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First in Decades: Enfortumab Vedotin + Pembrolizumab Beats Chemo in First-Line Metastatic Urothelial Cancer


Enfortumab vedotin plus pembrolizumab not only beat chemotherapy in the first-line setting for locally advanced metastatic urothelial cancer for the first time in decades, but it nearly doubled progression-free survival and overall survival vs chemotherapy.

For decades chemotherapy has been the standard of care in the first line for patients with locally advanced metastatic urothelial cancer, but new results for enfortumab vedotin plus pembrolizumab present a new standard of care and hope for patients.

The combination therapy significantly improves outcomes in these patients with a nearly double median progression-free survival (PFS) and overall survival (OS) vs chemotherapy, according to the results of an open-label randomized phase 3 study.

Thomas Powles, MBBS, MRCP, MD

Image credit: Barts Cancer Institute

Thomas Powles, MBBS, MRCP, MD

Image credit: Barts Cancer Institute

Thomas Powles, MBBS, MRCP, MD, professor of genitourinary oncology and director of the Barts Cancer Centre at St. Bartholomew's Hospital in London, United Kingdom, presented the results of EV-302/KEYONTE-A39 during ESMO Congress 2023, held October 20-24, 2023, virtually and in Madrid, Spain.

“We’ve never beaten chemotherapy in the first-line setting. This is the first time we’ve achieved that goal,” he said to applause in the middle of his presentation.

The median survival for these patients has been stuck at 12 to 14 months for a generation, with poor long-term survival. In this space, immune checkpoint inhibition as a monotherapy has not been transformative as it has never before beaten first-line chemotherapy. Instead, it has been established as a maintenance therapy.

Enfortumab vedotin plus pembrolizumab did receive accelerated approval earlier in 2023 for patients who are ineligible for cisplatin chemotherapy in the first-line setting.1

A total of 886 patients were included in the study who were previously untreated but were eligible for cisplatin- or carboplatin-containing chemotherapy. They were randomized 1:1 to receive 3-week cycles of enfortumab vedotin and pembrolizumab (n = 442) or gemcitabine with cisplatin or carboplatin (n = 444).

The median follow-up at data cutoff was 17.2 months and PFS was significantly prolonged with the combination therapy with a median PFS of 12.5 months compared with 6.3 months for chemotherapy, which reduced the risk of progression or death by 55% (HR, 0.45; 95% CI, 0.38-0.54; P < .00001).

The subgroup analysis showed enfortumab vedotin plus pembrolizumab was favored across broad subgroups of patients, regardless of platinum eligibility, PD-L1 expression, and visceral metastasis.

Enfortumab vedotin plus pembrolizumab also significantly prolonged OS with a median OS of 31.5 months vs 16.1 months for chemotherapy, reducing the risk of death by 53% (HR, 0.47; 95% CI, 0.38-0.58; P < .00001). The confirmed objective response rate was 67.7% for the combination arm and 44.4% for the chemotherapy arm (P < .00001). There was a complete response rate of 29.1% for the combination therapy vs 12.5% for the chemotherapy.

“That's not something we've seen before,” Powles said. In addition, the median duration of response had not been met for enfortumab vedotin plus pembrolizumab compared with 7.0 months for chemotherapy. “So, it's the durability, as well as the higher response rate that's translated into this overall survival signal.”

In the combination arm, grade 3 or higher treatment-related adverse events (TRAEs) occurred in 55.9% of patients, and in the chemotherapy arm they occurred in 69.5% of patients. The most common for enfortumab vedotin were maculopapular rash (7.7%), hyperglycemia (5.0%), and neutropenia (4.8%). The most common for the chemotherapy arm were anemia (31.4%), neutropenia (30.0%), and thrombocytopenia (19.4%).

"I would like to thank the patients and their families—but not of this trial, but of all of the previous trials that we've done in bladder cancer," Powles concluded. "The dozens of trials have been negative that have not achieved an overall survival. Those patients have made a huge sacrifice, but they have got us to where we are today with this new standard of care, appropriate protection."

After the results on enfortumab vedotin plus pembrolizumab were presented, additional positive results in the space were presented on nivolumab plus gemcitabine-cisplatin vs gemcitabine-cisplatin alone. While this is also historic, during the invited discussion, Andrea Apolo, MD, senior investigator, Genitourinary Malignancies Branch, National Cancer Institute, noted that enfortumab vedotin plus pembrolizumab improved survival, which would make it the standard of care over nivolumab plus gemcitabine-cisplatin.

The results make it unclear what the role will be for the combination of nivolumab plus gemcitabine-cisplatin.

“We welcome a new standard of care in the management of advanced metastatic urothelial carcinoma in enfortumab vedotin plus pembrolizumab, but with new standards of care come questions and challenges,” Apolo said.

With a new standard of care, providers will need to figure out what is the best second line of care and even the third and fourth lines of care. Additional studies will need to be conducted to answer these questions and assess the efficacy and toxicity after enfortumab vedotin plus pembrolizumab.

In addition, the combination is expensive, so it remains to be seen if insurance and public systems will be able to afford the treatment, she pointed out.

“I leave you with the message that the future looks bright for our patients with urothelial carcinoma,” Apolo concluded. “[Enfortumab vedotin plus pembrolizumab] has raised the bar for overall survival in metastatic urothelial carcinoma.”


Rosa K. FDA approves enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. OncLive® website. April 3, 2023. Accessed October 22, 2023.

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