Enfortumab Vedotin/Pembrolizumab Signals Shift in Urothelial Carcinoma Treatment Paradigm

Matthew Galsky, MD

The expanded FDA approval of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) for patients with urothelial carcinoma represents one of the first successful improvements upon standard, frontline platinum chemotherapy in decades and provides patients in this population with a new, highly effective first-line standard of care, according to Matthew Galsky, MD.

The FDA granted full approval to enfortumab vedotin plus pembrolizumab for patients with previously untreated, locally advanced or metastatic urothelial cancer on December 15, 2023.¹ This regulatory decision was based on data from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), in which the combination produced a statistically significant survival benefit vs cisplatin- or carboplatin-based chemotherapy and was deemed safe and tolerable in this population.

Patients treated with enfortumab vedotin plus pembrolizumab experienced a median progression-free survival (PFS) of 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5) in the platinum-based chemotherapy arm (HR, 0.45; 95% CI, 0.38-0.54; P < .0001). Additionally, the median overall survival (OS) was 31.5 months (95% CI, 25.4-not estimable) vs 16.1 months (95% CI, 13.9-18.3) with the combination vs chemotherapy, respectively (HR, 0.47; 95% CI, 0.38-0.58; P < .0001).

“There are major implications of these findings both in terms of advancing the field for the first time in decades and based on the effect size, as this was not a small benefit that was seen; it was a large benefit,” said Galsky, who is a professor of medicine, director of genitourinary medical oncology, co-director of the Center of Excellence for Bladder Cancer, and the associate director for translational research at the Tisch Cancer Institute at Mount Sinai in New York City, New York.

In an interview with OncLive^®, Galsky highlighted the main implications of this approval for the frontline treatment paradigm in urothelial cancer; key efficacy and safety data with the regimen as seen in the EV-302 trial; and how this research inspired ongoing trials attempting to address remaining questions in the frontline setting.

OncLive: What is the significance of the FDA approval of enfortumab vedotin plus pembrolizumab for patients with urothelial cancer?

Galsky: For the first-line treatment of patients with metastatic urothelial cancer, there’s been no progress in treatment over several decades. Platinum-based chemotherapy combinations were developed many decades ago, and there has been a series of phase 3 trials trying to improve upon those. There was no benefit shown in a series of phase 3 studies until the 2023 ESMO Congress, where 2 studies were presented in the same session demonstrating improvements in survival [with regimens] beyond platinum-based chemotherapy alone. One of those [studies] was EV-302, which studied enfortumab vedotin plus pembrolizumab vs platinum-based chemotherapy. The trial showed a marked survival benefit with the combination.

Please expand on the design and methodology of the EV-302 trial. What key efficacy findings from EV-302 supported this regulatory decision?

EV-302 assessed enfortumab vedotin plus pembrolizumab vs platinum-based chemotherapy. In this study, eligible patients included those who could receive cisplatin- or carboplatin-based chemotherapy, so [patients on] the control arm [received] a mix of the 2 [chemotherapy regimens]. The key efficacy metrics were overall response rate [ORR], PFS, and OS.

The ORR with platinum-based chemotherapy was 44.4%, whereas the ORR was 67.7% with enfortumab vedotin plus pembrolizumab. [There was also] an improvement in the rates of complete responses, at 12.5% with platinum-based chemotherapy vs 29.1% with enfortumab vedotin plus pembrolizumab. The median PFS was 6.3 months with platinum-based chemotherapy vs 12.5 months with enfortumab vedotin plus pembrolizumab, with an HR of 0.45. A median OS of 16.1 months [was achieved] with platinum-based chemotherapy vs a median OS of 31.5 months with enfortumab vedotin plus pembrolizumab, with an HR of 0.47.

What should be known about the safety profile of this combination in urothelial cancer based on the current body of research?

There are different safety profiles with platinum-based chemotherapy vs enfortumab vedotin plus pembrolizumab. There are largely non-overlapping adverse effects [AEs] between the 2 regimens. AEs to look out for with enfortumab vedotin plus pembrolizumab are rash, which can range from mild to more serious; peripheral neuropathy, which tends to be a cumulative, treatment-related AE; and hyperglycemia, which can occur in some patients treated with enfortumab vedotin. Those are the key AEs to look out for [that are] somewhat unique to this combination regimen. Cytopenias, [which] we see with platinum-based chemotherapy, tend not to be a major issue with enfortumab vedotin plus pembrolizumab.

Where does enfortumab vedotin plus pembrolizumab fit into the current treatment armamentarium in urothelial cancer, considering positive data from the phase 3 CheckMate 901 study (NCT03036098)?

EV-302 was a clinical trial exploring enfortumab vedotin plus pembrolizumab vs platinum-based chemotherapy in all comers for the frontline treatment of [patients with] metastatic urothelial cancer. Based on the effect size, and since there does not seem to be a difference in the effect size when conducting subset analyses in patients who received cisplatin- vs carboplatin-based chemotherapy on the control arm, enfortumab vedotin plus pembrolizumab was [shown to be a] first-line standard treatment in an all-comer population.

[Findings from] the CheckMate 901 study of gemcitabine/cisplatin vs gemcitabine/cisplatin plus nivolumab [Opdivo] were [presented] at the 2023 ESMO Congress and are now published in the New England Journal of Medicine. This [trial evaluated] a slightly different patient population [than that observed in EV-302], as [the population] was restricted to patients who were cisplatin eligible. CheckMate 901 also shows a survival benefit [with the nivolumab plus chemotherapy combination] compared with gemcitabine/cisplatin alone. Perhaps there are some patient characteristics for which 1 regimen, [either enfortumab vedotin plus pembrolizumab or gemcitabine/cisplatin plus nivolumab] might be considered over the other, but for the overall [population of] patients with metastatic urothelial cancer in the frontline setting, based on the results of [these 2 trials], enfortumab vedotin plus pembrolizumab represents a first-line treatment standard.

Looking ahead, what other studies in urothelial cancer are you or your colleagues highly anticipating, and how might this research address unanswered questions in the field?

There are 2 remaining questions in the frontline treatment of patients with metastatic urothelial cancer. A generation of studies all initiated around the same time asked some similar questions. One study [from which data are pending] combined chemotherapy with immune checkpoint blockade. That’s the [phase 3] NILE study [NCT03682068], which randomly assigned patients to receive platinum-based chemotherapy or platinum-based chemotherapy plus PD-L1 blockade with durvalumab [Imfinzi] or a quadruplet regimen of platinum-based chemotherapy plus durvalumab plus tremelimumab [Imjudo], PD-L1 blockade plus CTLA-4 blockade. We haven’t seen those results yet.

The other results we haven’t seen yet are from the CheckMate 901 study. One portion [this trial] is comparing ipilimumab [Yervoy] plus nivolumab vs platinum-based chemotherapy. The final story of CTLA-4 blockade in the frontline treatment of patients with metastatic urothelial cancer has not been written yet. We need to see the results from those 2 pending studies.

After those 2 pending studies, there’s a gap in studies initiated in the frontline [setting] in patients with metastatic urothelial cancer because a lot of the community was waiting for the results of the EV-302 study. Now that EV-302 has been read out, studies are moving forward in the frontline setting in patients with metastatic urothelial cancer. One intriguing study, [the phase 3 DV-001 trial (NCT05911295)] will investigate whether an anti-HER2 antibody-drug conjugate plus immune checkpoint blockade yields beneficial results in that setting. We look forward to seeing the results from that phase 3 study in the future.

Reference

FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed February 14, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer