Editor's Note: The landscape of advanced urothelial cancer (UC) treatment is rapidly evolving. Historically dominated by platinum-based chemotherapies, recent years have seen a paradigm shift towards more targeted therapies and immunotherapy combinations. This article delves into the current state and future directions of advanced UC treatment, featuring insights from Dr. Thomas Powles. We explore the unmet needs within this area, the potential of new treatments like disitamab vedotin, and the broader implications of these developments for patient care.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.
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.
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.
