Enfortumab Vedotin Plus Pembrolizumab Stands Strong as the Frontline Bladder Cancer SOC

Jacqueline Brown, MD

The addition of enfortumab vedotin-ejfv (Padcev) to the bladder cancer treatment paradigm has sparked a new era in the management of this disease in which treatment history informs subsequent therapy decisions, according to Jacqueline Brown, MD. She added that monitoring for adverse effects (AEs) must be done more diligently than before as treatment interruptions are expected with the agent. However, if a patient is unable to tolerate chemotherapy, Brown has concerns that they will be able to tolerate enfortumab vedotin.

“Over the past year and a half, we’ve had a massive shift in the way we treat patients with advanced bladder cancer in the first-line setting,” Brown said in an interview with OncLive following a State of the Science Summit on genitourinary cancers, which she cochaired.

In December 2023, the FDA granted full approval to the combination of enfortumab vedotin and pembrolizumab (Keytruda) for the treatment of all-comer patients with locally advanced or metastatic urothelial cancer.¹ This regulatory decision followed the April 2023 accelerated approval of the combination for patients who were not eligible for cisplatin-containing chemotherapy.

The full approval of enfortumab vedotin plus chemotherapy was based on findings from the phase 3 EV-302 trial (NCT04223856), in which patients who received the combination (n = 442) achieved a median progression-free survival of 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5) for those who received chemotherapy (n = 444; HR, 0.45; 95% CI, 0.38-0.54; 2-sided P < .001).² The median overall survival (OS) was also higher in the enfortumab vedotin arm, at 31.5 months (95% CI, 25.4-not reached) vs 16.1 months (95% CI, 13.9-18.3) in the chemotherapy arm (HR, 0.47; 95% CI, 0.38-0.58; 2-sided P < .001).

In the interview, Brown discussed the role that adjuvant nivolumab (Opdivo) plays in the efficacy of enfortumab vedotin plus pembrolizumab in patients with bladder cancer, tips for conveying the importance of early AE monitoring and management to patients, and potential future directions for enfortumab vedotin in this disease.

Brown is an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and the associate medical director of the Ambulatory Infusion Center at the Winship Cancer Institute of Emory University in Atlanta, Georgia.

OncLive: How has the bladder cancer treatment paradigm changed to include the addition of enfortumab vedotin?

Brown: Historically, we’ve always treated patients with bladder cancer with cisplatin chemotherapy. Cisplatin was king and that’s what we used. Now, ever since data from EV-302 were first presented at the 2023 ESMO Congress, enfortumab vedotin plus pembrolizumab has been the standard of care for all-comers in the first line. This is an effective drug combination that generated a great OS benefit, and it’s a new combination for all of us who treat patients. Oncologists are getting used to [identifying and managing] the new AEs that are associated with new drugs. Understanding that shift and why some other treatment options are potentially not as effective as enfortumab vedotin plus pembrolizumab [is important]. Don’t reach for cisplatin in the first line in 2024.

How does prior exposure to adjuvant immunotherapy affect patient selection for enfortumab vedotin plus pembrolizumab and the efficacy of the combination?

Patients with localized, muscle-invasive disease [should receive] neoadjuvant chemotherapy [followed by] cystectomy as the gold standard of treatment. If they have high-risk disease at the time of surgery, meaning muscle-invasive or node-positive disease on their cystectomy specimen, we recommend they receive adjuvant nivolumab for up to 1 year, or approximately 12 doses.

[If a patient receives] adjuvant nivolumab and progresses [during this treatment], would we treat them with enfortumab vedotin plus pembrolizumab in that newly metastatic setting, even though they’ve been receiving nivolumab in the adjuvant setting? Another scenario is: What if the patient has completed 1 year of adjuvant nivolumab, and then later has recurrent metastatic disease? Would we use enfortumab vedotin plus pembrolizumab at that time? This [question] is tricky because there is some nuance as to what amount of time has passed since they completed immunotherapy.

If a patient completed adjuvant nivolumab 1 or 2 years ago, at the time of recurrent metastatic disease I would treat them with enfortumab vedotin plus pembrolizumab because the half-life of immunotherapy and checkpoint inhibitors is not [just a few] weeks. [These agents stay in the] body for months. If [the patient is] at least 6 months, if not 12 months, out [from their last dose of immunotherapy] I’m going to retreat them because perhaps at that time, they have lost that prior immunotherapy effect and are still sensitive to [these agents].

[This decision] gets trickier if the patient progresses during or just after receiving adjuvant nivolumab, such as 2 months later, because this shows me that their disease is resistant to immunotherapy. What bang for my buck am I getting by combining pembrolizumab with enfortumab vedotin? Am I just giving the patient the risk of immune-related AEs without a lot of benefit because they’ve already shown their cancer is resistant to immunotherapy? That question hasn’t been answered.

The parallel is, in kidney cancer, we have ample data from the phase 3 CONTACT-03 [NCT04338269], phase 1/2 TiNivo [NCT03136627], and phase 3 TiNivo-2 [NCT04987203] studies showing that retreatment with immunotherapy after progression on prior immunotherapy is not helpful. We have a much more solid answer in kidney cancer. We don’t have these studies in urothelial cancer yet, so that remains to be seen. In this data-free zone, if I have a patient who is progressing on adjuvant nivolumab, I’m going to treat them with enfortumab vedotin monotherapy rather than enfortumab vedotin plus pembrolizumab. The gray zone is what we should do if [the patient progresses on immunotherapy] 3 or 4 months later. I take that on a case-by-case basis, but that [answer is] anyone’s guess at this point.

Are patients who are ineligible for chemotherapy eligible to receive enfortumab vedotin?

Plenty of data show that in our quick visits with patients, we are notoriously bad at estimating performance status. Patients want to receive treatment, so they tend to say they are doing okay and we tend to take them at their word. How we [classify] patients as chemotherapy eligible is sometimes different than how patients are as they live their lives outside our clinic rooms.

That said, [we often ask]: Is this patient robust enough? Do they have good enough organ function to receive chemotherapy? [We determine patients to be eligible for chemotherapy if they are] up moving around at least half of every day. Their weight needs to be stable [as well]. We need to know their body is going to tolerate chemotherapy.

Is enfortumab vedotin chemotherapy? Most people would agree that yes, it is chemotherapy. It’s just chemotherapy attached to an antibody, which makes it a smart and targeted chemotherapy but a chemotherapy nonetheless, and one that is associated with lots of off-target effects. It can cause the same alopecia, cytopenia, fatigue, and gastrointestinal symptoms [as chemotherapy] but can also cause skin symptoms, hyperglycemia, and peripheral sensory neuropathy, among other AEs. In my mind, it’s not easier [to tolerate] than chemotherapy, it’s just different than chemotherapy.

If I have a patient who I do not think would tolerate traditional chemotherapy in the way that old-school oncologists consider cisplatin and carboplatin [eligibility], I have serious concerns about their ability to tolerate enfortumab vedotin. My patients will say they read about enfortumab vedotin and it looks like an immunotherapy because they read it’s attached to an antibody. I have to reeducate them and say it’s a chemotherapy with a homing device.

How might the severity of certain toxicities associated with enfortumab vedotin be reduced?

The key here, having gotten used to using this combination, is early detection and early intervention. As I start patients on enfortumab vedotin plus pembrolizumab, I tell them my job is to take good care of them, and their job is to tell me anything new [they experience during treatment]. I need them to not grin and bear it at home, not be stoic, and not keep it to themselves.

If they have a small rash on their legs, they have to let me know. [Patients might think] I don’t care, I don’t want to know, or I’m busy. However, if that small rash on their legs progresses to a total body blistering rash that lands them in an intensive care unit, they’re in serious trouble. Whereas, had they told me, I could have immediately stopped [enfortumab vedotin], treated them with steroids, and reduced this toxicity.

To facilitate [those types of conversations with patients about AEs], oncologists have to be familiar with the AE profiles of new drugs. Enfortumab vedotin is a new drug to us. [We need to] look out for skin rashes and blood sugar levels that are newly 400 mg/dL. [If a patient’s blood sugar level is] 250 mg/dL, I [might not] necessarily hold treatment that day, even though the package label says to—I’m going to have a risk-benefit discussion with the patient who has an incurable disease who needs to be treated. [However, if these levels are] suddenly 400 mg/dL or 500 mg/dL, I need to be aware of that, immediately hold [the enfortumab vedotin], and immediately treat that patient in the outpatient setting, so I’m not landing them in the hospital with severe hyperglycemia.

[Another notable AE] is neuropathy. Peripheral neuropathy is a big consideration with enfortumab vedotin, and I tend to be acutely aware when it progresses to grade 1, meaning symptoms are there, but there’s not [an] impingement on function. I [assess] this by asking patients: Are you buttoning your buttons? Are you opening jars? Are you turning doorknobs without an issue? If they are, I will usually keep going [with the therapy]. However, the second they say it’s a bit harder to button their shirt in the morning, I hold the enfortumab vedotin because if they keep going, [the peripheral neuropathy] will get exponentially worse quickly.

I try to explain to patients that this is a long game. I want to treat them for as long as I can. When we first discuss this combination, I tell them they will take breaks [and] I will have to hold [enfortumab vedotin]. [I tell patients that] when that happens, they have not failed me, and they have not done anything wrong. [Enfortumab vedotin treatment interruptions are] expected, and they are how we’re going to hopefully get that long game.

How is ongoing research incorporating enfortumab vedotin into the later-line bladder cancer setting?

We have an ongoing, investigator-initiated, phase 1 trial [NCT04878029] at Emory investigating enfortumab vedotin plus a VEGF-targeting agent, cabozantinib [Cabometyx], in the later-line setting. [This trial is] open for patients [with locally advanced or metastatic urothelial cancer] who have received prior immunotherapy and platinum chemotherapy. We’ve enrolled approximately 12 patients so far. We’ve seen nice responses in those patients with a manageable AE profile.

One of the challenges to enrollment in this trial is that a lot of patients are already receiving enfortumab vedotin in the first line setting because of the paradigm shift that happened after we opened this trial. Those patients are not eligible to enroll in the trial. This is a study we’re trying to wrap up, and it is showing that combining these agents is possible. It is opening the door for future enfortumab vedotin–containing combinations to improve outcomes for patients in all lines. Can VEGF-directed agents be successfully combined with enfortumab vedotin? Our study is showing that might be possible.

References

1. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed October 9, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
2. 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