Platinum-based combination chemotherapy remains the cornerstone of treatment for advanced urothelial carcinoma (UC), but it still falls short of meeting long-term survival needs. At the 39th Annual Congress of the European Association of Urology (EAU24) held in Paris, France, Dr. Jens Bedke, from Klinikum Stuttgart Katharinen Hospital, shared the results of the EV-302/KEYNOTE-A39 study. Urology Frontier had the privilege of inviting renowned expert Dr. Jens Bedke to discuss the current status of immunotherapy, recent major advances in clinical trials, and future directions in UC treatment.
Urology Frontier: Currently, platinum-based combination chemotherapy is still the first-line standard treatment for advanced urothelial carcinoma (UC). What unmet needs do you think exist for patients with advanced UC?
Dr. Jens Bedke: Thank you for having me. Addressing the unmet clinical needs in bladder cancer, especially metastatic bladder cancer, is of utmost importance. With the aging population, we’re witnessing a continuous rise in the incidence and overall burden of metastatic urothelial cancer. The primary treatment approach currently revolves around platinum-based chemotherapy, which indeed shows efficacy. However, only a small fraction of patients, about 5% to 10%, achieve long-term survival with cisplatin and carboplatin-based regimens. Even with maintenance regimens post-platinum-based chemotherapy, although response rates are notable, achieving long-term survival remains challenging. This prompts the question: How can we improve and move beyond the current platinum-based chemotherapy strategies?
Urology Frontier: Immunotherapy for UC has progressed rapidly in recent years, with NEJM also announcing the latest EV-302/KEYNOTE-A39 study results. What breakthroughs did this research achieve?
Dr. Jens Bedke: Over the past five to six years, the introduction of immune checkpoint inhibitors in the metastatic setting of bladder cancer has been pivotal. Immune checkpoint inhibitors have undoubtedly improved outcomes, survival rates, and progression-free survival rates in metastatic bladder cancer patients, whether after platinum-based chemotherapy induction or for platinum-ineligible patients, including those with PD-L1 positivity receiving checkpoint monotherapy with Pembrolizumab or Atezolizumab. The EV-302 study represents a novel approach, combining the PD-1 antibody Pembrolizumab with the specially designed antibody-drug conjugate Enfortumab Vedotin. Enfortumab Vedotin targets Nectin-4, a protein expressed on tumor cell surfaces, delivering the chemotherapy agent MMAE to Nectin-4-expressing cells, inducing both direct cytotoxicity and bystander effects, leading to tumor cell death. In the phase 3 trial EV-302, patients received Enfortumab Vedotin plus Pembrolizumab in three-week cycles, demonstrating significant improvements in both progression-free survival and overall survival as dual primary endpoints.
Urology Frontier: Combined immunotherapy may increase adverse reactions. How do you think it should be managed in clinical practice?
Dr. Jens Bedke: As with any new class of drugs, we must be vigilant about potential side effects. Dermatitis, particularly induced by immune checkpoint inhibitors, is a known concern, and skin reactions are closely monitored adverse events, especially in combination therapies. Additionally, neuropathy, both sensory and motor, may arise with Enfortumab Vedotin plus Pembrolizumab treatment. Management involves interdisciplinary collaboration, early awareness, and monitoring for side effects, allowing for prompt intervention through dose modifications or interruptions when necessary.
Urology Frontier: How should we identify the advantaged groups and thereby improve the clinical benefits for patients?
Dr. Jens Bedke: The challenge lies in preventing the development of metastatic disease in patients with UC. Significant progress has been made in the perioperative and neoadjuvant settings, with promising strategies such as Enfortumab Vedotin plus Pembrolizumab and other ADC combinations in clinical trials, alongside updates from trials like CheckMate-274, evaluating adjuvant Nivolumab post-cystectomy. Biomarkers play a crucial role in patient selection, as highlighted by the IMvigor011 trial’s ctDNA analysis, demonstrating its potential to predict bladder cancer recurrence post-cystectomy.
Dr. Jens Bedke
Klinikum Stuttgart Katharinen Hospital
