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Multicenter Study
. 2023 Jan 1;41(1):22-31.
doi: 10.1200/JCO.22.01643. Epub 2022 Aug 30.

Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer

Christopher J Hoimes  1   2 , Thomas W Flaig  3 , Matthew I Milowsky  4 , Terence W Friedlander  5 , Mehmet Asim Bilen  6 , Shilpa Gupta  7 , Sandy Srinivas  8 , Jaime R Merchan  9 , Rana R McKay  10 , Daniel P Petrylak  11 , Carolyn Sasse  12 , Blanca Homet Moreno  13 , Yao Yu  14 , Anne-Sophie Carret  14 , Jonathan E Rosenberg  15
Affiliations
Multicenter Study

Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer

Christopher J Hoimes et al. J Clin Oncol. .

Abstract

Purpose: Cisplatin-based combination chemotherapy remains the standard of care for locally advanced or metastatic urothelial cancer (la/mUC); however, toxicity is substantial, responses are rarely durable, and many patients with la/mUC are ineligible. Each enfortumab vedotin and pembrolizumab have shown a survival benefit versus chemotherapy in UC, are not restricted by cisplatin eligibility, and warrant investigation as a first-line (1L) combination therapy in patients ineligible for cisplatin.

Methods: In this ongoing phase Ib/II, multicenter, open-label study, 1L cisplatin-ineligible patients with la/mUC received enfortumab vedotin 1.25 mg/kg once daily on days 1 and 8 and pembrolizumab 200 mg (day 1) intravenously once daily in 3-week cycles. The primary end point was safety. Key secondary end points included confirmed objective response rate, duration of response (DOR), and overall survival (OS).

Results: Forty-five patients received enfortumab vedotin plus pembrolizumab. The most common treatment-related adverse events (TRAEs) were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%). Twenty-nine patients (64.4%) had grade 3 or higher TRAEs; the most common were increased lipase (17.8%), maculopapular rash (11.1%), and fatigue (11.1%). One death (2.2%) was classified as a TRAE. The confirmed objective response rate after a median of nine cycles was 73.3% with a complete response rate of 15.6%. The median DOR and median OS were 25.6 months and 26.1 months, respectively.

Conclusion: Enfortumab vedotin plus pembrolizumab showed a manageable safety profile. Most patients experienced tumor shrinkage. The median DOR and median OS exceeding 2 years in a cisplatin-ineligible patient population make this a promising combination currently under investigation in a phase III study (ClinicalTrials.gov identifier: NCT04223856).

Trial registration: ClinicalTrials.gov NCT03288545 NCT04223856.

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Conflict of interest statement

Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Figures

FIG 1.
FIG 1.
Screening, allocation, follow-up, and analyses. 2L, second-line; EV, enfortumab vedotin; pembro, pembrolizumab.
FIG 2.
FIG 2.
Change in target lesions from baseline. (A) Waterfall plot of change from baseline in the sum of the diameters of target lesions by investigator per RECIST v1.1. (B) Change from baseline of the sum of diameters of target lesions (the dotted horizontal line indicates threshold for partial response (–30%) but is not necessarily indicative of response) and (C) Swimmer plot of time to response and duration of response in patients achieving confirmed objective response per RECIST v1.1. PD-L1 expression status was assessed using the combined positive score (low, < 10; high ≥ 10) with a validated PD-L1 IHC assay using the 22C3 antibody. Two patients did not have any post-baseline response assessments before the end of the study and did not have change from baseline in sum of the diameters of target lesions. CPS, combined positive score; CR, complete response; IHC, immunohistochemistry; PR, partial response.
FIG 3.
FIG 3.
(A) DOR, (B) PFS, and (C) OS by the investigator per RECIST v1.1. DOR, duration of response; EV, enfortumab vedotin; OS, overall survival; PD, progressive disease; pembro, pembrolizumab; PFS, progression-free survival.
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