The expansion of tools and treatment options for patients with bladder cancer with the addition of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda), as well as nivolumab (Opdivo) plus gemcitabine/cisplatin, to the first-line arsenal has led to a shift in optimism and changing mindsets regarding prognosis for both patients and providers, according to Peter H. O’Donnell, MD, who added that more research is needed to identify which patients are most likely to respond to these regimens.

To continue pushing the needle forward in urothelial cancer, oncologists are now awaiting results from ongoing studies with immunotherapy in the perioperative setting; considering questions around re-treatment with immunotherapy-based regimens in the event of recurrent disease; and exploring combinations of antibody-drug conjugates (ADCs) with or without immunotherapies in later lines, O’Donnell detailed in an interview with 

“My main message to providers is don’t think that it’s still 1995, because the tools have changed dramatically,” said O’Donnell, who is a faculty physician and associate professor of medicine at the University of Chicago in Illinois. “Therefore, the optimism and outlook that we have for patients [with bladder cancer] coming through our door should be completely different.”

In the interview O’Donnell shared his insights on exciting developments in bladder cancer treatment, including the significance of having enfortumab vedotin plus pembrolizumab for patients with locally advanced or metastatic bladder cancer, and ongoing efforts to move these agents into earlier lines; how emerging agents in non–muscle-invasive bladder cancer (NMIBC) could engender earlier intervention and improved survival; and how combination regimens with ADCs and immunotherapy could improve response rates beyond those seen with the current standard of care (SOC).

: How have data from the the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), which supported 

the FDA approval of enfortumab vedotin plus pembrolizumab

1 shifted the treatment paradigm in urothelial cancer?

: Enfortumab vedotin plus pembrolizumab has revolutionized the way we’re treating [patients with] metastatic urothelial cancer. It has completely changed the paradigm. We used to think that all patients have to get platinum [chemotherapy] as their first treatment. That’s been turned upside down now because survival [outcomes with] enfortumab vedotin plus pembrolizumab [were] nearly double [that of] platinum-based therapy. It’s hard to argue with that, and I find myself hard pressed to justify giving anything but this regimen in the frontline setting.

 has also joined the first-line urothelial cancer treatment arsenal alongside enfortumab vedotin plus pembrolizumab. What is the significance of having this additional regimen available for patients?

The urothelial cancer field had [conducted] prior trials looking at the idea of combining immunotherapy with platinum-based chemotherapy, but it had not panned out. The difference [in the phase 3 CheckMate-901 study (NCT03036098)] was that this was a cisplatin-only treated population where the immunotherapy was being combined. Now we see a positive trial. The biggest takeaway from that dataset is that there are patients who can [achieve] a complete response [CR] with cisplatin-based therapy combined with immunotherapy in [the form of] a triplet regimen, and that those CRs [can be] quite durable. That was the most eye-catching part of those data. The other take-home [message] is that there is maintenance therapy built into that triplet. It’s a triplet upfront but [it involves] maintenance nivolumab in that trial. [This] recapitulates the data that we had seen before [indicating] that maintenance immunotherapy makes a difference in this disease.

What factors could help identify patients who may achieve a CR with the nivolumab triplet and help guide treatment decision-making?

Those are probably patients who we knew about before who have lymph node only or lymph node–predominant disease, a lack of liver metastases, and a lack of bone metastases. These patients are much more likely to [achieve] a durable CR. [However], they might be the same patients who also experience durable responses with enfortumab vedotin plus pembrolizumab. [Identifying those factors is] not helping us choose a regimen, it’s probably just identifying patients who are likely to do better overall.

Could enfortumab vedotin with or without pembrolizumab have utility in the perioperative setting prior to the development of metastatic or locally advanced disease?

[This regimen is] being studied right now in the perioperative setting, and we will await those data. There have been some early data already released about enfortumab vedotin as a single agent in the preoperative space, and there’s been data on immunotherapy in the preoperative space. The combination is showing tremendous efficacy in the metastatic setting. We wonder if that will also bear fruit in the perioperative space, but [that remains] to be seen. If we do see positive data there, the question will become, “What are we going to do in the first line [for] metastatic disease if a patient should progress after getting enfortumab vedotin plus pembrolizumab the perioperative setting?” That’s when we will [have to ask,] “How long has it been since they received these agents, and what is the advantage of switching [therapy] if the patient recurs?” Those will be the types of questions [we ask], which are great questions to have, because we now have many active agents.

What ongoing research in early-stage bladder cancer is generating excitement?

We’re seeing an explosion of agents that are being approved or are likely to be approved in the near future in NMIBC. If we start to see more activity there, it’s hopefully going to prevent patients from having MIBC and therefore [developing] metastatic disease. We get this possible survival benefit by capturing patients even before they [develop] metastatic [disease]. There’s a lot of excitement there. There are exciting data coming out for some of these new intravesical therapies showing high response rates and durability. If that [continues to prove] true, then we have a chance to [improve] disease [outcomes], as the chance for cure is before the patient [presents with] metastatic [disease] in most cases.

As the development of ADCs for patients in later lines continues, what questions must be answered to successfully grow this treatment class?

[One of] the questions on the table now is [whether] we are going to be combining ADCs or combining ADCs and then [adding] immunotherapy. The response rate we’re seeing for enfortumab vedotin plus pembrolizumab right now is approximately 70%. Can we think about regimens that push that response rate to [higher] levels that we never thought were possible? That’s on the table as being something to strive for with these combinations. The [issue] will be tolerability. When we start adding more agents, [we must ask whether] these patients are going to be able to tolerate so many agents together. [Additionally,] do we think about selecting patients based on the likelihood of expression of a given marker and what the mechanisms of resistance are? If a patient progresses on 1 ADC, is it because they’re resistant to the target, or is it the payload being resistant? Those questions will determine how we think about future ADCs.

What is your main message for colleagues regarding the impact of these advances and research on the bladder cancer realm?

It’s such an exciting time in bladder cancer treatment. For most providers, this was a disease where we had essentially 1 option for many decades: platinum-based chemotherapy. For many patients, it was carboplatin-based therapy, and we know that that [doesn’t produce very] durable [responses] for most patients. There was a tendency for providers to [have a] real pessimistic view when a patient with bladder cancer would come into their clinic, knowing that the tools we had were not very promising. This has completely changed. There is an opportunity to salvage even patients who are rapidly progressing. If a patient has a performance status that’s rapidly declining, and it’s because of cancer, agents such as enfortumab vedotin can resurrect those patients and it happens over and over again.

FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed May 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer

FDA approves nivolumab in combination with cisplatin and gemcitabine for unresectable or metastatic urothelial carcinoma. FDA. March 6, 2024. Accessed May 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-combination-cisplatin-and-gemcitabine-unresectable-or-metastatic-urothelial

Articles

Peter H. O’Donnell, MD, provides insights on key developments in bladder cancer management and how they have generated optimism within the field. 

Expansion of Frontline Immunotherapy Regimens Improves Prognosis, Increases Optimism in Urothelial Cancer 

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.

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).

 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; 

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 

 = .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.

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.

, 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.

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

 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 

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.

FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed May 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer

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. https://news.bms.com/news/details/2023/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/default.aspx

FDA approves nivolumab in combination with cisplatin and gemcitabine for unresectable or metastatic urothelial carcinoma. FDA. March 6, 2024. Accessed May 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-combination-cisplatin-and-gemcitabine-unresectable-or-metastatic-urothelial

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

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

Dr Siefker-Radtke on Toxicities With Enfortumab Vedotin Plus Pembrolizumab in Bladder Cancer

Arlene O. Siefker-Radtke, MD, professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses toxicities associated with the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) in patients with metastatic bladder cancer.

Enfortumab vedotin combined with pembrolizumab carries a boxed warning due to the risk of Stevens-Johnson Syndrome, which is a severe skin reaction, Siefker-Radtke begins. This reaction may be linked to enfortumab vedotin’s targeting of Nectin-4, which is expressed in skin tissue, leading to skin desquamation in affected patients, according to Siefker-Radtke. Additionally, there is increased toxicity associated with enfortumab vedotin in patients with borderline liver function, she explains, adding that it is recommended to avoid using enfortumab vedotin in patients with moderate-to-severe liver dysfunction. Other antibody-drug conjugates using the vedotin payload have been associated with increased liver toxicity, indicating potential risks in this patient population, Siefker-Radtke states.

For patients with a borderline Child-Pugh score of A to B, initiating treatment with a reduced dose of enfortumab vedotin may be attempted; however, many patients experience significant toxicity, making treatment continuation challenging, she notes. Monitoring for skin toxicity is crucial during treatment; if patients exhibit blistering, peeling of the skin, or a diffuse beefy erythematous rash, this may signal the onset of severe skin toxicity and warrant dose adjustment or discontinuation, Siefker-Radtke reports. Hyperglycemia should also be closely monitored, as elevated fasting glucose levels above 250 mg/dL may indicate toxicity and increase the risk of insulin-resistant diabetic ketoacidosis, Siefker-Radtke emphasizes.

Furthermore, patients with underlying liver cirrhosis require careful monitoring and consideration when administering enfortumab vedotin, especially those with a truly cirrhotic liver, Siefker-Radtke expands. Given the challenges posed by toxicity in patients with borderline Child-Pugh scores of A to B, alternative treatment options, such as gemcitabine/cisplatin plus nivolumab (Opdivo) should be considered to optimize safety and efficacy, she says. These recommendations underscore the importance of vigilant monitoring and personalized treatment strategies to mitigate risks associated with enfortumab vedotin and pembrolizumab combination therapy, particularly in vulnerable patient populations, Siefker-Radtke concludes.

Videos

Arlene O. Siefker-Radtke, MD, discusses toxicities associated with enfortumab vedotin plus pembrolizumab in patients with bladder cancer.


Dr Siefker-Radtke on the Safety of Enfortumab Vedotin Plus Pembrolizumab in Bladder Cancer

Joaquim Bellmunt, MD, PhD, discusses how the FDA approval of enfortumab vedotin plus pembrolizumab impacts the urothelial cancer treatment paradigm.

Dr Bellmunt on the Impact of Treatment With Enfortumab Vedotin Plus Pembrolizumab in Urothelial Cancer

Joaquim Bellmunt, MD, PhD, associate professor of medicine, Harvard Medical School; director, Bladder Cancer Center, Genitourinary Oncology Program, Dana-Farber Cancer Institute, discusses the significance of the full FDA approval of treatment with enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial carcinoma, highlighting how this decision has impacted global treatment recommendations for patients in the frontline setting.

FDA approval of enfortumab vedotin plus pembrolizumab

 for locally advanced or metastatic urothelial carcinoma marked a significant advancement in frontline therapy, Bellmunt begins. The decision was supported by data from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), in which the combination demonstrated a substantial overall survival (OS) benefit compared with traditional cisplatin- or carboplatin-based chemotherapy and was well tolerated, he reports. This led to its inclusion as a recommended frontline treatment regimen by the ESMO Guidelines Committee, of which Dr Bellmunt serves as a member.

approval of nivolumab (Opdivo) plus cisplatin-based chemotherapy

 in first-line metastatic or unresectable urothelial carcinoma, supported by data from the phase 3 CheckMate 901 trial (NCT03036098), provided additional options for frontline treatment, Bellmunt continues. The significant improvement in median OS that was achieved with this triplet regimen underscores the evolving landscape of immunotherapy-based approaches in bladder cancer management, he states.

These trials provide level 1 evidence of a survival advantage when using immunotherapy-based approaches vs traditional chemotherapy, Bellmunt says. Although cross-trial comparisons cannot be performed, the consensus that emerged from these investigations supported enfortumab vedotin plus pembrolizumab as the optimal frontline therapy based on its substantial survival benefit, he details. This recommendation considers the broad initial approval and consistent benefit observed with the regimen across various patient subgroups, Bellmunt expands.

Despite the regimen’s proven efficacy, challenges remain regarding access to approved therapies globally. Bellmunt adds that there are several European countries where enfortumab vedotin plus pembrolizumab may not yet be available. Alternative induction-maintenance strategies, such as chemotherapy followed by maintenance avelumab (Bavencio) or cisplatin-based combinations with nivolumab offer viable options for patients unable to receive the preferred regimen, he says.

Overall, the incorporation of these novel combinations into treatment guidelines reflects a paradigm shift in bladder cancer management, emphasizing the importance of tailored approaches to optimize patient outcomes and address unmet needs in different health care settings, Bellmunt concludes.

The combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda), which is becoming more widely used for patients with locally advanced or metastatic urothelial carcinoma, should be used as a foundation for the further investigation of targeted agents in this patient population, according to Jonathan E. Rosenberg, MD.

“[These are] still not curative agents, so we need to consider what [else we can] do, but it’s gratifying to see that change,” Rosenberg said in an interview with 

the FDA granted full approval to enfortumab vedotin plus pembrolizumab

 for the treatment of patients with locally advanced or metastatic urothelial cancer. This regulatory decision was supported by findings from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), in which the combination elicited statistically significant improvements in overall survival (OS) and progression-free survival (PFS) vs platinum-based chemotherapy in the frontline setting.

the FDA approved frontline nivolumab (Opdivo) plus cisplatin and gemcitabine

 for the first-line treatment of adult patients with unresectable or metastatic urothelial cancer.

 In the pivotal phase 3 CheckMate 901 trial (NCT03036098), the combination generated statistically significant OS and PFS benefits vs cisplatin and gemcitabine alone.

In the interview, Rosenberg discussed how these approvals have revolutionized the standard of care for patients with locally advanced or metastatic bladder cancer, potential future directions with enfortumab vedotin for patients with this disease, and the growing role of Nectin-4–directed antibody-drug conjugates (ADCs) in this armamentarium.

Rosenberg is chief of the Genitourinary Oncology Service in the Division of Solid Tumor Oncology and the Enno W. Ercklentz, Jr. Chair at Memorial Sloan Kettering Cancer Center (MSK) in New York, New York.

: What has been the significance of the full FDA approval of enfortumab vedotin plus pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma?

: Data from EV-302 blew away the distinctions around the types of treatments patients should receive for first-line metastatic disease. We had spent decades debating cisplatin eligibility, who’s ineligible and who’s eligible. In 1 broad stroke, EV-302 eliminated that whole debate.

The results are dramatically better for patients who receive enfortumab vedotin plus pembrolizumab, regardless of the type of chemotherapy they get and regardless of platinum eligibility. The results aren’t subtle. [We saw] a doubling of PFS, a doubling of OS, and hazard ratios of approximately 0.5 or less [with the combination compared with platinum-based chemotherapy], which transformed the field quickly. 

In the United States [(US), this combination] has full approval; around the world, access is spotty. Eventually [this combination may] become the global first-line standard until maybe something better comes along. It’s been exciting to see that change.

The primary progression rate with this combination seems quite low, at approximately 10%. Although [primary progression] does happen, most patients experience a response. The confirmed overall response rate was 67.7%, and 29.1% of patients had complete responses [CRs]. We haven’t seen the data on duration of CR from the phase 3 trial, but my guess is it’s long. I’m hopeful we might be giving durable, long-term remissions to some of these patients. 

The long-term follow-up data from the [phase 1/2] EV-103 trial [NCT03288545] indicate that approximately 40% of cisplatin-ineligible patients from the first cohort [are surviving for years]. That’s astounding considering [the historical OS rate in this patient population was approximately] 15% at 5 years. Hopefully we will see updated data over the next several years, both from the phase 2 and phase 3 trials with the combination. [This is an] extraordinary leap forward.

What advice do you have for community oncologists who may not be as familiar with using an agent such as enfortumab vedotin?

The combination [of enfortumab vedotin and pembrolizumab] is administered on a 3-week schedule, not a 4-week schedule like [we do for] enfortumab vedotin monotherapy, [which is] a practical point. [We need to monitor] patients [more] frequently earlier on in the course of treatment.The severe skin toxicity we hear about with enfortumab vedotin tends to occur within the first 1 to 2 months. Perhaps you don’t need to see patients at every day 8 visit going forward after the first few cycles, but in the beginning, make sure they’re seen frequently, because that’s when life-threatening toxicity might emerge. 

Over time, peripheral neuropathy becomes the more prominent problem [because] patients who are responding are on treatment for quite a while. The sensory and motor neuropathy can be bothersome, and sometimes, if not managed, can be incapacitating. Dose reductions [can make treatment more manageable] for those patients.

The skin toxicities are frequent early in the course of disease but [you can often] get them under control. I have a friend who is a dermatologist to help manage some of [these toxicities]. By seeing patients early during treatment and recognizing the onset of some of these skin toxicities, you can ameliorate them or abort them by holding the dose, reducing the dose, and having an intervention [ready] such as topical steroids and maybe [other forms of] steroids, depending on the severity [of the toxicities] and what you think the cause is. My general experience is that many of these patients do well even with the skin toxicity. As long as it’s not the severe blistering type of skin toxicity, it can be managed, and treatment can be continued, although sometimes with a break.

In what other treatment settings might enfortumab vedotin be used to improve outcomes for patients with bladder cancer?

The perioperative setting is the next frontier for enfortumab vedotin plus pembrolizumab. Two phase 3 trials are evaluating that [combination], 1 for cisplatin-eligible patients, [where the combination is being] compared with cisplatin-based chemotherapy, and 1 for cisplatin-ineligible patients [where the combination is being] compared with surgery alone. Those are probably the next big data to come through and might move enfortumab vedotin plus pembrolizumab up to the perioperative setting. That would then give us a whole new set of challenges about what to do in the metastatic setting after patients relapse, if they relapse. 

My gut feeling is that at least 1 if not both of those trials will be positive, based on the data in EV-302. We may be faced with the question of how to integrate this [regimen] most effectively into the care of patients with muscle-invasive bladder cancer. The magnitude of benefit will determine whether platinum-based chemotherapy as a standard goes away as a primary therapy for these patients. All of that remains to be seen, but it is the next big thing.

What has been the significance of the March 2024 FDA approval of nivolumab plus chemotherapy for patients with unresectable or metastatic bladder cancer, and how might this combination fit into the treatment paradigm alongside enfortumab vedotin plus pembrolizumab?

The approval of gemcitabine plus cisplatin and nivolumab was good to see. It is hard for me to imagine that there are patients in the US for whom that regimen is preferred over enfortumab vedotin plus pembrolizumab. One of the interesting findings from the [CheckMate 901] trial was the duration of CR in patients who had CRs [with the nivolumab combination]. If there’s a way to pick [those patients] in advance and have a robust predictive biomarker, then perhaps that is a way forward for that combination. The perioperative trial with that combination has not been reported yet, but that may be a place where that triplet will live as well, depending on the results of the trials with enfortumab vedotin plus pembrolizumab in that setting.

Perhaps in a patient with poorly controlled diabetes, you might consider gemcitabine plus cisplatin and nivolumab, although many of those patients don’t tolerate cisplatin well. Patients with bad neuropathy probably shouldn’t get cisplatin or enfortumab vedotin, so the role [of the nivolumab combination] in the US may be relatively limited. There are areas around the world though where we won’t see access to enfortumab vedotin plus pembrolizumab for some time, but where there is access to nivolumab in combination with chemotherapy. In that context outside the US, perhaps we’ll see more uptake [of the nivolumab combination].

This raises the question of sequencing immune checkpoint blockade with chemotherapy in urothelial cancer. Maintenance avelumab [Bavencio] is better than not giving immunotherapy after chemotherapy response or stable disease, whereas at least in combination with cisplatin, starting earlier seems to be better. However, a lot of the benefit seems to be from the maintenance phase when you look at the shape of the survival curves.

I also worry that we are missing a whole swath of the population who never get to maintenance therapy because they have progression, or they stop and [undergo observation]. Some of those patients never get a checkpoint inhibitor at all. My bias is that for cisplatin-eligible patients who are getting gemcitabine plus cisplatin as their metastatic first-line therapy, gemcitabine plus cisplatin and nivolumab is appropriate. If enfortumab vedotin plus pembrolizumab moves up to the perioperative setting, and a patient relapses maybe a year or more after, gemcitabine plus cisplatin and nivolumab might be the preferred treatment option. However, there are several “ifs” in that statement, so we need to see what the data show.

What unmet needs remain to be addressed in patients with bladder cancer, and what kind of future research might be aimed at addressing these needs, particularly in the metastatic setting?

There’s a lot of opportunity to improve our current treatments for metastatic disease. Many patients will relapse and progress after enfortumab vedotin plus pembrolizumab. One of the big questions is whether Nectin-4 is still a viable target in those patients. Many trials are now launching with novel Nectin-4–directed ADCs with novel antibodies, different linkers, and different payloads to try to see whether we can build perhaps a more tolerable agent that has activity and will work well in refractory patients and maybe even in untreated patients. I don’t know whether [these agents] will displace enfortumab vedotin plus pembrolizumab. I suspect we’re going to see some drugs that still hit the pathway, even after progression on enfortumab vedotin plus pembrolizumab.

We now have a HER2-targeted ADC that we can prescribe for patients who have HER2 3+ overexpression. Fully fleshing out the role of HER2-targeted therapy in urothelial cancer is a major focus. We have an investigational agent, tisotumab vedotin-tftv [Tivdak] which is another ADC that also has monomethyl auristatin E, is highly active, and seems to synergize with immune checkpoint blockade based on data from China. It’s being investigated now in the US, and there’s a global phase 3 trial.

We also need better FGFR inhibitors. Erdafitinib [Balversa] is now fully FDA approved for patients [with 

-positive locally advanced or metastatic urothelial cancer] who’ve had a prior checkpoint inhibitor and, presumably, enfortumab vedotin and/or chemotherapy in the past. The toxicity profile is not what we’d love it to be, with a lot of [toxicities that affect] quality of life but are not necessarily life-threatening. For the next generation of drugs, FGFR3-selective agents are being investigated. Those are exciting. I’m hopeful we’ll see some of those hit the market in the next several years. They’re all in clinical trials now and may be the [most effective way of managing] 

What other urothelial cancer clinical trials are you interested in seeing results from?

We’re about to open 2 phase 1/2 trials of 2 Nectin-4–directed ADCs [in patients with urothelial cancer] at MSK and other sites around the US and the world. These are both [investigating] novel Nectin-4–directed antibodies [with] novel linkers and topoisomerase payloads, [which are] different payloads than SN38 and deruxtecan. We’re excited about the possibility of testing these agents sequentially after enfortumab vedotin to determine definitively on a clinical level whether these agents have activity.

The preclinical data with these agents are intriguing and promising, showing activity in enfortumab vedotin–refractory animal models. If the same holds up in people, perhaps we’ll be able to plan for Nectin-4–directed therapy following progression on Nectin-4–directed therapy. [This would be] similar to the breast cancer story in the past with ado-trastuzumab emtansine [T-DM1; Kadcyla] followed by fam-trastuzumab deruxtecan [T-DXd; Enhertu] which [later] replaced T-DM1. [There is] more to come on all that. More than a few [ADCs are] in development at the moment.

Since May is bladder cancer awareness month, what would you like colleagues to know about the progress being made in this field?

For patients who are diagnosed with advanced disease, the future is much brighter than it used to be. We haven’t yet cracked the case completely, unfortunately, and there’s still a lot of work to be done. We’d like to prevent patients from getting metastatic disease, so moving some of these highly active agents up to earlier lines of therapy is a huge priority, and understanding how well they work in the perioperative setting is terrific.

Ultimately, prevention [strategies are] probably the best way to prevent bladder cancer from ever happening. [Advocating for] smoking cessation and investigating other causes of bladder cancer beyond tobacco are going to be important down the road. Right now, for patients with aggressive, advanced disease, we’re finally seeing the types of advances we have been hoping to see for the past 20 years.

FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed May 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer

Jonathan E. Rosenberg, MD, discusses how recent FDA approvals have revolutionized the treatment paradigm for locally advanced or metastatic bladder cancer.



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