Outcomes of immune-checkpoint inhibitor rechallenge in urothelial carcinoma: Results from a global real-world evidence study.
Authors: Maiorano Brigida Anna , Cigliola Antonio , Tateo Valentina , Mercinelli Chiara , Pastorino Giovanni Luigi , Dizman Nazli , Ebrahimi Hedyeh , Pal Sumanta Kumar , Gupta Shilpa , Grivas Petros , Kamat Ashish M. , Spiess Philippe E. , Agarwal Neeraj , Necchi Andrea 
Published: February 2025

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Background:
Immune-checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of urothelial carcinoma (UC) across clinical stages. Several ICIs have been approved by regulatory agencies for both adjuvant and metastatic settings. Limited information is available regarding the efficacy of rechallenge with ICI following progression on prior ICI-based therapy. We hypothesized that ICI rechallenge could be effective in selected pts with UC.
Methods:
A retrospective study was performed using the TriNetX analytics platforms for a large-scale search of patients (pts) with UC who underwent 2 lines of ICI (± other treatments between ICIs, either alone or in combo with other agents) at healthcare organizations collaborating through a TriNetX-mediated network across international sites. Descriptive statistics were used to summarize the clinical and demographic characteristics of pts. Kaplan-Meier analysis was used to estimate progression-free and overall survival (PFS, OS) with ICI rechallenge. Data were analyzed in October 2024.
Results:
From a total of 35,789 pts with UC, a cohort of 267 pts, treated with 2 sequential ICIs between 2014 and 2024, was identified (195M, 71F). The baseline median age was 73 years. Overall, 86% had bladder vs. 14% upper tract primary tumor. At initial diagnosis, 27% had stage IV, while 73% had stage I-III disease; 19% of pts had undergone radical cystectomy. 12% of pts were reported to have
FGFR3
alterations, 12% PD-L1 positive. The median time on prior ICI was 19.5 months (mos - range: 16-27.5). The median time from the end of ICI to the start of ICI rechallenge was 6.4 mos. The most common ICI sequence was nivolumab followed by pembrolizumab (28.5%), then avelumab followed by pembrolizumab (22.4%), atezolizumab followed by pembrolizumab (20.8%), pembrolizumab followed by nivolumab (14.9%), pembrolizumab followed by avelumab (13.4%). The longest median (m)PFS was observed with anti-PD1 after anti-PD-L1 therapy (11.1 mos, range 0.89-38.4). The efficacy of ICI rechallenge was independent of the setting of prior ICI: perioperative vs. metastatic stage (p=0.16). mPFS with ICI rechallenge was 10.3 mos in pts treated with ICI ³12mos after the end of their prior ICI vs 6.0 mos in those rechallenged within <12mos (p=0.15); mPFS was 9.0 mos in pts treated with ICI ³6mos after the end of prior ICI vs. 3.4 mos in those rechallenged within <6mos (p=0.19). After a median follow-up of 22.7 mos, the mOS of ICI rechallenge was 25.8 mos.
Conclusions:
Although it is an uncommon strategy, ICI rechallenge after prior ICI-based therapy may benefit a subset of pts with UC, with outcomes varying based on the specific ICI regimen. Limitations include retrospective nature, variability in the timing of imaging across practices, and potential selection and confounding biases.