Efficacy and toxicity profile of antibody-drug conjugate (ADC) based combination therapy in patients with advanced urothelial carcinoma (aUC): A systematic review of clinical trials.

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813 Background: ADCs have revolutionized the treatment landscape of aUC and are being evaluated as part of combination regimens with checkpoint inhibitors (CPI) or other ADCs. We sought to evaluate the efficacy and safety/tolerability profile of ADC-based combination therapy in aUC. Methods: We systematically searched the PubMed and Embase databases for published prospective clinical trials through July 2024. Peer-reviewed clinical trials evaluating ADCs as part of a combination regimen in aUC were included. We extracted safety and efficacy outcomes, including objective-response rate (ORR), any-grade adverse events (AEs), and grade ≥3 AEs. We excluded reviews, editorials, retrospective studies, and case reports. Two independent reviewers screened titles and abstracts for relevance, followed by a full-text review to confirm eligibility. Results: 627 evaluable patients from 5 prospective trials investigating enfortumab vedotin or sacituzumab govitecan were identified. Overall, we recorded an ORR of 66.2%. 366 patients across all studies experienced ≥ grade 3 AEs, for a risk rate (RR) of 58.4%. By using a random-effects model, the pooled RR for AEs (Grade≥3) was 61% (95% CI, 52%–69%; P=0.18; Table). The most common grade ≥3 AEs were neutropenia (RR 0.14 [95% CI 0.04- 0.40]), anemia (RR 0.10 [95% CI 0.03-0.30]), and maculopapular rash (RR 0.10 [95% CI 0.04-0.23]). Distribution of specific AEs varied significantly based on regimen, with a higher incidence of ≥grade 3 anemia, neutropenia, and diarrhea in SG-based combinations (SG+ EV and SG+ CPI). Conclusions: While ADC-based combination regimens show promising responses, they also have high rates of AEs in patients with aUC. Further clinical trials evaluating these combination regimens are crucial to further optimize the role of ADCs in this disease setting. Safety/tolerability profile for any grade and grade ≥3 AEs. Toxicity Any Grade Grade≥3 Risk rate, 95% CI Risk rate, 95% CI Anemia 0.31 [0.09; 0.66] 0.10 [0.03; 0.30] Neutropenia 0.24 [0.05; 0.65] 0.14 [0.04; 0.40] Diarrhea 0.51 [0.19; 0.82] 0.07 [0.02; 0.17] Peripheral sensory neuropathy 0.50 [0.47; 0.54] 0.03 [0.02; 0.05] Fatigue 0.45 [0.26; 0.65] 0.06 [0.03; 0.13] Maculopapular rash 0.36 [0.26; 0.47] 0.10 [0.04; 0.23]

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