(UroToday.com) Dr. Terence Friedlander presents an additional 3 months worth of data for the trial of Enfortumab Vedotin (EV) with or without pembrolizumab (P) in patients (pts) who are cisplatin-ineligible with previously untreated locally advanced or metastatic urothelial cancer (la/mUC). This brings the total follow-up to 18 months.
As the authors note, there is an unmet need for effective and durable first-line (1L) treatment options in cisplatin-ineligible first line metastatic urothelial carcinoma (mUC). EV and Pembrolizumab have shown survival benefit as monotherapies in the second line and as 1st line metastatic urothelial carcinoma settings. Naturally, a combination of the two may provide important synergy. This is supported by some preclinical work that demonstrates that treatment with EV induces immunogenic cell death – which can be enhanced by PD-1 inhibitors such as such as pembrolizumab.
Promising results from EV-103 dose escalation/Cohort A (DE/A) led to accelerated approval in April 2023 for cisplatin-ineligible patients and provided rationale for this randomized Cohort K for which the authors are now disclosing additional follow-up to previous reports (Rosenberg, ESMO 2022) on efficacy and safety.
In this study, untreated cisplatin-ineligible patients with newly diagnosed metastatic urothelial carcinoma were randomized 1:1 to either EV (1.25 mg/kg, day 1, day 8) as monotherapy (EV mono) or in combination with Pembrolizumab (200 mg, day 1) using 3-week cycles.
The primary endpoint was confirmed objective response rate (cORR) per RECIST v1.1 by blinded independent central review (BICR). Their secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.
149 pts were enrolled and treated on trial. This included 73 patients in the monotherapy arm vs. 76 patients receiving combination therapy.
Of note, this included 30-40% of patients with upper tract urothelial carcinoma. 80% or more had visceral disease in both arms.
Importantly, EV monotherapy activity is consistent with prior results in the same stage and later settings. The addition of pembrolizumab did demonstrate improved ORR over EV monotherapy alone.
While the PFS and OS median have not been achieved, the 12-month results are trending similarly to results from the dose-escalation trial, which is better than monotherapy alone.
EV treatment-related adverse events of special interest (AESIs) include skin reactions (EV+P, 67.1%; EV mono, 45.2%), peripheral neuropathy (EV+P, 63.2%; EV mono, 54.8%), and hyperglycemia (EV+P, 14.5%; EV mono, 11.0%). In EV+P, the most frequent treatment-emergent adverse events of special interest were severe skin reactions (27.6%), hypothyroidism (13.2%), and pneumonitis (9.2%).
As the authors note, the combination of EV+P continues to show a high cORR with rapid and durable responses in the first line for cisplatin-ineligible patients with metastatic urothelial carcinoma. The safety profile remains unchanged with no new signals despite extended treatment exposure. The authors do expect (and will eventually report on) updated DOR, PFS and OS with further follow-up – though they expect these to trend similarly to those of dose escalation trial. EV monotherapy results were consistent with prior results.
They note that EV-302 is another trial looking at the potential benefit of EV+P in the first line compared against chemotherapy in cisplatin-eligible and ineligible patients.
Clinical trial information: NCT03288545.
Presented by: Terence W. Friedlander, MD, University of California, San Francisco Medical Center, San Francisco, CAWritten by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Associate Professor of Urology, University of California, Davis, @tchandra_uromd @UCDavisUrology on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.