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

Abstract

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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%). CONCLUSION 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.

Real world evidence of enfortumab vedotin in patients with advanced urothelial cancer: A multicenter observational study

“…The incidence of treatment-related rash was lower than in the EV-301 trial, although this disparity diminished for grade 3 or higher rashes, 5 suggesting milder rashes may often go undetected in clinical settings. Moreover, the incidences of alopecia and hematological adverse events were also lower than those reported in previous clinical 5,14 Considering that other real-world data also indicated an absence of alopecia, 15 it is possible that mild to moderate adverse events in this study are underreported. Importantly, nine patients (8.7%) died within 4 weeks of initiating EV therapy due to cancer.…”

“…These factors are known to directly impact the effectiveness of treatments in clinical practice, 8,9 creating a gap in the generalizability of findings from current randomized controlled trials to the real‐world setting. With increasing interest in extending EV therapy to first‐line treatment options and potentially to the neoadjuvant setting, 10,11 assessing its effectiveness in the real‐world setting is essential.…”

UpToDate®

“…In a randomized phase II trial of approximately 150 previously untreated, cisplatin-ineligible patients with UC, the addition of pembrolizumab to enfortumab vedotin (EV) resulted in an objective response rate of 65 versus 45 percent for EV alone, although this difference did not reach statistical significance. 3 Based on these data, the US Food and Drug Administration granted accelerated approval for EV plus pembrolizumab in adults with locally advanced or metastatic UC who are ineligible for cisplatin-based chemotherapy. 4,5 We consider this combination to be an acceptable option in this population.…”

Combinations, Sequencing, and the Contribution of Components: New Frontline Standards for Metastatic Urothelial Carcinoma

“…In the article that accompanies this editorial, 4 we see promising results from a randomized yet noncomparative trial of enfortumab vedotin (EV) with pembrolizumab compared with EV alone in patients who are not candidates for frontline, cisplatin-based chemotherapy. As a result of this work, the US Food and Drug Administration granted accelerated approval to the combination of EV with pembrolizumab in cisplatin-ineligible patients.…”

“…In the article that accompanies this editorial, 4 we see very promising results from a randomized yet noncomparative trial of EV with pembrolizumab and EV alone in patients who are not candidates for cisplatin-based chemotherapy. The combination cohort achieved a clinical objective response rate (cORR) of 64% with a median duration of response (mDOR) that has not yet been reached while EV monotherapy achieved a cORR of 45% with an mDOR of 13.2 months.…”