Enfortumab Vedotin/Pembrolizumab vs Nivolumab/Chemo: Selecting a Frontline Therapy for Advanced Urothelial Carcinoma


Thomas Flaig, MD, discusses how enfortumab vedotin/pembrolizumab and nivolumab/chemotherapy fit in the frontline treatment of advanced urothelial carcinoma.

Thomas Flaig, MD

Thomas Flaig, MD

Following the December 2023 and March 2024 FDA approvals of enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda) and nivolumab (Opdivo) in combination with cisplatin and gemcitabine for the frontline treatment of patients with unresectable or metastatic urothelial carcinoma, respectively, clinicians are now tasked with selecting an appropriate regimen for patients in this setting, according to Thomas Flaig, MD.

The approval of enfortumab vedotin plus pembrolizumab was supported by findings from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), which showed that the combination improved overall survival (OS; HR, 0.47; 95% CI, 0.38-0.58; P <.0001) and progression-free survival (PFS; HR, 0.45; 95% CI, 0.38-0.54; P <.0001) compared with platinum-based chemotherapy.1

The regulatory decision for nivolumab plus chemotherapy was based on data from the phase 3 CheckMate 901 study (NCT03036098), which demonstrated that nivolumab plus gemcitabine/cisplatin improved OS (HR, 0.78; 95% CI, 0.63-0.96; 2-sided P = .0171) and PFS (HR, 0.72; 95% CI, 0.59-0.88; 2-sided P = .0012) vs gemcitabine/cisplatin alone.2

“As I hear people talk about [enfortumab vedotin plus pembrolizumab vs nivolumab plus gemcitabine/cisplatin], due to the strength of the efficacy data with enfortumab vedotin [plus pembrolizumab], many providers [may be] likely to [select] that [regimen in the frontline setting for patients with advanced urothelial carcinoma], and the role for the nivolumab plus gemcitabine/cisplatin may be defined better over time,” Flaig explained.

In an interview with OncLive®, Flaig, a medical oncologist and the vice chancellor for research at the University of Colorado (CU) Denver, CU Anschutz Medical Campus, expanded on the evolution of enfortumab vedotin in the urothelial carcinoma realm and the data that supported its frontline approval in combination with pembrolizumab; and detailed where nivolumab plus gemcitabine and cisplatin could fit into the treatment paradigm alongside enfortumab vedotin plus pembrolizumab.

OncLive: How have recent FDA approvals altered the frontline treatment space for advanced urothelial carcinoma?

Flaig: For a very long time, there weren't any developments in [the treatment of patients with advanced urothelial carcinoma], and that has really changed in the last few years. Some years ago, we saw the addition of immune checkpoint inhibitors to the armamentarium for metastatic urothelial carcinoma. In the last 3 to 5 years, antibody-drug conjugates [entered] the picture as additional options.

The big theme of my recent presentation at the National Comprehensive Cancer Network [NCCN] was combination [therapy in metastatic urothelial carcinoma]. There are 2 main combinations: enfortumab vedotin plus pembrolizumab and nivolumab plus gemcitabine/cisplatin. These are 2 first-line therapy options for metastatic urothelial carcinoma that have incorporated immune checkpoint inhibitors.

What were some of the key highlights from the data for enfortumab vedotin plus pembrolizumab?

Enfortumab vedotin came into picture a number of years ago and it represented an active subsequent line of therapy. This is an ADC [with] a target of NECTIN-4 and payload of monomethyl auristatin E [MMAE], which is a very potent anti-microtubule agent. In later-line settings [in the phase 3 EV-301 trial (NCT03474107)], we had a control arm with [investigator’s choice of] taxane-based chemotherapy with an overall response rate [ORR] of 17.9% [95% CI, 13.7%-22.8%]. However, with enfortumab vedotin, we had an active agent with an ORR of 40.6% [95% CI, 34.9%-46.5%].3 There was a lot of excitement at that time [because] we had a much more active subsequent line of therapy.

More recently, we've taken pembrolizumab and added it to enfortumab vedotin. In [data from] the phase 3 [EV-302] study recently published in March 2024 in the New England Journal of Medicine, we saw an ORR for first-line urothelial carcinoma of 67.7% [95% CI, 63.1%-72.1%] with enfortumab vedotin plus pembrolizumab vs 44.4% [95% CI, 39.7%-49.2%] in the control arm with cisplatin or carboplatin plus gemcitabine.4

Patients who were both cisplatin-eligible and -ineligible were included in [EV-302]; and [cisplatin or carboplatin plus gemcitabine] had been our active regimen. If you look back over the last 10 or 20 years, the combination of gemcitabine with 1 of these platinum-based chemotherapies has been a standard first-line therapy. Essentially, with positivity in this trial, we moved aside a long-standing first-line regimen.

In terms of PFS, the hazard ratio [HR] favoring enfortumab vedotin was 0.45, [translating to a 55%] improvement in [the risk of disease progression or death] with enfortumab vedotin. When we look at OS, the HR was 0.47 [for a 53%] improvement in [the risk of death] with still somewhat limited follow-up of this trial.

We've had a standard of care in gemcitabine/cisplatin for decades, and in rather dramatic fashion, we've seen this new combination of enfortumab vedotin plus pembrolizumab show superiority in efficacy to that regimen.

For community oncologists who may be more familiar with prescribing enfortumab vedotin alone or an immune checkpoint inhibitor alone, what should they be aware of regarding the use of enfortumab vedotin in combination with pembrolizumab in the frontline setting?

There is this active combination where you're seeing a very high ORR and significant improvements in PFS and OS; however, how's it tolerated? For oncologists who have used enfortumab vedotin or pembrolizumab alone, you're going to see both adverse effect [AE] profiles represented [with the combination; however, I wouldn't necessarily say there are any worsening or additive, synergistic-type AEs. In my experience, you can see both AE [profiles] come together.

Some [safety concerns] that are notable about this combination would be neuropathy, which is something that has been monitored carefully. There is some NECTIN-4 expression, which is the target of enfortumab vedotin, in cutaneous tissues; you must look carefully for skin toxicity. This should be something that you talk to your patients about. In addition, for patients who have a higher body mass index or a history of diabetes, you have to watch carefully. That AE is not talked about as much with enfortumab vedotin in this combination, but you can see elevated blood sugar and worsened diabetic control, and some serious cases of that have been reported.

Does it hurt treatment decision-making to not have biomarker of response for enfortumab vedotin plus pembrolizumab?

Patients [treated with] the combination of enfortumab vedotin or pembrolizumab aren't necessarily biomarker selected. Therefore, this [combination] could be used very widely. For example, if you look at the NCCN Guidelines, which have recently been updated with this publication [of the EV-302 data], enfortumab vedotin [plus pembrolizumab] is now the preferred first-line therapy for both cisplatin-eligible and -ineligible patients, which is a substantial difference.

One question would be: what about the biomarker for enfortumab vedotin? You need NECTIN-4 expression for this to work. Some of the early trials looked at NECTIN-4 expression, and since such a high percentage of patients did have expression of NECTIN-4, it wasn't felt as necessary to screen for that. We do have some biomarkers for immune checkpoint inhibitors, such as PD-L1 [combined positive score] or tumor mutational burden. When you have an ORR that's so high, the biomarkers may play less of a role for [treatment selection], at least at this point. Over time, we hope we can refine [biomarkers for this combination] and identify patients who aren't as likely to respond to this therapy. For the time being, [the combination] is open to patients regardless of biomarker status.

Although frontline enfortumab vedotin plus pembrolizumab was approved prior to frontline nivolumab plus chemotherapy, what role will the latter regimen play in the treatment of advanced urothelial carcinoma?

If we had seen the publication [of the data for nivolumab plus chemotherapy from the phase 3 CheckMate 901 trial (NCT03036098)] at any other time in the last 10 years, it would have been blockbuster news. With gemcitabine/cisplatin [plus] nivolumab, we saw the ORR go from 43.1% [95% CI, 37.5%-48.9%] with chemotherapy [alone] to 57.6% [95% CI, 51.8%-43.1%] with the [nivolumab] combination [in CheckMate 901]. We saw significant changes and improvement in PFS [HR, 0.72; 95% CI, 0.59-0.88; 2-sided P = .0012] and OS [HR, 0.78; 95% CI, 0.63-0.96; 2-sided P = .0171]. These were meaningful and statistically significant improvements in [PFS and OS]; however, with the enfortumab vedotin data coming out around the same time, it will take time to understand how [nivolumab plus gemcitabine/cisplatin] fits into [the frontline treatment paradigm].

I have heard some investigators say that because [nivolumab plus gemcitabine/cisplatin] is a limited duration of chemotherapy—up to 6 cycles—that may be preferred for some patients, rather than having the more open-ended use of enfortumab vedotin in the other regimen.


  1. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed May 2, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
  2. FDA approves nivolumab in combination with cisplatin and gemcitabine for unresectable or metastatic urothelial carcinoma. FDA. March 6, 2024. Accessed March 7, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-combination-cisplatin-and-gemcitabine-unresectable-or-metastatic-urothelial
  3. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-1135. doi:10.1056/NEJMoa2035807
  4. Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390(10):875-888. doi:10.1056/NEJMoa2312117
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