Real world toxicity profile of enfortumab vedotin (EV) with or without pembrolizumab (P) in ultra elderly urothelial carcinoma (UC) patients (pts).
Authors: Mar Nataliya , Go Jeanah , Cabral Marsenne Y. , Kaakour Dalia , Dwabe Sami , Seyedin Steven Neema , Drakaki Alexandra 
Published: February 2025

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Background:
EV is an antibody drug conjugate that was approved in the United States as monotherapy for pretreated advanced UC and, then, in combination with P in untreated pts. However, EV is associated with multiple toxicities, which are mostly non-overlapping with those of P. In the EV-302 study, grade (G) 3 or higher treatment-related adverse events (TRAEs) occurred in 55.9% of pts and led to treatment discontinuation in 35.0% of those on EV+P. Pts aged 80 years or older (i.e. the ultra elderly) are a special population, who may be particularly vulnerable to EV toxicity.
Methods:
This is a retrospective analysis of UC pts, who received EV monotherapy or EV+P at 2 academic institutions in Southern California from 12/2019 to 9/2024. Pts had to be aged 80 years or older at EV start to qualify and must have received at least 1 EV dose. Toxicity was graded using the CTCAE version 5 criteria.
Results:
A total of 26 pts were included, with 83.6% being male. Median age was 86.5 years [range, 80 to 97], with 38.5% of pts aged 80-84 years (group 1), 46.2% aged 85-89 years (group 2), and 15.4% aged over 90 years (group 3). 53.8% identified as Caucasian, 23.1% as Asian, 15.4% as Hispanic, and 7.7% as “other”. 69.2% received EV monotherapy and 30.8% EV+P. In those on EV alone, 88.9% had a prior PD-1/PD-L1 inhibitor. At time of data cut off, 27.0% of pts were still receiving EV. Median number of EV infusions given was 10.5 [range, 2 to 25], while median number of weeks on EV was 19.5 [range, 1 to 52]. In group 1, starting EV dose was 1.25 mg/kg in 30.0% of pts and 1.0 mg/kg in 70.0%. In group 2, starting EV dose was 1.25 mg/kg in 16.7% of pts, 1.0 mg/kg in 25.0%, 0.75 mg/kg in 41.7%, and 0.5 mg/kg in 16.7%. In group 3, starting EV dose was 1.25 mg/kg in 25.0% of pts, 1.0 mg/kg in 50.0%, and 0.5 mg/kg in 25.0%. After EV start, 50.0% had at least 1 EV dose reduction, 42.3% had at least 1 dose delay, and 30.8% had EV discontinued due to TRAEs. Toxicity severity in the overall study population was as follows: G0 in 26.9%, G1 in 30.8%, G2 in 26.9%, and G3 in 15.4%. No G4/5 toxicities were noted. Starting EV dose and associated toxicity are outlined in the table. Specific TRAEs included neuropathy in 34.6% of pts, ocular symptoms in 19.2%, rash/pruritus/fatigue/abnormal electrolytes in 15.4% each, nausea and diarrhea in 3.8% each.
Conclusions:
Despite its small sample size and retrospective nature, this dataset did not identify any excessive or unexpected toxicity in the ultra elderly population. More pts in groups 2/3 received up-front EV dose reduction, with less G2/3 TRAEs noted at lower starting EV doses. Up-front dose reduction of EV may be a good strategy to mitigate TRAE risk.

Starting EV dose and associated EV-related TRAEs.

Dose (mg/kg)
% of pts
% of pts with G0 TRAEs
% of pts with G1 TRAEs
% of pts with G2 TRAEs
% of pts with G3 TRAEs

1.25
23.1
16.7
0
66.7
16.7

1.0
46.2
25.0
33.3
25.0
16.7

0.75
19.2
40.0
40.0
0
20.0

0.5
11.5
33.3
66.7
0
0