Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer

Author(s): Peter H. O’Donnell, MD1; Matthew I. Milowsky, MD2; Daniel P. Petrylak, MD3; Christopher J. Hoimes, DO4; Thomas W. Flaig, MD5; Nataliya Mar, MD6; Helen H. Moon, MD7; Terence W. Friedlander, MD8; Rana R. McKay, MD9; Mehmet A. Bilen, MD10; Sandy Srinivas, MD11; Earle F. Burgess, MD12; Chethan Ramamurthy, MD13; Saby George, MD14; Daniel M. Geynisman, MD15; Sergio Bracarda, MD16; Delphine Borchiellini, MD17; Lionnel Geoffrois, MD18; Jose Pablo Maroto Rey, MD19; Christiano Ferrario, MD20; Anne-Sophie Carret, MD21; Yao Yu, PhD21; Maria Guseva, MD, PharmD22; Blanca Homet Moreno, MD, PhD23; and Jonathan E. Rosenberg, MD24
Source: DOI: 10.1200/JCO.22.02887 Journal of Clinical Oncology 41, no. 25 (September 01, 2023) 4107-4117.
Anjan J Patel MD

Dr. Anjan Patel's Thoughts

A very compelling option to keep an eye out for as larger studies are sure to come in the future. EV + pembrolizumab had an ORR of ~65% with durable responses. The combo arm had unsurprisingly higher grade 3-4 AE’s.  For platinum-ineligible patients, it would be worth considering this regimen even today.


Patients with locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible for cisplatin-based therapy have limited first-line (1L) treatment options and significant need for improved therapies. Enfortumab vedotin (EV) and pembrolizumab (Pembro) individually have shown a survival benefit in urothelial cancer in second-line + la/mUC settings. Here, we present data from the pivotal trial of EV plus Pembro (EV + Pembro) in the 1L setting.


In Cohort K of the EV-103 phase Ib/II study, cisplatin-ineligible patients with previously untreated la/mUC were randomly assigned 1:1 to receive EV as monotherapy or in combination with Pembro. The primary end point was confirmed objective response rate (cORR) per blinded independent central review. Secondary end points included duration of response (DOR) and safety. There were no formal statistical comparisons between treatment arms.


The cORR was 64.5% (95% CI, 52.7 to 75.1) and 45.2% (95% CI, 33.5 to 57.3) for patients treated with EV + Pembro (N = 76) and EV monotherapy (N = 73), respectively. The median DOR was not reached for the combination and was 13.2 months for monotherapy; 65.4% and 56.3% of patients who responded to the combination and monotherapy, respectively, maintained a response at 12 months. The most common grade 3 or higher treatment-related adverse events (TRAEs) in patients treated with the combination were maculopapular rash (17.1%), fatigue (9.2%), and neutropenia (9.2%). EV TRAEs of special interest (any grade) in the combination arm included skin reactions (67.1%) and peripheral neuropathy (60.5%).


EV + Pembro showed a high cORR with durable responses as 1L treatment in cisplatin-ineligible patients with la/mUC. Patients who received EV monotherapy had a response and safety profile consistent with previous studies. Adverse events for EV + Pembro were manageable, with no new safety signals observed.

Author Affiliations

1University of Chicago, Chicago, IL; 2University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; 3Yale Cancer Center, New Haven, CT; 4Duke Cancer Institute, Duke University, Durham, NC; 5University of Colorado Comprehensive Cancer Center, Aurora, CO; 6University of California at Irvine, Irvine, CA; 7Kaiser Permanente Southern California, Riverside, CA; 8University of California at San Francisco, San Francisco, CA; 9University of California at San Diego, San Diego, CA; 10Emory University Winship Cancer Institute, Atlanta, GA; 11Stanford Cancer Center, Stanford, CA; 12Levine Cancer Center, Charlotte, NC; 13University of Texas Health Sciences Center at San Antonio, San Antonio, TX; 14Roswell Park Cancer Center, Buffalo, NY; 15Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA; 16Azienda Ospedaliera Santa Maria di Terni, Terni, Italy; 17Centre Antoine Lacassagne, Université Côte d’Azur, Nice, France; 18Institut de Cancerologie de Lorraine, Vandoeuvre Les Nancy, France; 19Hospital de la Santa Creu i Sant Paul, Barcelona, Spain; 20Jewish General Hospital, Montreal, Quebec, Canada; 21Seagen Inc, Bothell, WA; 22Astellas Pharma, Northbrook, IL; 23Merck & Co Inc, Rahway, NJ; 24Memorial Sloan Kettering Cancer Center, New York, NY

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