In a phase Ib/II study reported in the Journal of Clinical Oncology, Christopher J. Hoimes, MD, and colleagues found that first-line enfortumab vedotin-ejfv plus pembrolizumab produced a high response rate and prolonged response durations in cisplatin-ineligible, previously untreated patients with advanced urothelial cancer.
Enfortumab vedotin plus pembrolizumab has received Breakthrough Therapy designation from the U.S. Food and Drug Administration and is under further investigation in phase II and III studies.
Christopher J. Hoimes, MD
As stated by the investigators: “Cisplatin-based combination chemotherapy remains the standard of care for locally advanced or metastatic urothelial cancer; however, toxicity is substantial, responses are rarely durable, and many patients with locally advanced or metastatic urothelial cancer are ineligible. Enfortumab vedotin and pembrolizumab have shown a survival benefit vs chemotherapy in urothelial cancer, are not restricted by cisplatin eligibility, and warrant investigation as a first-line combination therapy in patients ineligible for cisplatin.”
Study Details and Responses
In the ongoing multicenter U.S. study, 45 patients with locally advanced or metastatic disease received enfortumab vedotin at 1.25 mg/kg once daily on days 1 and 8 and pembrolizumab at 200 mg on day 1 in 3-week cycles.
Confirmed objective response was observed in 33 patients (73.3%, 95% confidence interval [CI] = 58.1%–85.4%), with a complete response in 7 (15.6%). Responses were observed independent of Nectin-4 and PD-L1 expression levels. The disease control rate was 93.3%. Median duration of response was 25.6 months (95% CI = 8.3 months to not evaluable), with a median follow-up of 20.0 months. Median progression-free survival was 12.3 months (95% CI = 8.0 months to not evaluable). Median overall survival was 26.1 months (95% CI = 15.7 months to not evaluable), with a median follow-up of 24.9 months.
The most common treatment-related adverse events of any grade were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%). Grade ≥ 3 treatment-related adverse events occurred in 29 patients (64.4%), most commonly increased lipase levels (17.8%), maculopapular rash (11.1%), and fatigue (11.1%). Serious treatment-related adverse events occurred in 7 patients (15.6%), and treatment-related adverse events led to discontinuation of treatment in 11 patients (24.4%; most commonly peripheral sensory neuropathy, in 4 patients). One patient died of a treatment-related adverse event (multiple organ dysfunction syndrome).
Jonathan E. Rosenberg, MD
The investigators concluded: “Enfortumab vedotin plus pembrolizumab showed a manageable safety profile. Most patients experienced tumor shrinkage. The median duration of response and median overall survival 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).”
Disclosure: The study was supported by Astellas Pharma US; Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc; Seagen Inc; and the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.