P demonstrated a transient worsening at week 3 (-6.3) that returned to baseline from weeks 4 through 26, while patients treated with PBC demonstrated deterioration from week 1 through week 17 (range -1.2 to -7.1) where scores returned to baseline. TTCD for EORTC QLQ-C30 GHS/QoL was 5.9 mos with EV+P vs 3.2 mos with PBC (HR = 0.98 [95% CI]: 0.79 – 1.2). Conclusions: Pts treated with EV+P have improved survival compared with PBC without detriment to quality of life and functioning, further supporting the value of EV+P for pts with la/mUC. Compliance, especially after progression, was lower than expected (particularly in the PBC arm) and may have impacted the results. Clinical trial information: NCT04223856 .

BACKGROUND:HER2 amplification (HER2+) occurs in approximately 3% of patients with metastatic colorectal cancer (mCRC). Despite the recent addition of HER2-directed therapies to treatment recommendations in the NCCN Guidelines, until more recently there were no FDA-approved treatments. This study examined real-world treatment patterns in patients with HER2+ mCRC in the United States before and after the emerging awareness of HER2-directed therapies in 2018.METHODS:This was a retrospective observational study of patients with HER2+ mCRC from the GuardantINFORM database, which contains claims data for patients with Guardant360 genomic testing results. Patients were aged ≥18 years, were diagnosed with mCRC between January 2014 and September 2020, and had confirmed ERBB2 amplification via the blood-based Guardant360 test. Treatment patterns and real-world time to next treatment (rwTTNT) were evaluated.RESULTS:This study included 142 patients with a median age of 59 years; 31 (21.8%) patients with ERBB2 amplifications also had ERBB2 mutations. Treatment patterns were heterogeneous and evolved over time; before 2018, the most common regimen prescribed after detection of ERBB2 amplification was anti-VEGF therapy with or without chemotherapy (31.6%; n=25), and after 2018, HER2-directed therapies were the most commonly prescribed (36.5%; n=23). Median rwTTNT among the overall cohort was 8.4 months (95% CI, 6.5-10.0); rwTTNT was numerically longer in patients who received HER2-directed therapy compared with those who received non-HER2-directed therapies (11.0 months [95% CI, 6.3-12.3] vs 7.2 months [95% CI, 5.8-9.6]).CONCLUSIONS:This real-world study of the largest clinically annotated dataset of patients with HER2+ mCRC showed that many patients do not receive HER2-directed therapy despite its inclusion in NCCN Guidelines, with heterogeneous treatment patterns suggesting that standard of care remains undefined and targeted therapy remains underutilized. Greater awareness of the unmet need in this patient population, together with new effective therapies, will facilitate strategies for improved, targeted treatment approaches.

To compare efficacy outcomes for all approved and investigational first-line (1L) treatment regimens for locally advanced or metastatic urothelial carcinoma (la/mUC) with standard of care (SOC), a network meta-analysis (NMA) was conducted. A systematic literature review (SLR) identified phase 2 and 3 randomized trials investigating 1L treatment regimens in la/mUC published January 2001-September 2021. Three networks were formed based on cisplatin (cis) eligibility: cis-eligible/mixed (cis-eligible patients and mixed populations of cis-eligible/ineligible patients), cis-ineligible (strict; exclusively cis-ineligible patients), and cis-ineligible (wide; including studies with investigator's choice of carbo). Analyses examined comparative efficacy by hazard ratio (HR) for overall survival (OS), and progression-free survival (PFS), and odds ratio (OR) for overall response rate (ORR), with 1L regimens vs. SOC. SOC was gemcitabine + cis (GemCis) or carboplatin (GemCarbo), cis-eligible/mixed network, and GemCarbo cis-ineligible networks. Of 1906 SLR identified citations, 55 trials were selected for data extraction. The NMA comprised 11, 6, and 8 studies in the cis-eligible/mixed, cis-ineligible (strict), cis-ineligible (wide) networks, respectively. In a meta-analysis of SOC control arms, median (95% CI) overall survival (OS) in months varied by network: 13.19 (12.43, 13.95) cis-eligible/mixed, 11.96 (10.43, 13.48) cis-ineligible (wide), and 9.74 (6.71, 12.76) cis-ineligible (strict). Most differences in OS, PFS, and ORR with treatment regimens across treatment networks were not statistically significant compared with SOC. Outcomes with current 1L regimens remain poor, and few significant improvements over SOC have been made, despite inclusion of recent clinical trial data, highlighting an unmet need in the la/mUC patient population.

OBJECTIVES:New and emerging therapies have significantly changed the bladder cancer (BC) treatment landscape and can potentially affect spending and patient care in CMS' Oncology Care Model (OCM), a service delivery and payment model for voluntarily participating practices. The objectives of this analysis were to estimate health care resource utilization (HCRU) and benchmark spending per OCM episode of BC, and to model spending drivers and quality metrics.STUDY DESIGN:Retrospective cohort study.METHODS:A retrospective cohort study was conducted of OCM episodes triggered by receipt of anticancer therapy among Medicare beneficiaries from 2016 to 2018. Based on this, an average performance estimation was conducted to assess the impact of hypothetical changes in novel therapy use by OCM practices.RESULTS:BC accounted for approximately 3% (n = 60,099) of identified OCM episodes. Relative to low-risk episodes, high-risk episodes were associated with greater HCRU and worse OCM quality metrics. Mean spending per high-risk episode was $37,857 (low-risk episode: $9204), with $11,051 spent on systemic therapies and $7158 on inpatient services. In the estimation, high- and low-risk BC exceeded the spending target by 1.7% and 9.4%, respectively. This did not affect payments to practices and no retrospective payments were necessary.CONCLUSIONS:As 3% of OCM episodes were attributed to BC, with only one-third classified as high-risk, controlling expenditure on novel therapies for advanced BC is unlikely to affect overall practice performance. The average performance estimation further emphasized the minimal impact that novel therapy spending in high-risk BC has on OCM payments to practices.

INTRODUCTION:Patients with locally advanced/metastatic urothelial carcinoma (la/mUC) have a poor prognosis. With recent therapeutic advances, data on real-world treatment patterns and overall survival (OS) in patients with la/mUC treated with first-line therapy are limited, particularly when comparing patients who are cisplatin-ineligible versus cisplatin-eligible. METHODS:This was a retrospective observational study of real-world first-line treatment patterns and OS in patients with la/mUC stratified by cisplatin-eligibility and treatment. Data were from a nationwide electronic health record-derived de-identified database. Eligible patients were adults diagnosed with la/mUC from May 2016 to April 2021 and followed until death or end of data availability in January 2022. OS stratified by first-line treatment and cisplatin eligibility was estimated using Kaplan-Meier methods and compared via multivariable Cox proportional-hazard models adjusted for clinical covariates. RESULTS:Of 4,757 patients with la/mUC, 3,632 (76.4%) received first-line treatment, with 2,029 (55.9%) cisplatin-ineligible and 1,603 (44.1%) cisplatin-eligible. Patients who were cisplatin-ineligible were older (mean age, 74.9 vs. 68.8 years) and had lower CrCl (median, 46.4 vs. 87.0 ml/min). Only 43.8% of patients receiving first-line treatment (37.6% cisplatin-ineligible vs. 51.6% cisplatin-eligible) received second-line therapy. Median OS in all patients receiving first-line treatment was 10.8 (95% CI, 10.2-11.3) months and was shorter in patients who were cisplatin-ineligible than cisplatin-eligible (8.5 [95% CI, 7.8-9.0] vs. 14.4 [13.3-16.1]; hazard ratio [HR], 0.9 [0.7-1.1]). Cisplatin-based therapy was associated with longer OS (17.6 [15.1-20.4] months) than other first-line treatments (the shortest OS was with PD-1/L1 inhibitor monotherapy; 7.7 [6.8-8.8] months), including among patients who were classified as cisplatin-ineligible. CONCLUSIONS:Outcomes for patients with newly diagnosed la/mUC are poor, particularly for patients who are cisplatin-ineligible and/or do not receive cisplatin-based therapy. Many patients with la/mUC did not receive first-line treatment and among those who did, fewer than half received second-line therapy. These data highlight the need for more effective first-line therapies for all patients with la/mUC.

439 Background: The EV-103 Cohort K trial evaluated 1L EV+P or EV alone (NCT03288545) in pts with la/mUC who were cisplatin-ineligible. EV+P showed a clinically meaningful objective response rate (64.5%; 95% CI, 52.7–75.1) with a manageable safety profile. Because la/mUC is associated with symptoms with a frequent impact on quality of life (QOL) and functioning (Mamtani et al. JCO 2021), we describe the impact of EV+P or EV alone on QOL and symptoms. Methods: In this open-label, Phase 1b/2 trial, cisplatin-ineligible pts with la/mUC were randomized 1:1 to EV+P or EV alone. For exploratory PRO endpoints, pts completed EORTC QLQ-C30 and the BPI-SF at baseline, weekly for cycles 1–3, and once every cycle for the remainder of treatment period. The PRO analysis set included only pts who were treated and completed the questionnaire at baseline. Mixed effect models for repeated measures (MMRM; least squares [LS] mean, standard error [SE]) not adjusted for multiplicity, estimated change vs baseline until Week 24; established thresholds (EORTC QLQ-C30: 10-point change; BPI-SF: 2-point change) were applied to determine clinically meaningful change. Results: Of the 76 pts treated with EV+P, 65 were included in the PRO analysis set. EORTC QLQ-C30 and BPI-SF were completed by 100% and 95%, respectively, at baseline; compliance rates were ≥84% for both instruments through Week 24. In the EORTC QLQ-C30 MMRM analyses, QOL was maintained through Week 24 for EV+P; functioning and symptom scores remained stable over time, with improvements in emotional functioning, pain and sleep disturbance vs observed baseline. In the EV+P arm, clinically meaningful reductions in pain were seen at Week 12 (-12.64 [3.208]) vs baseline and persisted through Week 24 (-13.20 [3.406]). In the BPI-SF MMRM analyses, worst and average pain, pain interference and severity consistently showed improved scores from Week 4–24 for EV+P; clinically meaningful change in worst pain was seen at Week 21 (-2.08 [0.361]). Similar completion and compliance rates were seen for the EV alone PRO analysis set (n=63). EV alone demonstrated clinically meaningful improvements in pain at Week 24 in the EORTC QLQ-C30 (-10.63 [4.110]) and consistent small-to-moderate improvements in the BPI worst and average pain, and pain severity (0.5–1.0 points). Sleep disturbances demonstrated improvement, and other symptom scales, QOL and functional domains remained stable. Conclusions: PRO data showed that EV+P in cisplatin-ineligible pts with la/mUC was associated with preservation or improvement of QOL, functioning, and symptoms. Improvement in pain was demonstrated consistently in both PRO instruments and treatment arms. These PRO data complement the clinical outcomes of EV+P in 1L cisplatin-ineligible pts with la/mUC. Clinical trial information: NCT03288545 .

4565 Background: Advanced urothelial carcinoma (aUC) has a poor long-term prognosis. Despite new clinical trial data for novel therapies including PD-1/L1 inhibitors, data on real-world (RW) treatment patterns and overall survival (OS) in aUC patients (pts) treated with first line (1L) therapy are limited. Methods: This retrospective observational study describes the contemporary RW 1L treatment patterns and OS in aUC pts stratified by cisplatin (cis)-eligibility (based on accepted criteria) and treatment. Data were from the nationwide Flatiron Health longitudinal electronic health record-derived database, comprising de-identified patient-level structured and unstructured data. Eligible pts were adults diagnosed with aUC from May 2016-Oct 2020 and followed until death or end of data availability in July 2021. OS was estimated using Kaplan-Meier methods and compared via multivariable Cox proportional-hazard models adjusted for clinical covariates. Results: Of 4,300 aUC diagnosed pts, 3,311 (77.0%) received 1L treatment; 1836 (55.5%) cis-ineligible, 1475 (44.5%) cis-eligible. Differences between cis-ineligible and cis-eligible pts were observed, with cis-ineligible more likely to be older (mean age, 75.0 vs 69.0 yrs), have lower CrCl (median, 45.3 vs 80.7 mL/min), and worse ECOG-PS (2+, 29.2 vs 0%). Only 44.4% received 2L therapy: 38.3% cis-ineligible vs 52.0% cis-eligible. Median OS in all 1L treated pts was 11.0 (95% CI, 10.3 – 11.5) mo and was shorter in cis-ineligible than cis-eligible pts (8.6 [95% CI, 8.1 – 9.2] vs 14.4 [95% CI, 13.4 – 16.4]; hazard ratio [HR], 0.8 [0.7 – 1.0]). A number of cis-ineligible pts received cis, and many cis-eligible pts did not (Table), suggesting physicians consider clinical factors beyond conventional criteria to determine cis-eligibility. Cis + gemcitabine (gem) or MVAC was associated with longer OS vs other treatments regardless of cis-eligibility (Table). Conclusions: Clinical outcomes in 1L aUC pts were poor, particularly for cis-ineligible pts, which may be partly driven by the specific regimen administered. Many aUC pts did not receive 1L treatment and among those who did, less than half received 2L therapy. These data highlight the need for more effective and tolerable 1L therapy for all aUC pts. [Table: see text]