Episode 1: The EV-302/KEYNOTE-A39 study
Presented by Prof Emmanuel Seront (UCL Louvain) and Prof Christof Vulsteke (Maria Middelares Gent)
Professor Vulsteke is a principal investigator in the EV-302 trial, one of the most noteworthy studies presented at ESMO2023. This trial investigates the first-line treatment efficacy of the combined application of enfortumab vedotin (EV) and pembrolizumab (P) compared to the standard of care (SOC) chemotherapy in patients with locally advanced or metastatic urothelial carcinoma (la/m UC).
In recent times, several novel treatment protocols, including KEYNOTE-361, P with chemotherapy and IMvigor010, evaluating atezolizumab, have faced setbacks. The highly favourable outcomes observed in the EV-302 trial provide a sense of new hope for both patients and physicians.
In the context of the EV-302 trial, participants, regardless of their eligibility for cisplatin treatment or PD-L1 expression, were included. The control group, which received platinum-based chemotherapy, demonstrated a noteworthy median OS of 16 months. However, the combination of EV+P demonstrated a remarkable improvement, extending beyond 30 months, with an HR surpassing 0.40. PFS doubled from 6 to 12 months in the treatment arm, and the median DOR has not yet been reached, in contrast to the expected 7 months in the control arm. These impressive metrics, coupled with a response rate of 67.5%, including 30% complete responders, paint a promising picture.
It is noteworthy to mention a critical aspect of the trial, namely, the change in the SOC during patient recruitment. Initially, some patients received chemotherapy alone, but after reimbursement in Belgium, 30% of patients were offered the option of maintenance treatment with avilumab.
Regarding treatment duration, the durability of response is anticipated from checkpoint inhibition, while careful monitoring is advised for EV treatment. Experts recommend a thorough evaluation of patient status before initiation, particularly monitoring for skin toxicity signals in the initial and second cycles, prompting treatment interruption if necessary. Considering the cumulative nature of polyneuropathy, discontinuation until resolution to below grade 1 is considered a viable option. Glycemia should also be taken into consideration.
Importantly, the EV-302 trial demonstrated the feasibility of administering this regimen to cisplatin-ineligible patients. Experts find no inherent contradictions in this treatment approach, other than the well-known contraindications associated with checkpoint inhibition.
References:
Powles T et al. (2023). LBA6 EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC)) Antibody-drug conjugates: the evolving field of targeted chemotherapy for breast cancer treatment. Annals of Oncology 2023;34(S2), S1340.