Single-Agent ADCs in Urothelial Carcinoma: Where We Stand and Where We Are Going

Elizabeth Plimack, MD, MS, FASCO, Deputy Director at Fox Chase Cancer Center, provides a summary of her presentation at the Society of Urologic Oncology (SUO) Annual Meeting on the progress of antibody-drug conjugates (ADCs) in bladder cancer research. Updates on the effectiveness of trastuzumab deruxtecan and disitamab vedotin anchor her discussion.

Can you provide an overview of the current ADC landscape in urothelial carcinoma?

Dr. Plimack: During my 10-minute presentation at SUO, I aimed to familiarize urologists with the concept of ADCs. Crafting the talk was enjoyable as it involved delving into the design intricacies of these agents. ADCs are essentially engineered antibodies featuring a specific target and a payload. In urothelial cancer, the targets include HER2, TROP-2, or NECTIN-4, while the payloads consist of MMAE, SN-38, and DXd chemotherapy derivatives. This involves a creative mix-and-match process of pairing targets with antibodies, along with proprietary linkers that determine the drug’s stability.

What makes these conjugates intriguing is their design to remain completely stable in circulation, only dissolving and being deployed within the cell once in the tumor microenvironment. However, we are not yet achieving this goal. Currently, less than 1% of the drug meets the tumor microenvironment, and approximately 10% dissolves or dissociates in the circulation, leading to toxicity. Undoubtedly, ongoing efforts by engineers and scientists are underway to improve these conjugates and shift the ratio of tumor effect to systemic effect in a more favorable direction.

In the realm of urothelial carcinoma, 3 or 4 ADCs are either in development or approved. Notably, enfortumab vedotin and sacituzumab govitecan are already in use, while the HER2-directed therapies, disitamab vedotin and trastuzumab deruxtecan, are in earlier stages of development. Enfortumab vedotin and sacituzumab govitecan are approved drugs for patients previously treated for urothelial carcinoma, and enfortumab vedotin, in combination with pembrolizumab, has recently gained approval for front-line treatment in metastatic urothelial carcinoma.

For the HER2-directed therapies, it seems that their use will likely be limited to patients with the HER2 biomarker and demonstrated overexpression. While there is some evidence suggesting activity in patients without the biomarker, the primary focus of development has been on those expressing the biomarker.

What does the DESTINY-PanTumor02 trial tell us about the effectiveness of trastuzumab deruxtecan and its likely place in the treatment paradigm?

Dr. Plimack: Regarding trastuzumab deruxtecan, the most recent data was presented at the European Society for Medical Oncology Congress 2023 through the DESTINY-PanTumor trial. This trial explored trastuzumab deruxtecan at a standard dose across 7 different tumor types, with a comprehensive analysis. For the purpose of my SUO talk, I focused specifically on the bladder cohort. The data revealed that these were biomarker-selected patients with IHC3+ or 2+ for HER2. The overall response rate for IHC3+ was 56%, and for IHC2+, it was 35%. Interestingly, regardless of HER2 expression, the progression-free survival endpoint remained consistent.

The trial included patients with varying prior therapies: half with 0, 1, or 2 prior treatments, and the other half with more extensive treatment history. Realistically, we are likely to position trastuzumab deruxtecan after enfortumab vedotin, pembrolizumab, and potentially chemotherapy, depending on the evolving landscape, particularly the uncertainty around chemotherapy in the second-line space.

When examining subsets of these data, my focus is on how more heavily pre-treated patients fare and whether there are any discernible signals in their outcomes.

What does the recent pooled study of disitamab vedotin suggest about its potential in the treatment armamentarium for urothelial carcinoma?

Dr. Plimack: The latest analysis on disitamab vedotin, recently published, combines data from 2 single-arm trials focusing on HER2-positive urothelial carcinoma in patients with at least 1 prior therapy. Notably, approximately 33% of the patients in this study had only undergone 1 prior therapy, although this is not the typical treatment sequence. Generally, patients receive at least a checkpoint inhibitor and chemotherapy before transitioning to an ADC, unless they undergo upfront enfortumab vedotin and pembrolizumab.

The study demonstrated a favorable response rate of 49%, with 18% experiencing progression. The remaining patients achieved some level of disease control or stability. Of particular interest is the substantial tumor shrinkage evident in the waterfall plot, even among patients without resist responses. It is worth noting, however, that the durability of response for disitamab vedotin, as well as other ADCs with similar data, appears to be relatively short. In the pooled analysis, most patients on disitamab vedotin progressed within a year.

Exploring ways to extend the duration of response, potentially through combination therapies, is a promising avenue. While not covered in my 10-minute talk, there are intriguing data on combining disitamab vedotin with immunotherapy that warrant further consideration.

What are the noteworthy adverse events associated with these therapies, and what should clinicians understand when weighing the benefits against the risks?

Dr. Plimack: In essence, my philosophy, shared by many colleagues, is that if a patient is well enough to consider a treatment, they are likely well enough to try an ADC. The key is to select the ADC with the anticipated highest efficacy and then address any associated toxicity through measures like dose holds, reductions, and supportive care. In my view, there are no specific side effects that would deter me from treating a patient if I believe the treatment could be effective.

However, I might exercise more caution or express greater concern for patients with glucose intolerance when considering enfortumab vedotin, those with a history of autoimmune skin disease with enfortumab vedotin, or individuals with pre-existing neuropathy when dealing with topoisomerase-based payloads such as SN-38 and DXd. This pertains to sacituzumab govitecan and trastuzumab deruxtecan. For these cases, gastrointestinal side effects and cytopenias may arise, and the approach is to initiate the drug and observe the patient’s response while providing necessary support. While encountering grade 3 or grade 4 side effects is not ideal, early detection and management can mitigate the impact of these issues.