Toxicity profile of enfortumab vedotin with or without pembrolizumab in patients with metastatic urothelial carcinoma: A systematic review and meta-analysis.

Abstract

e16567 Background: Enfortumab Vedotin (EV), an antibody-drug conjugate targeting Nectin-4, has recently been integrated into the treatment landscape for metastatic urothelial carcinoma (MUC). Its use, either as monotherapy or in combination with the immune checkpoint inhibitor Pembrolizumab (P), has demonstrated remarkable efficacy with significant improvements in survival outcomes. However, a comprehensive understanding of the associated toxicity profile is critical to optimize patient care. This meta-analysis was conducted to assess the incidence and tolerability of adverse events of special interest associated with EV alone and in combination with Pembrolizumab. Methods: We systematically searched Pubmed, Embase, and Cochrane for studies assessing EV with or without Pembrolizumab in patients with locally advanced or metastatic urothelial carcinoma. Clinical trials reporting data on treatment-related peripheral neuropathy, skin reactions and hyperglycemia were included. The analysis followed PRISMA guidelines. Event rates per 100 patients with 95% confidence intervals (CI), were calculated for binary outcomes. Statistical analyses were conducted using R software version 4.4.0. Results: Nine studies with 1311 patients were included, of whom 795 (60%) received EV monotherapy and 516 (40%) were treated with EV plus Pembrolizumab (EV+P). Hyperglycemia incidence was numerically higher with EV (14.69%; 95% CI: 6.06-31.48) compared to EV+P (13.19%; 95% CI: 10.53-16.39), as was treatment discontinuation due to hyperglycemia (0.85%; 95% CI: 0.27-2.59 vs. 0%; 95% CI: 0.00-0.83). EV+P showed higher rates of skin reactions (66.86%; 95% CI: 62.68-70.79 vs. 52.63%; 95% CI: 43.85-61.33), grade ≥3 peripheral neuropathy (5.35%; 95% CI: 2.35-11.74 vs. 4.12%; 95% CI: 2.11-7.88), and treatment discontinuation due to peripheral neuropathy (11.07%; 95% CI: 8.64-14.09 vs. 4.03%; 95% CI: 2.55-6.31). Grade ≥3 hyperglycemia and treatment discontinuation due to skin reactions were comparable in both groups. Conclusions: Our analysis provides important insights into the toxicity profiles of EV, both as monotherapy and in combination with P. While hyperglycemia was slightly more common with EV monotherapy, the combination with pembrolizumab appeared to increase the incidence of skin reactions and severe peripheral neuropathy. Although these findings suggest potential differences in toxicity when Pembrolizumab is added, the lack of direct comparative studies between the two regimens limits definitive conclusions. Future research is warranted to further explore these patterns, enabling more informed treatment decisions and optimizing patient care.