Enfortumab Vedotin/Pembrolizumab Extends PFS and OS in Metastatic Urothelial Cancer

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Article

Thomas Powles, MD, MBBS, MRCP, discusses key background information about the EV-302 trial; the efficacy and safety findings from this trial; and the future implications of the data from several emerging trials in urothelial cancer.

Thomas Powles, MD, MBBS, MRCP

Thomas Powles, MD, MBBS, MRCP

Enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda) produced statistically significant and clinically meaningful progression-free survival (PFS) and overall survival (OS) improvements vs chemotherapy, as well as a tolerable safety profile, in patients with previously untreated, locally advanced or metastatic urothelial carcinoma, according to Thomas Powles, MD, MBBS, MRCP.

In the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), the combination elicited a median PFS of 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5) in this patient population. Moreover, the median OS was 31.5 months (95% CI, 25.4-not reached) vs 16.1 months (95% CI, 13.9-18.3) with enfortumab vedotin/pembrolizumab and chemotherapy, respectively.

“The combination [of enfortumab vedotin plus pembrolizumab] is tolerable and in line with expectations, the [combination] works across broad subgroups of patients, and the control arm performed as expected,” Powles said in an interview with OncLive® during the 2023 ESMO Congress.

In the interview, Powles discussed key background information about the EV-302 trial; the efficacy and safety findings from this trial; and the future implications of the data from several emerging trials in urothelial cancer.

Powles is a professor of urology cancer at the University of London, as well as the director of the Barts Cancer Centre in the United Kingdom.

OncLive: What was the rationale for investigating enfortumab vedotin in combination with pembrolizumab in locally advanced or metastatic urothelial carcinoma?

Powles: Enfortumab vedotin is an antibody-drug conjugate [ADC]. It targets Nectin-4 and has monomethyl auristatin E as the payload. Pembrolizumab is a PD-1 inhibitor. Both [agents] are widely used in urothelial cancer, particularly in platinum-refractory disease in the second- or third-line setting. In urothelial cancer, chemotherapy, either gemcitabine/cisplatin or gemcitabine/carboplatin, has been the standard of care [SOC] for a generation. There’s been a desire to try and supersede that with non-chemotherapy or platinum chemotherapy regimens.

The rationale [for EV-302] was to combine these 2 active drugs. Enfortumab vedotin is good at getting control of the disease [and is] associated with durable responses. By combining [enfortumab vedotin and pembrolizumab], we hoped to show high response rates. We conducted the phase 2 [EV-103/KEYNOTE-869] trial [(NCT03288545) with this combination in patients with cisplatin-ineligible, locally advanced or metastatic urothelial carcinoma]. In [the dose-escalation, A, and K cohorts of] that study, we showed that the combination was associated with a 68% overall response rate [ORR], [and in cohort A, the combination elicited] a 12.7-month median PFS, and a 26.1-month median OS. [Those findings] looked higher in indirect comparisons [between this combination and] chemotherapy. For that reason, we embarked on a large, randomized phase 3 study comparing enfortumab vedotin plus pembrolizumab with standard chemotherapy in previously untreated patients with metastatic urothelial cancer. 

What were the methods and design of EV-302?

The EV-302 study focused on patients with first-line urothelial cancer. They had to have not had systemic therapy for advanced disease, and they had to have measurable cancer with adequate organ function, including adequate kidney function. [Patients also needed] to be eligible for gemcitabine/cisplatin or gemcitabine/carboplatin, [which is] standard chemotherapy, and have no contraindications to enfortumab vedotin or pembrolizumab.

The trial had 1:1 randomization [and was an] open-label trial with PFS and OS as the coprimary end points. [Patients in the chemotherapy arm received a maximum of] 6 cycles of chemotherapy. Pembrolizumab was given with enfortumab vedotin until disease progression. The trial followed a statistical analysis plan, and [at the 2023 ESMO Congress], we presented [findings from] the final analysis for PFS and the interim analysis that turned out to be the final analysis for OS, because that had positive results.

What were the key efficacy findings from this trial?

Eight-hundred and eighty-six patients were randomly assigned 1:1 [to receive either enfortumab vedotin/pembrolizumab or chemotherapy] in this trial. The population was characteristic of [that of the real-world] urothelial cancer [population]. [In the combination and control arms, respectively,] 71.9% and 71.6% of patients had visceral metastasis, 54.3% and 54.5% [of patients were eligible to receive] cisplatin-based therapy, and most patients had an ECOG performance status of 0 or 1. The population was nicely balanced between the 2 arms.

The median follow-up of the trial was 17.2 months. The results showed a dramatic increase in PFS [with enfortumab vedotin plus pembrolizumab vs chemotherapy]. The HR was 0.45, [translating to] a 55% reduction in the risk of progression [or death] compared with chemotherapy, which is somewhat unprecedented. More importantly, we also showed a 53% reduction in the risk of death [with the combination] with an HR of 0.47.

We have not previously managed to beat first-line chemotherapy in any trial in unselected, first-line urothelial cancer, so this is a big step in that direction. It’s important to recognize that there was a high response rate [with enfortumab vedotin plus pembrolizumab]: a 67.7% ORR and a 29.1% [complete response rate], which is impressive. The median duration of response has not yet been reached. This [trial had] a comprehensive suite of efficacy end points, all of which have been hit.

What is the safety profile of enfortumab vedotin plus pembrolizumab in this population?

The second component [of these trial findings] is the adverse effect [AE] profile. Grade 3/4 adverse effects occurred with chemotherapy in 70% of patients. With enfortumab vedotin plus pembrolizumab, [grade 3/4 AEs occurred] in 56% of patients.

AEs of special interest with enfortumab vedotin included skin toxicity, peripheral neuropathy, and hyperglycemia, all of which appeared manageable and in line with data we’ve seen in previous trials. Regarding treatment-related deaths, there were 4 in each arm. They were not related to skin toxicity, peripheral neuropathy, or hyperglycemia in the enfortumab vedotin arm.

It’s fair to say that these results are striking and transformative for patients with urothelial cancer. A 53% reduction in the risk of death is important, because we’ve never seen [outcomes] like that before in urothelial cancer. The control arm received 6 cycles of platinum-based chemotherapy. Thirty-one percent of those patients also received maintenance avelumab [Bavencio], which became the SOC during the conduct of the trial. Real-world data indicate that under 50% of patients get maintenance avelumab. [This trial had], at least in part, a contemporary control arm, [which] performed well in the OS component in the trial.

It’s also important to recognize the benefits we’ve seen [with enfortumab vedotin plus pembrolizumab] irrespective of [prior] platinum-based chemotherapy, PD-L1 status, [primary disease] site, and [metastatic category]. In summary, the trial is positive. These data will be important for doctors and patients moving forward.

What future research with enfortumab vedotin is on the horizon in urothelial cancer?

The future of urothelial cancer [management] is bright. These data will change the way we treat patients, but also front a series of new trials. Some of those trials are ongoing.

We’re studying enfortumab vedotin plus pembrolizumab and enfortumab vedotin plus durvalumab [Imfinzi] and tremelimumab-actl [Imjudo] in the neoadjuvant setting. We’re [investigating the administration of] enfortumab vedotin intravesically. We have a spectrum of [studies with] enfortumab vedotin [with or without] checkpoint inhibition, particularly pembrolizumab and durvalumab/tremelimumab, moving forward in muscle-invasive disease.

Additionally, the EV-302 data [reflect] the first combination of immune checkpoint inhibition and ADC therapy [across cancer types]. We need to explore this combination, because it’s been so active in urothelial cancer, in other cancers that have high expression of Nectin-4. This is an exciting time.

What other data were you excited to see presented at the 2023 ESMO Congress?

[The 2023 ESMO Congress] had several exciting presentations in bladder cancer. EV-302 was a prominent study, but there was the [phase 3] CheckMate-901 trial [NCT03036098] as well, investigating chemotherapy plus nivolumab [(Opdivo) in patients with advanced urothelial carcinoma]. There was also the [phase 3] THOR study [NCT03390504] evaluating erdafitinib [Balversa] vs pembrolizumab. The THOR study showed that erdafitinib, in patients with FGFR-altered disease, was not better than pembrolizumab from an OS perspective, although the response rate was higher. This highlights the activity of pembrolizumab in this disease. The results were somewhat unexpected. The CheckMate-901 trial with chemotherapy plus nivolumab also demonstrated an OS advantage [with the investigative combination] in cisplatin-eligible patients, with an HR of 0.78. The discussion about how those trials compare [with each other took] place during a plenary session.

Additionally, the [phase 3] LITESPARK-005 trial [NCT04195750] investigated a drug called belzutifan [Welireg], which is a HIF2 inhibitor, which was compared with everolimus [(Afinitor) in patients with advanced renal cell carcinoma]. Several belzutifan studies [were presented] at the meeting. [At the second interim analysis of LITESPARK-005, belzutifan elicited an ORR] of 22.7% and a 26% reduction in the risk of disease progression [or death]. That is impressive. [Belzutifan] is now established as an active agent in renal cancer. I’d like to see it move forward into the earlier disease setting and [be used] in combinations. It may help patients more there. 

Disclosures: Dr Powles reports consulting or advisory roles for Bristol-Myers Squibb, AstraZeneca, Ipsen, Pfizer, Novartis, Seagen Inc., Roche, Exelixis, MSD, Merck Serono, Astellas Pharma, Johnson & Johnson, Eisai, Mashup Ltd, Merck, and Incyte; travel, accommodations, and expenses from Pfizer, MSD, AstraZeneca, Roche, and Ipsen; honoraria from AstraZeneca, Eisai, Gilead Sciences, Merck, Merck Sharp & Dohme LLC, Novartis, Pfizer, Roche Laboratories Inc, Astellas Pharma, BMS GmbH & Co. KG, Exelixis, Incyte, Ipsen, Seagen Inc, Merck Serono, Johnson & Johnson/Janssen, Mashup Ltd; and research funding from AstraZeneca, Roche, Bristol-Myers Squibb, Exelixis, Ipsen, MSD, Novartis, Pfizer, Seagen Inc, Merck Serono, Astellas Pharma, Johnson & Johnson, and Eisai.

Reference

Powles TB, Perez Valderrama B, Gupta S, et al. 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). Ann Oncol. 2023;34(suppl 2):S1340. doi:10.1016/j.annonc.2023.10.106

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