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Patients with locally advanced or metastatic bladder cancer have a permanent new first-line standard of care after the FDA granted full to the combination of enfortumab vedotin (Padcev) and pembrolizumab (Keytruda) regardless of cisplatin eligibility.

The action finalized the approval process for the combination, which received accelerated approval earlier this year, at the time contingent on additional supporting data and restricted to patients ineligible for cisplatin-containing chemotherapy.

That needed confirmatory data came 2 months ago at the European Society for Medical Oncology (ESMO) meeting, when results of the EV-302/KEYNOTE-A39 randomized trial demonstrated that the enfortumab vedotin/pembrolizumab combination doubled progression-free survival (PFS) and overall survival (OS) in previously untreated patients with advanced or metastatic urothelial cancer versus the long-time chemotherapy standard. The trial included patients who were both cisplatin-eligible and ineligible.

Following the ESMO presentation, invited discussant Andrea Apolo, MD, of the National Cancer Institute in Bethesda, Maryland, called the trial's outcome "monumental for our field."

"So we welcome a new standard of care in the management of advanced/metastatic urothelial carcinoma in enfortumab vedotin plus pembrolizumab," she said.

Principal investigator Thomas Powles, MD, of Barts Cancer Center in London, acknowledged feeling the gravity of the moment as he paused during his presentation of the primary results to say, "I'm a bit nervous, actually. I don't normally get nervous."

involved 886 patients with previously untreated locally advanced or metastatic urothelial cancer. They were randomized to enfortumab vedotin/pembrolizumab or to platinum-based chemotherapy, and the primary outcomes were OS and PFS. The results showed that enfortumab vedotin/pembrolizumab led to a median OS of 31.5 months versus 16.1 months with chemotherapy and a median PFS of 12.5 versus 6.3 months.

Grade ≥3 treatment-related adverse events (TRAEs) occurred in 56% of the enfortumab vedotin/pembrolizumab arm and 70% of the chemotherapy arm. The most common grade ≥3 TRAEs with enfortumab vedotin/pembrolizumab were maculopapular rash (7.7%), neutropenia (4.8%), peripheral neuropathy (3.6%), diarrhea (3.6%), and anemia (3.4%).

The trial outcome ended the decades-long reign of chemotherapy as standard of care for frontline treatment of advanced or metastatic urothelial cancer.

"As you know, we've never seen a survival signal before in urothelial cancer," Powles said at ESMO. "We've never beaten chemotherapy in the first-line setting. This is the first time we've achieved that goal."

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