Outcomes of enfortumab vedotin and pembrolizumab for patients previously treated with immune checkpoint inhibitors in the UNITE study.
Authors: Jindal Tanya , Jiang Cindy Y. , Alhalabi Omar , Sidhom Fady , Jang Albert , Bakaloudi Dimitra Rafailia , Narula Ishita , Jaime-Casas Salvador , Glover Michael , Nizam Amanda , Gupta Shilpa , Bilen Mehmet Asim , Shah Sumit , Tripathi Abhishek , Grivas Petros , Brown Jason Robert , Basu Arnab , Campbell Matthew T. , Alva Ajjai Shivaram , Koshkin Vadim S 
Published: February 2025

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Background:
In trials testing enfortumab vedotin and pembrolizumab (EVP), prior treatment with immune checkpoint inhibitors (ICIs) was not permitted, resulting in a knowledge gap regarding efficacy of EVP in patients (pts) previously treated with ICIs. We hypothesized that EVP would have efficacy in pts with prior ICI exposure.
Methods:
In the retrospective UNITE study, we identified all pts treated with ICI prior to receiving EVP. The observed response rate (ORR) was assessed in evaluable pts who had imaging after ≥1 cycle of EVP. The following factors were evaluated to assess effect on EVP outcomes: type of ICI received (PD-1 vs PD-L1), prior pembrolizumab vs other ICI, time from last ICI to start of EVP, duration on prior ICI treatment, whether patient had clinical benefit (SD/PR/CR) to prior ICI, whether ICI was the immediate prior therapy line and whether it was the only prior line. ORR for these categories was compared using logistic regression, while progression-free survival (PFS) and overall survival (OS) from EVP start were analyzed using the log-rank test and Cox proportional hazards model.
Results:
Among 220 pts treated with EVP across 10 US sites, 43 (20%) had previously received ICI. Median age was 69 years; 34 (79%) were men, 40 (93%) were Caucasian, and 27 (63%) had pure urothelial carcinoma, 9 (21%) liver mets and 31 (72%) ECOG PS 0/1. Of 43 pts, 4 received ICI in the peri-operative setting (3 nivolumab, 1 pembrolizumab) and 39 in the metastatic setting (19 pembrolizumab, 8 avelumab maintenance, 6 nivolumab, 2 pembrolizumab maintenance and 1 each of atezolizumab, ipilimumab/nivolumab, durvalumab/tremelimumab, nivolumab/NKTR214). ORR was 48% (95% CI: 31 - 66) in 33 evaluable pts, with 13 (39%) PR and 3 (9%) CR; 30% had SD as best response (DCR 79%), and 21% PD. After median follow-up of 14 mos, median PFS was 6.9 mos (95% CI: 3.91 – 12.2) and median OS 15.4 mos (95% CI: 8.7 – NR). Outcomes by group are shown in the Table.
Conclusions:
Pts treated with EVP after prior ICI experienced high ORR and disease control rate. Results from this multi-site retrospective study are hypothesis-generating and require prospective validation in larger cohorts.

Groups
ORR
PFS
OS

OR (95% CI)

p-value

HR (95% CI)

p-value

HR (95% CI)

p-value

Type of ICI (PD-1 vs PD-L1)
2.15 (0.36 – 17.49)
0.4
0.72 (0.32 – 1.61)
0.4
0.59 (0.23 -1.52)
0.3

Prior pembrolizumab vs not
0.54 (0.12 – 2.23)
0.4
0.55 (0.26 – 1.16)
0.1
0.40 (0.15 – 1.02)

0.05

Time from prior ICI*
1.01 (0.98 – 1.05)
0. 5
0.99 (0.98 – 1.01)
0.9
0.98 (0.96 – 1.02)
0.3

Time on prior ICI*
0.87 (0.74 - 0.98)

0.05

0.99 (0.94 – 1.05)
0.9
0.97 (0.89 – 1.05)
0.4

Clinical benefit to prior ICI (DCR vs PD)
0.50 (0.08 – 2.75)
0.4
0.70 (0.27 – 1.81)
0.5
0.89 (0.29 – 2.73)
0.8

Multiple prior lines vs ICI as only prior line
0.51 (0.11 – 2.29)
0.4
1.40 (0.57 – 3.44)
0.5
1.87 (0.54 – 6.43)
0.3

ICI as immediate prior line vs not
0.93 (0.15 -5.82)
0.9
0.56 (0.20 – 1.57)
0.3
0.53 (0.17 – 1.64)
0.3

*Continuous.