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Bladder Cancer Awareness Month: Spotlighting Key Advances in the Paradigm
Volume 1
Issue 1

EV-302 Trial Ushers in Era of Novel Combos in First-Line Metastatic Urothelial Cancer

Joaquim Bellmunt, MD, PhD, discusses the impact of enfortumab vedotin plus pembrolizumab on the treatment paradigm in first-line urothelial cancer.

Joaquim Bellmunt, MD, PhD

Joaquim Bellmunt, MD, PhD

Effective frontline treatment options for patients with metastatic urothelial cancer continue to expand with the full FDA approval of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda), as well as the approval of nivolumab (Opdivo) plus gemcitabine and cisplatin,according to Joaquim Bellmunt, MD, PhD. He added that these approvals are sparking a complete shift in the management of metastatic urothelial carcinoma, and particularly address the need for alternatives to traditional cisplatin-based chemotherapy for ineligible patients.

The FDA’s decision to approve enfortumab vedotin plus pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma in December 2023 was supported by data from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856).1 The combination provided a statistically significant and clinically meaningful overall survival (OS) benefit vs traditional cisplatin- or carboplatin-based chemotherapy (HR, 0.47; 95% CI, 0.38-0.58; P < .0001) and was deemed tolerable.

This report followed a readout of data from the phase 3 CheckMate 901 trial (NCT03036098) evaluating the addition of nivolumab to cisplatin-based chemotherapy in metastatic or unresectable urothelial carcinoma. The regimen led to a median OS of 21.7 months (95% CI, 18.6-26.4) vs 18.9 months (95% CI, 14.7-22.4) with chemotherapy alone (HR, 0.78; 95% CI, 0.63-0.96; 2-sided P = .0171), and represents one of the first studies to demonstrate a prolonged survival benefit with concurrent checkpoint inhibitor and cisplatin-based chemotherapy administration in the front line.2 The regimen was later approved by the FDA for first-line use in March 2024.3

Although enfortumab vedotin plus pembrolizumab is considered the current standard of care (SOC) in frontline metastatic urothelial cancer, both the CheckMate 901 regimen and platinum-based therapies may still have utility for patients who cannot receive the regimen due to individual factors, limited accessibility, or treatment costs, Bellmunt noted.

“Enfortumab vedotin plus pembrolizumab is a big step forward, but we are still not curing our patients. They have prolonged survival, but we [still] need to do much better,” said Bellmunt, who is an associate professor at Harvard Medical School and director of the Bladder Cancer Center as part of the Genitourinary Oncology Program at the Dana-Farber Cancer Institute in Boston, Massachusetts.

In an interview with OncLive®, Bellmunt underscored the significance of enfortumab vedotin plus pembrolizumab for patients with locally advanced or metastatic bladder cancer, regardless of cisplatin eligibility; highlighted ongoing research efforts dedicated to bolstering the efficacy of enfortumab vedotin in triplet regimens or in combination with another antibody-drug conjugate (ADC); and discussed factors to consider when selecting between enfortumab vedotin plus pembrolizumab and other approved regimens in community practice.

OncLive: How has the EV-302 trial, which supported the FDA approval of enfortumab vedotin plus pembrolizumab, shifted the treatment paradigm in urothelial cancer?

Bellmunt: This study represents a significant advancement in the management of urothelial cancer. In fact, it is a paradigm shift. Now [the combination is] becoming the new SOC for patients with locally advanced or metastatic bladder cancer, including patients who are fit or unfit for cisplatin. That’s the new update because the trial included a comparison arm and did include patients who were receiving cisplatin-based chemotherapy and carboplatin-based chemotherapy.

Primary results from EV-302 showed an OS advantage with the immunotherapy-based regimen vs chemotherapy in the frontline setting. What was the significance of this achievement and how did this finding specifically influence subsequent reevaluations of global treatment guidelines in urothelial cancer?

I’m a member of the ESMO Guidelines Committee. We now have 3 trials that have level 1 evidence [showing a] survival advantage, and we cannot do cross-trial comparisons. However, in the guidelines, we finally said that enfortumab vedotin [plus pembrolizumab] is proposed as the optimal combination to use for frontline therapy in patients with advanced bladder cancer. This was based on the [combination producing a] median survival of 31.5 months, nearly doubling patient survival compared with standard chemotherapy, [which led to] a median overall survival of 16.1 months. A similar benefit in progression-free survival was seen [with the combination].

This regimen is now approved in the United States and several other countries, but not in all the countries in Europe. When writing these ESMO guidelines, [we need to] consider what to do if patients are not able to receive enfortumab vedotin plus pembrolizumab. These patients could receive alternative induction maintenance strategies, [such as cisplatin-based] chemotherapy followed by maintenance avelumab [Bavencio]. In patients who are fit for cisplatin, [they could also receive] the combination of cisplatin, gemcitabine, and nivolumab. There are some nuances. Because the approval for enfortumab vedotin plus pembrolizumab was initially so broad and then the benefit was seen across different subgroups of patients, [we felt that] this might be the preferred regimen [in first-line urothelial cancer]. This doesn’t mean it’s mandatory or [the only] regimen that can be used as first-line therapy in metastatic bladder cancer.

What is your advice for community oncologists regarding the successful integration of this regimen into clinical practice?

Those in the community are much more comfortable using enfortumab vedotin plus pembrolizumab in patients who are unfit because we know that carboplatin-based regimens are not the best for patients in the first line. Still, they are a bit reluctant to jump to enfortumab vedotin plus pembrolizumab, [as] you need to have some experience managing the adverse effects and neuropathy [associated with this regimen]. There are still a lot of nuances [when considering the use of] enfortumab vedotin plus pembrolizumab. If [oncologists are] treating occasional patients with bladder cancer, [they might be] more comfortable using cisplatin-based regimens followed by maintenance or combined with nivolumab.

In addition to [data from] the [phase 3] CheckMate-901 trial [NCT03036098], there was an unplanned analysis of patients from the [phase 3] JAVELIN Bladder 100 trial [NCT02603432] of maintenance avelumab. Patients who received cisplatin-based therapy [prior to maintenance avelumab] also achieved good [median OS, which] was 31.0 months [vs 25.8 months for patients given carboplatin prior to avelumab]. People are still convinced that cisplatin is a good option, but people will likely start using enfortumab vedotin plus pembrolizumab more because of [growing] experience.

With enfortumab vedotin plus pembrolizumab now considered the first-line SOC, where do you see the combination of nivolumab plus gemcitabine/cisplatin being used within the urothelial cancer treatment paradigm?

This is a broader question. The first question is whether cisplatin combinations with immunotherapy and maintenance could remain a viable option for select patients. As mentioned, the combination of cisplatin with gemcitabine and nivolumab did produce a survival benefit. There may be a subgroup of patients who could be eligible. This is because the high rate of complete responses seen with this combination is attractive. For patients who may not be candidates for [enfortumab vedotin plus pembrolizumab], cisplatin [and] gemcitabine [plus] nivolumab could be an option.

Are there any planned or ongoing research efforts to extend the benefits of enfortumab vedotin to other bladder cancer subtypes?

We have [several] trials [underway, including] one that was completed [recently. The phase 3 KEYNOTE-905/EV-303 trial (NCT03924895)] included patients who are unfit for neoadjuvant cisplatin-based therapy. In this trial, patients were randomly assigned to receive neoadjuvant pembrolizumab because they are cisplatin ineligible, to receive enfortumab vedotin plus pembrolizumab, or just straightforward cystectomy, [which] is the SOC [in this setting.] This trial has completed accrual and now we need to see the follow-up [data]. There is a component of adjuvant enfortumab vedotin and pembrolizumab in this trial, so there may be a [role for this combination] in the neoadjuvant setting.

There are even trials exploring this combination of an ADC plus immunotherapy in patients [who are] Bacillus Calmette-Guérin refractory, meaning that we are moving these regimens earlier and earlier. If these regimens are highly active in metastatic disease, they might [confer greater] benefit if moved to earlier disease stages.

Despite these advances, what unmet needs still need to be addressed for patients with bladder cancer in the advanced metastatic setting?

We reported [data from the phase 1 Double Antibody Drug (DAD) Conjugate trial (NCT04724018) evaluating] the combination of 2 ADCs: enfortumab vedotin, which is targeting Nectin-4, and sacituzumab govitecan-hziy [Trodelvy,] which is targeting TROP-2. This is [a study] that [we conducted] at Dana Farber. [In the DAD trial, we showed] that [it is] possible to combine 2 ADCs with no overlapping toxicity and with high response rates, and we published [these data] in the Annals of Oncology.

The next step is going to be moving to triplet regimens. In fact, we [will] have a phase 2 trial exploring the combination of enfortumab vedotin, sacituzumab govitecan, and pembrolizumab. Who knows whether this could be the next step moving forward from enfortumab vedotin plus pembrolizumab.

From here, there are other triplet therapies being explored in patients with first-line bladder cancer. Adding immunotherapy to compounds such as LAG3 inhibitors or others [is also being explored]. The future is going to be [focused on] testing whether a triplet therapy is better than dual therapy with enfortumab vedotin and pembrolizumab.

What message would you like to convey to colleagues regarding the future of urothelial cancer management?

We have more and more options [in urothelial cancer. Before] 2016, we only had chemotherapy. We have immunotherapy [with or without] ADCs now, and there are new compounds coming up. [Urothelial cancer research] is broad. ADCs [are being designed to] target Nectin-4 and TROP-2. We now have a compound, fam-trastuzumab deruxtecan-nxki [Enhertu], that can be used in patients with HER2-positive bladder cancer.

New targets being identified will broaden the options for our patients with bladder cancer. We have trials [investigating] potentially interesting targets that are, for example, [regulating] transcription factors. We have the PPARγ inhibitor, which is an oral compound that may be helpful for patients with luminal [bladder] cancers. It’s exciting to see a lot of advances in bladder cancer and the future [will hopefully] be bright for our patients.


  1. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed May 1, 2024.
  2. Opdivo (nivolumab) in combination with cisplatin-based chemotherapy followed by Opdivo demonstrates significant survival benefits for cisplatin-eligible patients with unresectable or metastatic urothelial carcinoma in phase 3 CheckMate-901 Trial. News release. Bristol Myers Squibb. October 17, 2023. Accessed May 10, 2024.
  3. FDA approves nivolumab in combination with cisplatin and gemcitabine for unresectable or metastatic urothelial carcinoma. FDA. March 6, 2024. Accessed May 1, 2024.

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