FDA Approval of Perioperative Enfortumab Vedotin Plus Pembrolizumab Redefines Cisplatin-Ineligible MIBC Care

The FDA’s decision to bring enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) into the perioperative cisplatin-ineligible muscle-invasive bladder cancer (MIBC) setting marks a meaningful shift for the management of this disease, according to Christof Vulsteke, MD, PhD.

With this approval, an antibody-drug conjugate/immunotherapy backbone has evolved from a transformative treatment in advanced disease to a curative-intent strategy, establishing a new systemic option before surgery and continuing after cystectomy to reduce recurrence risk.

The approval was supported by results from the phase 3 EV-303/KEYNOTE-905 trial (NCT03924895), which showed a significant improvement in event-free survival (EFS) with enfortumab vedotin plus pembrolizumab vs radical cystectomy plus pelvic lymph node dissection (RC + PLND).^1,2 The median EFS was not reached (NR; 95% CI, 37.3 months-NR) with perioperative enfortumab vedotin plus pembrolizumab (n = 170) vs 15.7 months (95% CI, 10.3-20.5) with surgery alone (n = 174; HR, 0.40; 95% CI, 0.28-0.57; P < .0001). Overall survival (OS) data also favored the investigational combination, with a median OS that was NR (95% CI, NR-NR) vs 41.7 months (95% CI, 31.8-NR), respectively (HR, 0.50; 95% CI, 0.33-0.74; P = .0002). Data presented at the 2025 ESMO Congress further demonstrated durable benefit, with 12- and 24-month EFS rates of 77.8% and 74.7% in the investigational arm vs 55.1% and 39.4% with RC + PLND.²

In an interview with OncLive^®, Vulsteke, head of the Integrated Cancer Center Ghent in Belgium, provided clinical and regulatory insight into what this FDA decision signals for the evolving perioperative paradigm in cisplatin-ineligible MIBC and what questions still need to be answered as the field moves toward more effective curative-intent strategies.

“[This] was the first trial that has shown an OS benefit in this patient population, and also the highest pathologic complete response [pCR] rate ever,” Vulsteke expressed. “With these end points that were [reached], this was a positive study.”

OncLive: What was the clinical rationale behind the KEYNOTE-905 trial?

Vulsteke: It all started in the metastatic setting. We saw [striking] results in the phase 3 EV-302 study [NCT04223856] with a doubling of the OS and progression-free survival [(PFS) with enfortumab vedotin plus pembrolizumab vs chemotherapy in patients with metastatic urothelial cancer], and [29.1%] of patients [in the investigational arm] had a CR. Even when they had metastasis to the lungs [or] to the liver, after 2 years, [59.6% of patients were] still in a CR. Maybe we cured some of the patients with [metastatic disease].

Why [not bring] these results [into] the early setting in [MIBC]? That is what we did in KEYNOTE-905. We used the same regimen as in the metastatic space in the early setting of patients with MIBC, and we chose the very [frail] patients with a lot of comorbidities [who were] cisplatin ineligible.

How was the KEYNOTE-905 study designed?

Patients with MIBC who were cisplatin ineligible [were enrolled] in the trial. Patients who were cisplatin eligible but declined cisplatin were also allowed, but most were cisplatin-ineligible patients. [Patients] had to have clinical T2 to T4a N0 or T1 to T4a N1 nonmetastatic, predominant urothelial histology, and we started with a [2-arm trial]—only perioperative pembrolizumab vs control. But based on the results in the metastatic setting, a third arm was added: perioperative enfortumab vedotin plus pembrolizumab. The pembrolizumab was given for 1 year, so 3 cycles before [surgery] and 14 cycles after. The enfortumab vedotin was given for 3 cycles before [surgery] and 6 cycles after.

Then the pembrolizumab arm stopped enrolling, and we continued with the other 2 arms: surgery upfront, followed by observation, and perioperative [enfortumab vedotin plus pembrolizumab]. [Those] were the results we presented at ESMO 2025 with [the] primary end point of centrally assessed EFS and key secondary end points of OS and pCR rate.

What were the key efficacy findings reported from KEYNOTE-905?

For EFS, [there] was an early and sustained separation of the Kaplan-Meier curves, resulting in a statistically significant HR of 0.40 in favor of the [investigational] arm. The median EFS in the control [arm was] 15.7 months and was NR in the [investigational] arm; this was amazing. At 2 years, [the EFS rates were 39.4%] in the control arm, vs 74.7% in the intervention arm.

[The benefit with enfortumab vedotin plus pembrolizumab] also translated in the key secondary end point of OS. The median OS [was 41.7] months in the control arm and NR in the [investigational] arm, also resulting [in a] statistically significant HR of 0.50 in favor of the [investigational] arm. Regarding the 2-year OS rates, [we saw an increase] from [63.1% to 79.7%, a] big difference.

Also, the other key secondary end point of pCR rate was [met] in [the] intent-to-treat population. The patient[s] who had an excellent response before surgery but chose not to [receive] surgery [were] considered nonresponders. [If we had also included their responses, the pCR rate with enfortumab vedotin plus pembrolizumab] would be even higher. But by doing this honestly, we saw a 57.1% pCR rate [(95% CI, 49.3%-64.6%) in the investigational arm]. In 57.1% of patients, we could tell them that after surgery, there was not a single cancer cell left in their specimens.

What were the key safety findings associated with enfortumab vedotin plus pembrolizumab in KEYNOTE-905?

In this population, when you try to cure them but include surgery, there are a lot of adverse effects [AEs]. In the control arm, where the patients did not receive systemic therapy, there were a lot of AEs, high-grade AEs, serious AEs, because [patients underwent] an invasive procedure. This trial may shape the future of surgery regimens [in the context of] very active systemic therapy.

But in the enfortumab vedotin/pembrolizumab arm, the safety profile was consistent with prior experience with enfortumab vedotin/pembrolizumab in the metastatic setting. With enfortumab vedotin, you expect skin toxicities, especially in the first 2 months. If patients have an experienced doctor, these are manageable. In the longer run, [this agent is associated with] polyneuropathy, mostly grades 1 and 2. If patients have grade 3 polyneuropathy, it’s often because their doctor didn’t stop [treatment] early on. Additionally, autoimmune disorders [were seen] with pembrolizumab, but they were the same as we saw from the pembrolizumab safety profile [in] other studies.

Now that enfortumab vedotin plus pembrolizumab is FDA-approved for cisplatin-ineligible MIBC, how does this regimen change the treatment approach?

All these patients should receive enfortumab vedotin [plus] pembrolizumab when it’s available in the region they live in, so I hope it will be widely available around the world. I’m so glad [about] the approval. I hope that [this approval will follow soon] for Europe and other regions, [so] we can give this as a standard of care for this patient population.

[The] cisplatin-eligible population was a minority in [KEYNOTE-905]. Based on this trial, [this approval is] for the cisplatin-ineligible [patients]. But a news release reported that in the cisplatin-eligible population, there [were OS and PFS benefits with enfortumab vedotin plus pembrolizumab], so I’m eagerly awaiting the full dataset. I think [this regimen] should be available as soon as possible for all patients with cisplatin-eligible MIBC [as well].

What unmet needs remain for cisplatin-ineligible patients with MIBC globally? How should future research focus on mitigating those gaps?

[Based on] the complication rates seen with invasive procedures, we should move forward to try to identify patients who have excellent responses with systemic therapy who can avoid surgery and radiochemotherapy. [This is likely a population where] a [stoma], ileal conduit, or neobladder is not needed, patients who we can cure with systemic therapy alone. But we have to be experienced to manage the AEs like skin toxicities [and] polyneuropathy.

We may be able to cure patients with [systemic therapy] alone in experienced hands, with a [regimen that has a] manageable safety profile. We should focus on systemic therapy alone. This is the gap we should fill.

References

1. FDA approves pembrolizumab with enfortumab vedotin-ejfv for muscle invasive bladder cancer. FDA. November 21, 2025. Accessed January 20, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-enfortumab-vedotin-ejfv-muscle-invasive-bladder-cancer
2. Vulsteke C, Kaimakliotis HZ, Danchaivijitr P, et al. Perioperative enfortumab vedotin plus pembrolizumab in participants with muscle-invasive bladder cancer who are cisplatin-ineligible: phase 3 KEYNOTE-905 study. Ann Oncol. 2025;36(suppl 2):S1648. doi:10.1016/j.annonc.2025.09.124