Cisplatin’s Prevalence in Bladder Cancer Falters With the Introduction of Enfortumab Vedotin

The addition of the combination of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) to the all-comer urothelial carcinoma treatment paradigm contests the role of platinum-doublet chemotherapy in this setting, although platinum-based regimens may still be considered on a case-by-case basis, according to Jacqueline Brown, MD. 

In an interview with OncLive^®, Brown explained the need for continued research to determine optimal second-line treatment strategies, and situations in which enfortumab vedotin plus pembrolizumab may not be tolerable or accessible. Additionally, she detailed potential reasons for the varying results seen with checkpoint inhibitors plus platinum-based chemotherapy across bladder cancer clinical trials.

Brown also highlighted the role of enfortumab vedotin plus pembrolizumab in the frontline bladder cancer setting, as well as management strategies for adverse effects associated with this combination, in an additional article. Brown is an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, as well as the associate medical director of the Ambulatory Infusion Center at the Winship Cancer Institute of Emory University in Atlanta, Georgia.

OncLive: Why was the phase 3 CheckMate 901 trial (NCT03036098) positive whereas the phase 3 KEYNOTE-361 (NCT02853305) and IMvigor130 (NCT02807636) trials were negative, even though all 3 trials evaluated platinum-based chemotherapy plus immune checkpoint inhibition in patients with treatment-naive, locally advanced or metastatic urothelial cancer?

Brown: CheckMate 901 enrolled cisplatin-eligible, untreated patients with advanced urothelial carcinoma. They were randomly assigned to receive cisplatin and gemcitabine plus nivolumab [Opdivo] for up to 6 cycles, followed by nivolumab maintenance thereafter, or chemotherapy alone. This study found that the addition of nivolumab showed an improvement in overall survival [OS], progression-free survival, and overall response rate compared with patients who received cisplatin-based chemotherapy alone. That’s big news.

The other 2 studies, KEYNOTE-361 and IMvigor130, investigated a similar concept; they just swapped out the immune checkpoint inhibitor. [However, there were] a couple caveats [between all these trials]. IMvigor130, instead of [treating patients with] nivolumab, investigated chemotherapy with or without atezolizumab [Tecentriq], another checkpoint inhibitor. KEYNOTE-361 examined chemotherapy with or without pembrolizumab.

One might think: Those are all similar trials; why would there be a difference [between the outcomes]? CheckMate 901 enrolled only patients who were cisplatin eligible, whereas the other 2 studies enrolled patients who were platinum eligible. Those patients might have been cisplatin eligible, but they might have been cisplatin ineligible, meaning they got carboplatin within the trial. That raises a lot of heterogeneity between these trials. Cisplatin-eligible [patients are generally] a healthier population than the population that is not cisplatin eligible. [That accounts for] some differences between these 3 trials. Perhaps CheckMate 901 enrolled healthier patients because of that caveat.

Additionally, a growing body of basic and translational science literature [indicates] that there may be something more immunomodulatory about cisplatin compared with carboplatin. Maybe cisplatin plays better with checkpoint inhibitors than carboplatin. Those are early data. We cannot say that definitively, but as we are considering these 3 sets of results and trying to figure out why CheckMate 901 had positive results, that’s a place a lot of our brains go toward.

As of May 2024, the National Comprehensive Cancer Network (NCCN) guidelines for bladder cancer cite enfortumab vedotin plus pembrolizumab as preferred for all patients, regardless of cisplatin eligibility. What other recent updates to the guidelines are important to note?

Platinum-doublet [chemotherapy with] gemcitabine plus cisplatin followed by avelumab [Bavencio] maintenance is a treatment option for cisplatin-eligible patients [with advanced bladder cancer, and] that has been our mainstay since 2020. [This regimen is still in the NCCN guidelines], but it has taken a backseat to enfortumab vedotin plus pembrolizumab in all settings, for both cisplatin-eligible and -ineligible patients.

The second-line NCCN treatment recommendations have gotten a bit messier because of this paradigm change because nobody knows what to use in the second line given this reordering of the paradigm. That’s an open space, and it’s hard for the guidelines to make recommendations [as to whether we should use second line] platinum-doublet chemotherapy, sacituzumab govitecan-hziy [Trodelvy], or erdafitinib [Balversa] for eligible patients. That’s a space where the guidelines have been shaken up, and they’re not giving us the guidance that practicing oncologists seek because the data do not exist yet.

In what ways has the FDA approval of enfortumab vedotin plus pembrolizumab for all patients with bladder cancer shifted the treatment paradigm?

At this point, cisplatin, gemcitabine, and dose-dense MVAC, which includes cisplatin in a 4-drug regimen [of methotrexate, vinblastine, doxorubicin, and cisplatin], should not be used in the first line setting if a patient is eligible for enfortumab vedotin plus pembrolizumab. With a median OS of 31.5 months with enfortumab vedotin plus pembrolizumab [seen in the phase 3 EV-302 trial (NCT04223856)], it’s hard for me to reach for a different combination if the patient is eligible [for enfortumab vedotin plus pembrolizumab] in every other way. If the patient has terrible peripheral neuropathy from uncontrolled diabetes, giving them enfortumab vedotin will be challenging. However, it will also be challenging to give them cisplatin. That will be a difficult patient to treat in general.

The elephant in the room here is that [enfortumab vedotin plus pembrolizumab] is a wildly expensive combination. It costs approximately $45,000 for every 3-week cycle of drugs, so it is not available to a lot of patients. We have underinsured patients, we have uninsured patients, and that’s not including patients who live in certain parts of the United States or other parts of the world where they’re never going to have access to this combination because it doesn’t exist there.

[The introduction of enfortumab vedotin plus pembrolizumab into the bladder cancer treatment paradigm] is a shift that applies to my patients who come to see me at the Winship Cancer Institute, but the paradigm hasn’t shifted for a lot of patients because cisplatin and gemcitabine are much more affordable than enfortumab vedotin and pembrolizumab. For that reason, we can’t let go of those tools in our toolbox.