Editor’s Note: Urothelial carcinoma is one of the most common malignancies of the urinary system, with high incidence and mortality rates. Despite the efficacy of platinum-based chemotherapy as the standard first-line treatment for advanced urothelial carcinoma, researchers have been relentless in their pursuit of more effective and personalized treatment options. Recent breakthroughs in targeted therapies and immunotherapies have spurred the development of various combination therapies, bringing new hope to patients with advanced urothelial carcinoma. At the recently concluded 39th Annual Congress of the European Association of Urology (EAU24), Oncology Frontier had the privilege of interviewing Professor Thomas Powles from the University of London and Barts Cancer Institute. In this interview, Professor Powles detailed the current status and challenges in the field of advanced urothelial carcinoma, as well as future directions worth exploring.
Study Overview
Vidicetumab Monotherapy and Combination Therapy with Pembrolizumab versus Chemotherapy in HER2-Expressing Locally Advanced or Metastatic Urothelial Carcinoma (Abstract No. A0746)
Vidicetumab has shown promising anti-tumor activity and manageable safety in patients with HER2-expressing locally advanced or metastatic urothelial carcinoma (LA/mUC), both as a monotherapy post-platinum treatment (HER2 IHC 3+/2+ ORR: 50.5%) and in combination with PD-1 inhibitors (HER2 IHC 3+/2+ ORR: 83.3%; HER2 IHC 1+ ORR: 64.3%).
DV-001 is an open-label, randomized, multicenter, controlled phase III trial designed to evaluate the efficacy and safety of vidicetumab combined with pembrolizumab versus chemotherapy in treatment-naive HER2-expressing LA/mUC patients. The primary endpoints are progression-free survival (PFS) and overall survival (OS), with secondary endpoints including objective response rate (ORR), duration of response (DOR), disease control rate (DCR), incidence of adverse events, and impact of treatment on quality of life. The study is currently recruiting in the USA, Canada, and Australia, with plans to expand to research centers in Europe, Latin America, and Asia.
Insights from the Researcher
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Oncology Frontier: Currently, platinum-based combination chemotherapy remains the standard first-line treatment for advanced urothelial carcinoma (UC). What unmet needs do you see for patients with advanced UC?
Professor Thomas Powles: The landscape of first-line treatment for metastatic urothelial carcinoma has indeed evolved. Globally, the combination of enfortumab vedotin and pembrolizumab has shown significantly better results than platinum-based chemotherapy (regardless of avelumab use), doubling overall survival, halving progression-free survival rates, and achieving a response rate of 70%, with a complete response rate of 30%. This makes enfortumab vedotin combined with pembrolizumab the new standard of care. For those unable to receive this combination therapy, platinum-based chemotherapy remains an option, which is still the case in many parts of the world. For instance, in the UK, we do not yet have access to this combination therapy.
Another critical aspect is the education and training on managing adverse events and toxicity. Interestingly, the combination of enfortumab vedotin and pembrolizumab is not more toxic than chemotherapy; in fact, the incidence of grade 3 or 4 adverse events is lower. However, skin toxicity and peripheral neuropathy do require attention, making dose reduction and treatment delays necessary. Additionally, immunotherapy sometimes necessitates the use of steroids. These are exciting times in the field of urothelial carcinoma treatment, with advancements that are reshaping treatment paradigms.
Oncology Frontier: Currently, platinum-based combination chemotherapy is still the first-line standard treatment for advanced UC. What unmet needs do you think exist for patients with advanced UC?
Dr. Thomas Powles: The frontline treatment landscape in metastatic urothelial cancer has indeed changed. Globally, the combination of enfortumab vedotin and pembrolizumab significantly outperforms platinum-based chemotherapy, with or without avelumab, doubling the overall survival, halving the progression-free survival rate, and achieving response rates of 70%, including complete response rates of 30%. This makes enfortumab vedotin plus pembrolizumab the new standard of care. Platinum-based chemotherapy remains an option for those who don’t have access to this combination, which is still the case in many parts of the world. In the UK, for instance, we do not yet have access to it. Another focus should be on education and training regarding adverse events and toxicity management. Interestingly, the combination of enfortumab vedotin and pembrolizumab is not more toxic than chemotherapy; actually, the grade 3 or 4 adverse event rate was lower. However, skin toxicity and peripheral neuropathy do require attention, necessitating dose reductions and delays. Additionally, immune therapy sometimes necessitates the use of steroids. It’s an exciting time in urothelial cancer treatment, with these advances changing the treatment paradigm.
02
Oncology Frontier: Previous studies have shown that patients with advanced UC overexpressing HER2 can benefit from vidicitumab treatment. This phase III study uses an immunotherapy combination strategy. What are your expectations for its results?
Professor Thomas Powles: Vidicitumab is a HER2-targeted antibody-drug conjugate (ADC) with monomethyl auristatin E (MMAE) as the payload, showing considerable potential. Chinese researchers have published significant articles in the Journal of Clinical Oncology (JCO) highlighting its activity in both HER2 low and overexpression cases. The current evaluation involves HER2 immunohistochemistry (IHC) 1, 2, or 3+ expression levels. This drug has been approved in China as a monotherapy and is now being explored in combination with immune checkpoint inhibitors. There is a possibility that it could achieve efficacy comparable to the combination of enfortumab vedotin and pembrolizumab in specific patient groups.
The front-line randomized phase III trial comparing this combination with chemotherapy is crucial, as this drug combination could become the global standard. The comparison with enfortumab vedotin plus pembrolizumab will be indirect, focusing on efficacy and potential differing toxicity profiles.
Another critical issue is the sequencing of these drugs, especially post-neoadjuvant treatment with enfortumab vedotin plus pembrolizumab, particularly for patients who relapse. The recent FDA approval of T-DXd (trastuzumab deruxtecan) for HER2-overexpressing solid tumors marks rapid progress in this field. We also need to consider the role of erdafitinib for FGFR-altered patients as a third-line option, and its unique toxicity profile needs to be confirmed.
Oncology Frontier: Previous studies have shown that patients with advanced UC with HER2 overexpression may benefit from treatment with disitamab vedotin. This phase 3 study uses a combination immune strategy. What are your expectations for its results?
Dr. Thomas Powles: Disitamab vedotin, a HER2-targeting antibody-drug conjugate (ADC) with monomethyl auristatin E (MMAE) as the payload, shows promise. Significant publication from China in the Journal of Clinical Oncology (JCO) highlighted its activity in both low and high HER2 expression contexts. It’s under evaluation in HER2 one, two, or three-plus expressions on immunohistochemistry (IHC). The drug is approved in China as a single agent and is being explored in combination with immune checkpoint inhibitors. This could potentially align with the efficacy of enfortumab vedotin and pembrolizumab in selected patients. Frontline randomized phase Ⅲ trials against chemotherapy are crucial, as this combination may become a global standard. The comparison to enfortumab vedotin plus pembrolizumab will be indirect, focusing on efficacy and potentially differing toxicity profiles.
Sequencing of these agents, especially post-neoadjuvant use of enfortumab vedotin plus pembrolizumab, is another critical question, particularly for patients who relapse. The FDA’s recent basket approval of T-DXd (trastuzumab deruxtecan) in HER2 high, 3 plus patients signifies rapid advancements in this area. We also need to consider the role of erdafitinib in FGFR-altered patients as a third-line option, acknowledging its unique toxicity profile.
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Oncology Frontier: What other directions do you think are worth exploring in the field of advanced UC?
Professor Thomas Powles: The introduction of enfortumab vedotin combined with pembrolizumab as a first-line therapy is transformative, potentially extending to the perioperative setting. This necessitates redefining first-line treatment for patients who have received this combination therapy. We are investigating combinations of ADCs, such as enfortumab vedotin with sacituzumab govitecan, which has shown a 70% response rate. This could challenge the current first-line standard. Upcoming studies, like TROPiCS-04, comparing sacituzumab govitecan with single-agent taxane chemotherapy, are crucial to establishing its global applicability.
Exploring combinations of chemotherapy and ADCs is also underway, such as carboplatin with T-DXd or sacituzumab govitecan. Using biomarkers, particularly ctDNA, in patients post-cystectomy offers a promising path for early intervention and potentially higher cure rates. In this context, trials involving agents like atezolizumab are vital.
Overall, the field is rapidly evolving, focusing on refining treatments for previously treated patients and using biomarkers for personalized therapy. The sooner we act, the more patients we can ultimately cure.
Oncology Frontier: What other directions do you think are worth exploring in the field of late-stage UC?
Dr. Thomas Powles: The introduction of enfortumab vedotin plus pembrolizumab as a first-line treatment has been transformative, potentially extending into the perioperative space and necessitating a redefinition of first-line therapy for those pre-treated with this combination. We’re looking at combinations of antibody-drug conjugates (ADCs), such as enfortumab vedotin with sacituzumab govitecan, showing a 70% response rate. This may challenge the current first-line standard. Upcoming studies, such as TROPiCS-04, comparing sacituzumab govitecan against single-agent taxane chemotherapy, are crucial for defining its global utility. Combining chemotherapy with ADCs, like carboplatin with T-DXd or sacituzumab govitecan, is also under exploration. Furthermore, the use of biomarkers, particularly ctDNA in patients post-cystectomy, offers a promising avenue for early intervention and potentially higher cure rates. Trials like the one with atezolizumab in this context are pivotal. Overall, the landscape is rapidly evolving, with a focus on refining treatments for pre-treated patients and leveraging biomarkers for personalized therapy. I think the early we go, in the end the more patients we cure.
Thomas Powles University of London Barts Cancer Institute
Professor Thomas Powles is a Professor of Urological Oncology at the University of London and the Director of the Barts Cancer Institute. He has played a pivotal role in the development of biomarkers and new drug strategies for urological cancers, particularly first-line immunotherapy/targeted therapy combinations for renal cell carcinoma and immune checkpoint inhibitors, both as monotherapy and in combination, for bladder cancer.
Professor Powles has led numerous clinical trials (including 21 randomized trials) and translational oncology research projects, all of which have been published in major journals. He currently serves as the Editor-in-Chief of the Annals of Oncology, a member of the ESMO Council, and a member of the EAU Renal Cancer Guidelines Committee. His current work focuses on new adjuvant/neoadjuvant therapies for early bladder and kidney cancers and identifying patients at risk of postoperative recurrence.
