In a Cohort K of the EV-103 study conducted among cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer, first-line treatment with enfortumab vedotin in combination with pembrolizumab showed a 64.5% overall response rate, with responses lasting beyond 1 year for 65.4% of responders, trending similarly with previously disclosed data from EV-103 Dose Escalation/Cohort A. Additionally, the median duration of response (DoR) has not yet been reached for the combination arm. The combination demonstrated a manageable safety profile.
The findings provide a strong foundation for the ongoing phase III studies of the enfortumab vedotin and pembrolizumab combination in muscle invasive bladder cancer. The results are published by Dr. Jonathan E. Rosenberg of the Memorial Sloan Kettering Cancer Center in New York, NY, US, and colleagues on 27 June 2023 in the Journal of Clinical Oncology.
The authors wrote in the background that approximately half of all patients with locally advanced or metastatic urothelial cancer are ineligible for first-line cisplatin-based chemotherapy because of impaired renal function, poor performance status, and other comorbidities. Carboplatin plus gemcitabine is a commonly used regimen for cisplatin-ineligible patients, but has shown lower activity and poor tolerability. Other treatment options are limited to subgroups of patients; avelumab maintenance therapy is approved for patients who have remained free from disease progression after first-line platinum-based treatment and has shown improved survival; however, only patients who do not progress after 4 to 6 cycles of first-line treatment are eligible.
Single-agent immune checkpoint inhibitors may be another first-line treatment option for cisplatin-ineligible patients; however, they have become increasingly restricted to certain populations. Currently, in the US, pembrolizumab is limited to patients for first-line treatment who are not eligible for any platinum-based chemotherapy. Furthermore, approximately 60% of cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who receive first-line treatment do not receive second-line treatment. This underscores the need for efficacious and tolerable first-line therapies.
Enfortumab vedotin and pembrolizumab as single agents have shown overall survival benefits compared with second or third-line treatment in patients with locally advanced or metastatic urothelial cancer. In the phase Ib/II EV-103 study, results from the Dose Escalation/Cohort A demonstrated high antitumour activity and durable responses with encouraging survival and a manageable safety profile for enfortumab vedotin plus pembrolizumab, providing the rationale for further evaluation. Randomised Cohort K is intended to provide efficacy and safety data on the treatment combination. Monotherapy arm with enfortumab vedotin was included to better understand the safety and efficacy in first-line treatment of cisplatin-ineligible patients. No statistical comparison between treatment arms was performed.
In the latest article published in the Journal of Clinical Oncology, the authors present the efficacy and safety results of EV-103 randomised Cohort K for cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer treated with enfortumab vedotin plus pembrolizumab or enfortumab vedotin monotherapy in the first-line setting. In Cohort K of the EV-103 phase Ib/II study, patients were randomly assigned 1:1 to receive enfortumab vedotin as monotherapy or in combination with pembrolizumab. The primary endpoint was confirmed objective response rate per blinded independent central review. Secondary endpoints included DoR and safety.
The confirmed objective response rate was 64.5% (95% confidence interval [CI] 52.7 to 75.1) for 76 patients treated with enfortumab vedotin plus pembrolizumab and 45.2% (95% CI 33.5 to 57.3) for 73 patients treated with enfortumab vedotin monotherapy. 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%). Enfortumab vedotin TRAEs of special interest (any grade) in the combination arm included skin reactions (67.1%) and peripheral neuropathy (60.5%).
Most skin reactions and peripheral neuropathy events were grade ≤ 2 in severity. Skin reactions and pneumonitis are an identified part of the safety profile for both enfortumab vedotin and pembrolizumab monotherapy and were more frequently observed in the combination arm. Higher rates of skin reactions were managed with enfortumab vedotin treatment interruption, dose reduction, treatment discontinuation (enfortumab vedotin and/or pembrolizuimab), and/or corticosteroids.
The safety results highlight the importance of educating both healthcare practitioners and patients. Toxicities although manageable are increased over enfortumab vedotin alone and maturation of the survival data may also shed light on addressing toxicity, both clinical and financial, concerns as well as sequencing approaches.
The findings were previously presented at the ESMO 2022 Congress on 12 September 2022 in Paris, France.
The study was supported by Astellas Pharma US; Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, NJ; and Seagen Inc, EV-103/KN-869. It was supported by the US National Cancer Institute (NCI) award and in part by NCI grant.
Reference
O’Donnell PH, Milowsky MI, Petrylak DP, et al. Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. JCO; Published online 27 June 2023. DOI: 10.1200/JCO.22.02887