Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer

Author(s): Christopher J. Hoimes, DO1,2;Thomas W. Flaig, MD3;Matthew I. Milowsky, MD4;Terence W. Friedlander, MD5;Mehmet Asim Bilen, MD6;Shilpa Gupta, MD7;Sandy Srinivas, MD8;Jaime R. Merchan, MD9;Rana R. McKay, MD10;Daniel P. Petrylak, MD11;Carolyn Sasse 12;Blanca Homet Moreno, MD, PhD13;Yao Yu, PhD14;Anne-Sophie Carret, MD14;Jonathan E. Rosenberg, MD15
Source: DOI: 10.1200/JCO.22.01643 Journal of Clinical Oncology
Lucio Gordan MD

Dr. Gordan's Thoughts

Impressive response rates and complete response in this setting, with moderate toxicities. Randomized trial is necessary to document survival, PFS differences. Cost will be very considerable in the setting value-based strategies. The clinical benefit must be quite superior in a randomized setting.

BACKGROUND

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 la/mUC patients are ineligible. Enfortumab vedotin and pembrolizumab have each 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 1b/2, multicenter, open-label study, 1L cisplatin-ineligible patients with la/mUC received enfortumab vedotin 1.25 mg/kg (Days 1 and 8) and pembrolizumab 200 mg (Day 1) intravenously in 3-week cycles. The primary endpoint was safety. Key secondary endpoints included confirmed objective response rate (ORR), 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. Confirmed ORR after a median of 9 cycles was 73.3% with a 15.6% complete response rate. Median DOR and median OS were 25.6 months and 26.1 months, respectively.

CONCLUSIONS

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 3 study (NCT04223856).

Author Affiliations

Christopher J. Hoimes, DO1,2;Thomas W. Flaig, MD3;Matthew I. Milowsky, MD4;Terence W. Friedlander, MD5;Mehmet Asim Bilen, MD6;Shilpa Gupta, MD7;Sandy Srinivas, MD8;Jaime R. Merchan, MD9;Rana R. McKay, MD10;Daniel P. Petrylak, MD11;Carolyn Sasse 12;Blanca Homet Moreno, MD, PhD13;Yao Yu, PhD14;Anne-Sophie Carret, MD14;Jonathan E. Rosenberg, MD15

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