Landmark Trial Produces New First-Line Standard for Advanced Bladder Cancer

— Enfortumab vedotin-pembrolizumab doubles OS, PFS versus chemotherapy


MADRID -- Chemotherapy's generation-long dominance in first-line advanced urothelial cancer ended with a resounding victory for the antibody-drug conjugate (ADC) enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda) in an international randomized trial.

Overall survival (OS) and progression-free survival (PFS) doubled with enfortumab-pembrolizumab (EV-P) at 12.5 and 31.5 months versus 6.3 and 16.1 months with platinum-containing chemotherapy. The superiority held up in a subgroup analysis that included cisplatin-eligible and ineligible patients and high or low PD-L1 expression. Objective response increased by more than 50% with EV-P versus chemotherapy, including complete responses in 29.1% of patients.

EV-P had a manageable safety profile with no new or unexpected adverse events (AEs), reported Thomas Powles, MD, of the Barts Cancer Center in London, at the European Society for Medical Oncology (ESMO) congress.

"As you know, we've never seen a survival signal before in urothelial cancer. We've never beaten chemotherapy in the first-line setting. This is the first time we've achieved that goal," Powles announced to a standing ovation. "I'm a bit nervous, actually. I don't normally get nervous."

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

The results of the trial overshadowed those of , which demonstrated a survival benefit over chemotherapy alone in first-line advanced/metastatic urothelial cancer. Adding nivolumab (Opdivo) to gemcitabine-cisplatin chemotherapy improved median OS from 18.9 months with chemotherapy alone to 21.7 months, a more modest but still statistically significant increase, reported Michiel van der Heijden, MD, PhD, of the Netherlands Cancer Institute in Amsterdam.

'Monumental' Achievement

The nivolumab-chemotherapy regimen is the first such combination to show a survival benefit over chemotherapy alone in first-line advanced/metastatic urothelial cancer, said ESMO invited discussant Andrea Apolo, MD, of the National Cancer Institute in Bethesda, Maryland. Previous trials pairing (Tecentriq) and with platinum-gemcitabine chemotherapy did not achieve statistical significance over chemotherapy alone.

Outperforming chemotherapy in first line is "monumental for our field," she said.

However, as compared with CheckMate-901, EV-302 produced better OS, a higher response rate, and longer duration of response, Apolo noted. The OS benefit in EV-302 held up across all key subgroups, regardless of PD-L1 status, presence or absence of liver metastases, and cisplatin eligibility.

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

Questions and challenges inevitably follow a new standard of care, Apolo continued. How can the toxicity of the combination be reduced? Why do microtubule-destabilizing drugs such as the one used in enfortumab vedotin combine so well with checkpoint inhibitors? Can a better understanding of the complementary mechanisms build on the therapeutic activity? Would other cytotoxic payloads work even better? How would the EV-302 combination work in the neoadjuvant or adjuvant setting?

Enfortumab vedotin targets nectin-4, a that regulates angiogenesis. Individually, the ADC and pembrolizumab have demonstrated a survival benefit in previously treated advanced/metastatic urothelial cancer. EV-302/KEYNOTE-A39 compared the combination with standard chemotherapy in patients with untreated advanced/metastatic urothelial, regardless of cisplatin eligibility or PD-L1 expression.

The trial involved 886 patients and had dual primary endpoints of PFS by independent review and OS. Patients allocated to chemotherapy could receive cisplatin or carboplatin in addition to gemcitabine.

A majority of patients in both arms were cisplatin eligible, 72% had visceral metastases, and 58% had PD-L1 combined positive score (CPS) ≥10.

The analysis of PFS showed that EV-P reduced the hazard for progression or death by 55% (95% CI 0.38-0.54, P<0.00001). More than twice as many patients in the EV-P arm were alive without progression at 12 months (50.7% vs 21.6%) and four times as many at 18 months (43.9% vs 11.7%).

The survival analysis after a median follow-up of 17.2 months showed a 53% reduction in the hazard in favor of EV-P (95% CI 0.38-0.58, P<0.00001). The hazard was similar for patients who were cisplatin eligible (0.53) or ineligible (0.43) and irrespective of whether patients had PD-L1 CPS ≥10 (0.49) or less (0.44). Almost 60% of patients in the chemotherapy arm subsequently received a PD-1/L1 inhibitor.

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


CheckMate-901 involved 608 patients, randomized to cisplatin-gemcitabine chemotherapy with or without nivolumab. All patients received a maximum of six cycles of chemotherapy, and those in the nivolumab arm received maintenance nivolumab until disease progression, unacceptable toxicity, or at 24 months. OS and PFS by independent review were the dual primary endpoints.

The primary analysis showed that the nivolumab regimen reduced the survival hazard by 22% (95% CI 0.63-0.96, P=0.0171) and the PFS hazard by 28% (95% CI 0.59-0.88, P=0.0012). Objective response rates were 58% with nivolumab (including complete responses in 22%) versus 43.1% (12%). Median duration of response was 9.5 months with nivolumab and 7.3 months with chemotherapy alone.

Grade ≥3 TRAEs occurred in 62% of the nivolumab arm versus 52% of the chemotherapy group. The most common grade ≥3 TRAEs in the nivolumab group were anemia (22%), neutropenia (19%) decreased neutrophil count (14%), and decreased white blood cell count (10%).

"Nivolumab plus gemcitabine-cisplatin is the first frontline concurrent immune checkpoint inhibitor plus chemotherapy combination to improve overall survival in this setting, with results supporting nivolumab plus cisplatin-based chemotherapy as a new standard of care for patients with unresectable or metastatic urothelial cancer," said van der Heijden.

The CheckMate-901 trial was in the New England Journal of Medicine.

  • author['full_name']

    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined app in 2007.


EV-302/KEYNOTE-A39 was sponsored by Astellas Pharma in collaboration with Merck Sharp & Dohme and Seagen.

Powles disclosed relationships with Bristol Myers Squibb (BMS), AstraZeneca, Ipsen, Pfizer, Novartis, Seagen, Rochen, Exelixis, MSD, Merck Serono, Astellas, Johnson & Johnson, Eisai, Mashup, Merck, Incyte, and Gilead Sciences.

CheckMate-901 was sponsored by BMS in collaboration with Ono Pharmaceutical. Some co-authors are BMS employees.

Van der Heijden disclosed relationships with AstraZeneca, BMS, Janssen, MSD, Pfizer, Seagen, and Roche.

Apolo disclosed no relationships with industry.

Primary Source

European Society for Medical Oncology

Powles T, et al "EV-302/KEYNOTE-A39: Open-lab, randomized phase III study of enfortumab vedotin in combination with pembrolizumab vs chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma" ESMO 2023; Abstract LBA6.

Secondary Source

European Society for Medical Oncology

Van der Heijden M, et al "Nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone for previously untreated unresectable or metastatic urothelial carcinoma: Results from the phase III CheckMate 901 trial" ESMO 2023; Abstract LBA7.

Additional Source

New England Journal of Medicine

Van der Heijden MS, et al "Nivolumab plus gemcitabine-cisplatin in advanced urothelial carcinoma" N Engl J Med 2023; DOI: 10.1056/NEJMoa2309863.