Safety and Efficacy Outcomes in Immune Checkpoint Inhibitor-Treated Patients With Metastatic Urothelial Carcinoma Requiring Treatment Interruption or Discontinuation Due to Immune-Related Adverse Events

• Published in: Clinical genitourinary cancer Vol. 22; no. 2; pp. 368 - 379
• Main Authors: Nizam, Amanda, Rader, Ryan K., Tzeng, Alice, Wei, Wei, Sheng, Iris Yeong-Fung, Martin, Allison, Wee, Christopher E., Gilligan, Timothy D., Gupta, Shilpa, Ornstein, Moshe C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2024
• Subjects: Anti-PD-1; Antineoplastic Agents, Immunological - therapeutic use; Bladder cancer; Carcinoma, Transitional Cell - drug therapy; Humans; Immune Checkpoint Inhibitors - adverse effects; Immunotherapy; Neoplasm Recurrence, Local - drug therapy; Retrospective Studies; Treatment Interruption; Treatment toxicity; Urinary Bladder Neoplasms - chemically induced; Urinary Bladder Neoplasms - drug therapy; CTCAE; Anti-PD-1; NR; OS; Anti-PD-L1; IO; TTI; Bladder cancer; ICI; ORR; KPS; TI; Immunotherapy; NE; mUC; Treatment toxicity; anti-CTLA-4; irAE; PFS
• ISSN: 1558-7673; 1938-0682
• DOI: 10.1016/j.clgc.2023.12.007

As most patients with metastatic urothelial carcinoma (mUC) will be treated with immune checkpoint inhibitors (ICI), familiarity with their associated immune-related adverse events (irAEs) is critical. We describe the characteristics and outcomes of ICI-treated mUC patients who experienced irAEs requiring treatment interruption (TI) or permanent discontinuation.
ICI-treated mUC patients who developed grade ≥2 irAEs were reviewed. Clinical-, treatment-, and toxicity-related data were evaluated. Toxicity was graded per common terminology for categorization of adverse events v5.0. Cohorts were divided into patients who underwent ICI rechallenge and those who required permanent ICI discontinuation. Time to treatment interruption (TTI), time to next treatment, and duration of clinical benefit were assessed descriptively. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier methodology.
Of 200 ICI-treated mUC patients at Cleveland Clinic between October 2015 and October 2020, 16 (8%) experienced ≥ grade 2 irAEs necessitating TI. Median TTI among all patients was 6.5 months (range, 1-19). Eleven patients (69%) required corticosteroids. ICI were held and rechallenged in 10 patients (62%) and permanently discontinued in 6 patients (38%). Of the 10 ICI-rechallenged patients, 7 (70%) experienced another irAE upon rechallenge with median time to irAE recurrence of 2.9 months (range, 0.1-10.9); 3 (30%) eventually discontinued ICI due to recrudescent irAEs. Four (40%) of the 10 ICI-rechallenged patients received subsequent therapy. Five (83%) of the 6 patients who permanently discontinued ICI demonstrated durable clinical benefit off therapy with median duration of clinical benefit 17.7 months (range, 14.2-55.2). Two-year OS was 40% (95% CI: 19%-86%) in the ICI rechallenge cohort and 67% (95% CI: 38%-100%) in the permanent discontinuation cohort.
ICI-treated mUC patients who developed irAEs requiring TI had a high rate of subsequent irAEs upon ICI rechallenge. Importantly, patients who permanently discontinued ICI due to irAE demonstrated durable clinical benefit off treatment.
As most patients with metastatic urothelial carcinoma will be treated with immune checkpoint inhibitors (ICI), familiarity with their toxicities is fundamental to clinical management. Our single-institution experience demonstrated a high rate of immune-related adverse events (irAEs) in patients undergoing ICI rechallenge following an initial irAE, while a durable clinical benefit off treatment was seen in those requiring permanent ICI discontinuation.