Two phase III trials presented at a Presidential Symposium during the European Society for Medical Oncology (ESMO) Congress 2023 showed an overall survival benefit for patients with advanced urothelial cancer. The results from both studies were hailed as practice-changing.
“We’ve never beaten chemotherapy in the first-line setting [in urothelial cancer]. This is the first time we’ve achieved that goal.”— Thomas Powles, MBBS, MRCP, MD
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The EV-302/KEYNOTE-A39 trial, presented by lead author Thomas Powles, MBBS, MRCP, MD, Professor of Genitourinary Oncology and Director of the Barts Cancer Centre at St. Bartholomew’s Hospital, London, demonstrated improved survival with the combination of enfortumab vedotin-ejfv plus pembrolizumab for the first time in this setting.1 The CheckMate 901 trial, presented by Michiel van der Heijden, MD, PhD, a medical oncologist and research group leader at the Netherlands Cancer Institute, Amsterdam, also showed improved overall survival results—albeit more modest—with the addition of nivolumab to chemotherapy.2 The CheckMate 901 findings were simultaneously published in The New England Journal of Medicine.3
In the international EV-302/KEYNOTE-A39 trial, a combination of the antibody-drug conjugate enfortumab vedotin plus the immune checkpoint inhibitor pembrolizumab was compared with platinum-based chemotherapy (with either cisplatin or carboplatin plus gemcitabine) in patients with metastatic urothelial cancer. The combination doubled both overall survival and progression-free survival.
Michiel van der Heijden, MD, PhD
Median progression-free survival was 12.5 months with enfortumab vedotin plus pembrolizumab vs 6.3 months with chemotherapy—a 55% reduction in the risk of disease progression or death (hazard ratio [HR] = 0.45; 95% confidence interval [CI] = 0.38–0.54; P < .00001). Median overall survival was 31.5 months vs 16.1 months, respectively (HR = 0.47; 95% CI = 0.38–0.58; P < .00001).
“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,” said Dr. Powles.
The antibody-drug conjugate enfortumab vedotin targets nectin-4, which regulates angiogenesis. Both enfortumab vedotin and pembrolizumab have separately shown a survival benefit in previously treated advanced or metastatic urothelial cancer. EV-302/KEYNOTE-A39 compared the combination with standard chemotherapy in patients with untreated disease.
The trial enrolled 886 patients regardless of cisplatin eligibility or PD-L1 expression. Dual primary endpoints were progression-free survival by independent review and overall survival. Most patients in each arm were cisplatin-eligible; 72% had visceral metastases, and 58% had a PD-L1 combined positive score ≥ 10.
More than twice as many patients were alive without disease progression in the experimental arm at 12 months (50.7% vs 21.6%, respectively), and four times as many were alive at 18 months (43.9% vs 11.7%, respectively). A subgroup analysis demonstrated the superiority of enfortumab vedotin plus pembrolizumab regardless of whether patients were cisplatin-eligible or -ineligible or had high or low levels of PD-L1 expression.
Objective response rate was 67.7% vs 44.4%, respectively (P < .00001). Complete response rate was 29.1% vs 12.5%, respectively. About 60% of patients treated with chemotherapy later received a PD-L1 inhibitor.
The safety of the enfortumab vedotin/pembrolizumab regimen was manageable. Grade ≥ 3 treatment-related adverse events were reported in 56% of the experimental arm and 70% of the chemotherapy arm. The most common grade ≥ 3 treatment-related adverse events with the combination were maculopapular rash (7.7%), neutropenia (4.8%), peripheral neuropathy (3.6%), diarrhea (3.6%), and anemia (3.4%).
At the end of his presentation, Dr. Powles added: “I would like to thank the patients and their families—not just for this trial, but for all the previous trials we’ve done in bladder cancer, the dozens of trials that have been negative, that have not achieved an overall survival benefit. Those patients made a huge sacrifice, but they got us to where we are today with this new standard of care.”
CheckMate 901 randomly assigned 608 patients to receive cisplatin/gemcitabine chemotherapy with or without nivolumab for a maximum of six cycles. Those in the nivolumab arm were treated for 24 months or until disease progression or unacceptable toxicity. The dual primary endpoints were progression-free survival and overall survival by blinded independent central review.
In the primary analysis, the nivolumab-containing arm reduced the risk of death by 22% (P = .0171) and the risk of disease progression or death by 28% (P = .001). With a median follow-up of 33.6 months, median overall survival was improved by the addition of nivolumab to 21.7 months vs 18.9 months with chemotherapy (HR = 0.78; 95% CI = 0.63–0.96; P = .0171).
Median progression-free survival by blinded independent central review was a median of 7.9 months for the experimental arm vs 7.6 months for the chemotherapy arm (HR = 0.72; 95% CI = 0.59–0.88; P = .0012). The rate of 12-month progression-free survival was 34.2% vs 21.8%, respectively; the 24-month progression-free survival rate was 23.5% vs 9.6%, respectively.
Objective response rate was 58% with nivolumab vs 43.1% with chemotherapy. The rate of complete response was 22% vs 12%, respectively. Median duration of response was 9.5 months with nivolumab and 7.3 months with chemotherapy alone.
Quality of life was similar on both study arms, according to the EORTC QLQ-30 questionnaire. Grade ≥ 3 treatment-related adverse events were reported in 62% of the nivolumab arm vs 52% of the chemotherapy group. The most common grade ≥ 3 treatment-related adverse events in the nivolumab-treated arm were anemia (22%), neutropenia (19%), decreased neutrophil count (14%), and decreased white blood cell count (10%).
“Nivolumab plus gemcitabine/cisplatin is the first front-line 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,” Dr. van der Heijden told listeners.
Disclosure: EV-302/KEYNOTE-A39 was sponsored by Astellas Pharma in collaboration with Merck Sharp & Dohme and Seagen. CheckMate 901 was sponsored by BMS in collaboration with Ono Pharmaceutical. Dr. Powles reported financial relationships with AstraZeneca, Roche, BMS, Exelixis, Ipsen, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, and Eisai; has received honoraria from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, Roche, and Mash Up Ltd; and has received travel funding from Roche, Pfizer, MSD, AstraZeneca, and Ipsen. Dr. van der Heijden reported financial relationships with AstraZeneca, BMS, Janssen, MSD, Pfizer, Roche, Seagen, and 4SC.
1. Powles T, Perez-Valderrama B, Gupta S, et al: EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab vs chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma. ESMO Congress 2023. Abstract LBA6. Presented October 22, 2023.
2. van der Heijden M, Sonpavde G, Powles T, 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 Congress 2023. Abstract LBA7. Presented October 22, 2023.
Andrea Apolo, MD
Invited discussant Andrea Apolo, MD, of the National Cancer Institute in Bethesda, Maryland, emphasized that the EV-302/KEYNOTE-A39 and CheckMate 901 trials mark a significant achievement.
“Outperforming chemotherapy in first-line therapy is monumental for our field. The two ...