Citations

TPS4642 Background: Although first-line (1L) EV + pembrolizumab has improved outcomes for patients with la/mUC, most experience disease progression, highlighting an unmet need for novel therapies. TROP2 is a glycoprotein highly expressed in several epithelial tumors, including UC. Dato-DXd is a TROP2-directed antibody–drug conjugate comprising an anti-TROP2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload (DXd), designed to induce selective tumor-cell death and reduce systemic exposure to the payload. Dato-DXd has demonstrated durable efficacy and a manageable safety profile in patients with la/mUC both as monotherapy (TROPION-PanTumor01 [NCT03401385]) and in combination with immunotherapy (TROPION-PanTumor03 [NCT05489211]). We describe a Phase 2/3 trial comparing the efficacy and safety of Dato-DXd + platinum CT (carboplatin or cisplatin) vs gemcitabine + platinum CT in participants with la/mUC with disease progression on or after EV + pembrolizumab. Methods: TROPION-Urothelial03 (NCT07129993) is a global, multicenter, randomized, open-label, Phase 2/3 trial. In Part A (Phase 2), ~60 participants will be randomized 1:1 to receive Dato-DXd 4 or 6 mg/kg + platinum CT. In Part B (Phase 3), ~570 participants will be randomized 1:1 to receive Dato-DXd at the recommended Phase 3 dose (determined using Part A data) + platinum CT vs gemcitabine + platinum CT. Randomization in Part A is stratified by assignment of platinum CT (carboplatin vs cisplatin), and in Part B, by assignment of platinum CT, presence vs absence of liver metastasis at screening, and time to progression on 1L EV + pembrolizumab (<6 vs ≥6 months). Study treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, death, loss to follow-up, or other reasons per protocol. Radiographic tumor assessments occur every 6 weeks for 54 weeks, then every 12 weeks. The primary endpoint of Part A is objective response rate (ORR) by investigator per Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1). The dual primary endpoints of Part B are progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1 and overall survival (OS). Secondary endpoints include duration of response by investigator per RECIST 1.1 (Part A), and PFS by investigator per RECIST 1.1 and ORR by BICR and investigator per RECIST 1.1 (Part B). In Part A, ORR will be summarized with 2-sided 95% exact confidence intervals using the Clopper–Pearson method by trial group. In Part B, PFS and OS will be compared between trial groups using a log-rank test stratified by randomization stratification factors, with hazard ratios from the stratified Cox regression model. Clinical trial information: NCT07129993 .

TPS890 Background: Although first-line (1L) EV + pembrolizumab has improved outcomes for patients with la/mUC, most experience disease progression, highlighting an unmet need for novel therapies. TROP2 is a glycoprotein highly expressed in several epithelial tumors, including UC. Dato-DXd is a TROP2-directed antibody–drug conjugate comprising an anti-TROP2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload (DXd), designed to induce selective tumor-cell death and reduce systemic exposure to the payload. Dato-DXd has demonstrated durable efficacy and a manageable safety profile in patients with la/mUC both as monotherapy (TROPION-PanTumor01 [NCT03401385]) and in combination with immunotherapy (TROPION-PanTumor03 [NCT05489211]). We describe a phase 2/3 trial comparing the efficacy and safety of Dato-DXd + platinum CT (carboplatin or cisplatin) vs gemcitabine + platinum CT in participants with la/mUC with disease progression on or after EV + pembrolizumab. Methods: TROPION-Urothelial03 (NCT07129993) is a global, multicenter, randomized, open-label, phase 2/3 trial. In part A (phase 2), ~60 participants will be randomized 1:1 to receive Dato-DXd 4 or 6 mg/kg + platinum CT. In part B (phase 3), ~570 participants will be randomized 1:1 to receive Dato-DXd at the recommended phase 3 dose (determined using part A data) + platinum CT vs gemcitabine + platinum CT. Randomization in part A is stratified by assignment of platinum CT (carboplatin vs cisplatin), and in part B, by assignment of platinum CT, presence vs absence of liver metastasis at screening, and time to progression on 1L EV + pembrolizumab ( < 6 vs ≥6 months). Study treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, death, loss to follow-up, or other reasons per protocol. Radiographic tumor assessments occur every 6 weeks for 54 weeks, then every 12 weeks. The primary endpoint of part A is objective response rate (ORR) by investigator per Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1). The dual primary endpoints of part B are progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1 and overall survival (OS). Secondary endpoints include duration of response by investigator per RECIST 1.1 (part A), and PFS by investigator per RECIST 1.1 and ORR by BICR and investigator per RECIST 1.1 (part B). In part A, ORR will be summarized with 2-sided 95% exact confidence intervals using the Clopper–Pearson method by trial group. In part B, PFS and OS will be compared between trial groups using a log-rank test stratified by randomization stratification factors, with hazard ratios from the stratified Cox regression model. Clinical trial information: NCT07129993 .

Abstract Aims Left ventricular hypertrophy (LVH) is a strong predictor of cardiovascular disease. We previously compared supervised machine learning techniques to classify cardiac magnetic resonance (CMR)-derived LVH using electrocardiogram (ECG) and clinical variables in 37 534 UK Biobank participants, obtaining an area under the receiving operating curve (AUROC) of 0.85, but with limited specificity and requiring external validation. In this study, we develop a deep learning (DL) model to improve classification with external evaluation in the Study of Health in Pomerania (SHIP). Methods and results We analysed 12-lead ECGs of 48 835 participants from the UK Biobank imaging study. The dataset was split into a training set (70%), validation set (15%), and test set (15%) for performance evaluation. The model architecture was a fully convolutional network, for which the input was the participants’ median ECG and clinical variables and the predicted indexed left ventricular mass (iLVM) as the output. A subsequent logistic regression model was used to recalibrate iLVM predictions. In UK Biobank, 717 (1.5%) participants had CMR-derived LVH and the AUROC for the DL model was 0.97. The ECG components most predictive of LVH were the QRS complex and ventricular rate. The DL model outperformed our supervised algorithms, previous DL modelling efforts and clinical ECG benchmarks. There was modest generalizability of the DL model to 1423 participants in SHIP (AUROC 0.78), with differences in clinical profile, ECG acquisition, and CMR labelling as important factors. Conclusion Our findings support the feasibility of scalable DL-based screening tools for the prediction of LVH from the ECG, whilst highlighting the need for model development using larger datasets with greater diversity to ensure generalizability.

Abstract Aims Alcohol-associated liver disease (ALD) and alcohol use disorder (AUD) are interconnected and highly prevalent. Integrating substance use disorder (SUD) treatment into medical clinics may increase access to specialized care and improve liver-related outcomes. Methods A scoping review and quantitative analysis were completed on published literature before 4 September 2024. Included articles described SUD treatment integrated in medical settings for adults with liver disease and alcohol use. Specific focus in the analysis was placed on integrations that utilized telehealth formats, facilitated access to medications for AUD (MAUD), and intervened in liver transplant populations. Results Twenty-three full-length manuscripts and 10 conference abstracts met the inclusion criteria. Fourteen articles discussed MAUD access in ALD populations. Nine utilized telehealth interventions, and 12 focused on pre- and post-liver transplant populations considered high-risk for returning to alcohol use. Nine full-length manuscripts were included in a quantitative analysis, which showed a 9.7% risk difference (95% CI: 5.9–13.4) in any alcohol use, favoring integrated care over treatment as usual. Conclusions Integrated care for AUD and concurrent ALD populations can effectively reduce returns to alcohol use and be successfully integrated in a medical setting. The core ingredient of such interventions was the inclusion of an addiction medicine specialist into a medical setting, rather than an outside referral. Strategic telehealth utilization can further reduce geographic and specialty-specific barriers to SUD care in medically ill populations. More consensus is needed on key components, processes, and optimal outcomes for such integrated programs for people with concurrent liver disease and AUD.

Background and objectives Arteriovenous malformations (AVMs) with perinidal aneurysms and single draining vein are associated with an elevated risk of rupture and increased procedural complexity. The role of preoperative embolization in this high-risk anatomical subset remains unclear. This study aimed to evaluate the safety and efficacy of microsurgery with preoperative embolization, compared with microsurgery alone in patients with such AVMs. Methods We conducted a multicenter retrospective analysis of an AVM registry from the MISTA (Multicenter International Study for Treatment of Brain AVMs) consortium and included AVMs with perinidal aneurysms and a single draining vein. Baseline characteristics, angiographic outcomes, functional outcomes, and complication rates were compared. Propensity score weighting (PSW) using the covariate balancing method was applied to adjust for baseline differences. Results Out of a total of 1919 patients, 65 met the inclusion criteria; 45 patients underwent preoperative embolization followed by microsurgery, and 20 underwent microsurgery alone. After adjustment, complete obliteration rates were similar between groups (OR 0.87, 95% CI 0.04 to 16.33, P=0.92), as were rates of functional independence at discharge and follow-up. Overall complication, symptomatic complication, and mortality rates did not differ significantly between groups. However, permanent complications were significantly lower in patients with preoperative embolization (OR 0.06, 95% CI 0.004 to 0.84, P=0.03). Discussion In patients with AVMs featuring perinidal aneurysms and single draining vein, preoperative embolization followed by microsurgery was associated with fewer permanent complications and no increase in adverse outcomes compared with microsurgery alone. However, given the small number of events, this finding should be interpreted cautiously.

Abstract Background Resident Doctors (RDs) in the UK must balance clinical training with non-clinical administrative tasks. Concerns increase over how these tasks impact their professional development, job satisfaction and patient care. The shift toward consultant-delivered care has led to a redistribution of responsibilities, increasing administrative burden on RDs. Aims This study aims to quantify how RDs allocate time between patient-facing and non-patient-facing tasks and assess impact on job satisfaction. Design National multicentre observational cohort study. Methodology The Time Allocation in Clinical Training study is a multicentre, observational cohort study conducted over seven months (January–July 2024) at secondary NHS centres. 137 RDs, from Foundation Year 1 to Specialty Training Year 8, were observed for 4-hour periods, with time tracked using stopwatches for five task categories. An optional survey assessed job satisfaction, rated on a five-point Likert scale. Results RDs spent 73.0% of their time on non-patient-facing tasks, and 17.9% on patient-facing activities. Women spent more time on non-patient-facing tasks compared to men (75.0% vs. 69.9%, P = 0.03). Junior RDs (Foundation years and Core trainees) spent significantly less time on patient-facing tasks compared to senior RDs (ST6-8) (38.4% vs. 17.8%; P = 0.004). Most RDs (62%) reported dissatisfaction with the administrative burden. Electronic health record users spent significantly more time on administrative tasks than paper-based record users (44.1% vs. 37.3%; P = 0.02). Conclusions The study reveals a significant imbalance between clinical and administrative tasks, with excessive administrative workload contributing to RD dissatisfaction. Streamlining administrative duties and integrating digital solutions is crucial for improving job satisfaction, clinical development and healthcare delivery in the NHS.

PURPOSE The COSMIC-021 study assessed the safety and efficacy of cabozantinib plus atezolizumab in advanced solid tumors. Presented here are results from the expansion cohorts with advanced urothelial carcinoma (UC). METHODS This phase Ib study (ClinicalTrials.gov identifier: NCT03170960 ) enrolled patients with inoperable locally advanced/metastatic UC into four tumor cohorts: first-line cisplatin-eligible (cis-eligible), first-line cisplatin-ineligible (cis-ineligible), previous platinum-containing chemotherapy (previous chemotherapy-treated), and previous immune checkpoint inhibitor (ICI)–treated. Patients received oral cabozantinib 40 mg once daily and intravenous atezolizumab 1,200 mg once every 3 weeks. The primary end point was objective response rate (ORR), as assessed by the investigator per RECIST v1.1 every 6 weeks for 12 months and every 12 weeks thereafter; the secondary end point was safety. RESULTS A total of 121 patients (previous ICI-treated cohort, n = 31, and each of the other cohorts, n = 30) received study treatment from March 2018 to November 2021. The ORR (95% CI) was 30% (15 to 49) for cis-eligible, 20% (8 to 39) for cis-ineligible, 27% (12 to 46) for previous chemotherapy-treated, and 10% (2 to 26) for previous ICI-treated cohorts. The median progression-free survival (95% CI) was 5.5 (1.6 to 11.6), 5.6 (3.1 to 11.1), 5.4 (1.6 to 7.6), and 3.0 (1.8 to 5.5) months, respectively. Grade 3 or 4 treatment-related adverse events (TRAEs) were experienced by 43%, 67%, 57%, and 45% of patients, respectively. TRAEs led to discontinuation of all treatment components in 17%, 13%, 3%, and 19%, respectively. No grade 5 TRAEs were reported in any cohort. CONCLUSION The novel combination of cabozantinib plus atezolizumab exhibited clinical activity in advanced UC that is cis-eligible, cis-ineligible, or previously treated with platinum-containing chemotherapy; clinical activity in previous ICI-treated UC was modest. The toxicity profile was consistent with that previously reported for the combination.

Abstract Purpose: The three-arm, phase III KEYNOTE-361 study did not meet its dual primary endpoints of progression-free survival (PFS) or overall survival (OS) with first-line pembrolizumab plus chemotherapy versus chemotherapy in advanced urothelial carcinoma. This prespecified exploratory analysis assessed the association of tumor mutational burden (TMB) and PD-L1 combined positive score (CPS) with clinical outcomes. Patients and Methods: TMB and PD-L1 CPS were determined via whole-exome sequencing and PD-L1 IHC 22C3 pharmDx, respectively. The association was evaluated in each treatment arm using logistic regression [objective response rate (ORR)] and Cox proportional hazards regression models (PFS and OS); one-sided (pembrolizumab monotherapy; pembrolizumab plus chemotherapy) and two-sided (chemotherapy) nominal P values were calculated. Significance was prespecified at α = 0.05 without multiplicity adjustment. Efficacy was evaluated by prespecified cutoffs of 175 mutations/exome (TMB) and CPS 10 (PD-L1). Results: Of the 993 treated patients, 820 (82.6%) and 993 (100%) had evaluable TMB and CPS data, respectively. Continuous TMB was positively associated with ORR, PFS, and OS for pembrolizumab monotherapy (one-sided P &lt; 0.001, P &lt; 0.001, and P = 0.007, respectively); PFS and OS for pembrolizumab plus chemotherapy (one-sided P = 0.007 and P = 0.010, respectively); and OS for chemotherapy alone (two-sided P = 0.040). Continuous PD-L1 CPS showed evidence of anticipated association with ORR and PFS for pembrolizumab monotherapy. The subgroup with TMB ≥175 mutations/exome and PD-L1 CPS ≥10 had the highest PFS and OS improvements with pembrolizumab alone or with chemotherapy versus chemotherapy alone. Conclusions: These data suggest that TMB may be predictive of the response to pembrolizumab alone or with chemotherapy in advanced urothelial carcinoma.