Post-EV/Pembro Progression: How Real-World Data is Shaping 2L Treatment Decisions

A virtual roundtable, hosted by Dr. Petros Grivas of Fred Hutchinson Cancer Center, contextualized the latest bladder cancer research updates and trials of relevancy to come out of the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium. Dr. Grivas was joined by Drs. Guru Sonpavde, Elizabeth Plimack, Christopher Wallis, Terence Friedlander, and Matthew Galsky.

In the third segment of the roundtable, the panel covers second-line treatment options for metastatic urothelial cancer post-EV/pembro, with emphasis on platinum-based chemotherapy, targeted therapies, and the need for better data to guide sequencing. They summarize findings from the NIAGARA and CheckMate 274 trials on perioperative immunotherapy, while also highlighting the importance of multidisciplinary care and evolving bladder-preserving strategies.

View the next segment on Bladder-Sparing with Systemic Therapy: Insights from RETAIN-2 and Future Directions.

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Dr. Grivas: Dr. Friedlander, before we expand on the perioperative setting, let me ask you about a patient receiving enfortumab vedotin and pembrolizumab (EV/pembro) in the frontline setting at UCSF. Suppose the patient does well but experiences disease progression a year later. What would be your approach in the second-line setting, assuming no clinical trial is available? What parameters influence your decision-making?

Dr. Friedlander: The treatment landscape has changed significantly with the introduction of EV/pembro. Despite this, most providers agree that platinum-based chemotherapy still plays an important role. It remains effective in treating urothelial cancer, although it does not seem to produce the durable, long-term responses observed with EV/pembro.

Without robust prospective data, platinum-based chemotherapy remains our primary second-line option. Approved alternatives in urothelial cancer include FGFR inhibitors for patients with FGFR-2 or FGFR-3 mutations and HER2-directed therapy with trastuzumab deruxtecan, which is currently used in later-line settings for patients with HER2/3-positive disease.

Sacituzumab govitecan, as presented at ESMO Asia, unfortunately failed to outperform taxane chemotherapy in a randomized phase 3 trial, leading to the company’s withdrawal of FDA approval. While still accessible to some patients, particularly in breast cancer, its use in urothelial carcinoma is now uncertain.

I consider clinical trials for nearly every patient who is refractory to EV/pembro. If a rapid response is necessary—such as in cases of liver progression or spinal cord disease—platinum-based chemotherapy is the preferred option. I have administered both cisplatin and carboplatin in the second-line setting and observed responses to both, with cisplatin offering superior outcomes when patients are eligible. However, we need prospective data to guide optimal treatment sequencing. Some recent studies presented at ASCO GU have explored response rates to platinum therapy in the post-EV/pembro setting, but given the recent adoption of this regimen worldwide, we are just beginning to gather meaningful data on treatment outcomes.

Dr. Grivas: I agree that real-world data provides an initial perspective on treatment patterns while we await prospective trials to refine therapeutic sequencing. The past few years have brought significant changes with the approval of first-line EV/pembro. Additionally, we now have two FDA-approved targeted therapies for metastatic urothelial cancer: the revised approval of erdafitinib for patients with FGFR-3 alterations and HER2-directed therapy.

With that discussion in mind, I would like to shift our focus to localized disease. Dr. Galsky, you have been involved in both the NIAGARA and CheckMate 274 trials. Could you summarize the key data from these studies to provide some context before we hear Dr. Wallis’ perspective as a urologist?

Dr. Galsky: It is important to highlight the differences between these treatment strategies, as they apply to distinct patient populations. NIAGARA enrolled patients with clinically localized muscle-invasive bladder cancer, randomizing them to either four cycles of gemcitabine and cisplatin plus durvalumab followed by cystectomy and eight cycles of adjuvant durvalumab, or four cycles of neoadjuvant gemcitabine and cisplatin followed by cystectomy with no planned adjuvant treatment.

This trial permitted patients with a creatinine clearance as low as 40 mL/min, allowing those with clearance between 40 and 60 mL/min to receive split-dose cisplatin. Although this expanded eligibility criteria slightly, the study did not include cisplatin-ineligible patients. Additionally, patients undergoing upfront cystectomy without neoadjuvant therapy—still common in many practices—would not have been candidates for this approach.

In contrast, CheckMate 274 included patients who had undergone neoadjuvant chemotherapy without immunotherapy but had pathological T2 or higher disease post-surgery, as well as patients who were ineligible for neoadjuvant chemotherapy with T3 or higher disease. The primary endpoint for NIAGARA was event-free survival, which showed improvement, along with an overall survival benefit as a secondary endpoint. CheckMate 274 met its co-primary endpoints, demonstrating improved disease-free survival in both the overall population and in patients with high PD-L1 expression. While an overall survival analysis is still pending, interim results suggest a similar trend favoring treatment.

Dr. Grivas: Dr. Wallis, from a urologist’s standpoint, how do these data impact your clinical practice?

Dr. Wallis: Muscle-invasive bladder cancer is an area where multidisciplinary care is essential to achieving the best outcomes. Effective management requires close coordination between specialties, and institutions need to establish structured approaches to ensure smooth transitions between care teams.

In our practice, we refer patients to medical oncology after diagnosis and avoid prescriptive decisions regarding specific systemic therapy regimens. Our neoadjuvant chemotherapy utilization is over 60%, which aligns with best practices. However, a subset of patients remains cisplatin-ineligible, particularly among older individuals. Current urology guidelines recommend upfront cystectomy in the absence of a clinical trial for these patients, making it a viable option for select cases.

Another key consideration is the need for tailored treatment strategies. Patients with strong pathological responses to neoadjuvant chemo-immunotherapy may be hesitant to undergo eight additional cycles of adjuvant durvalumab. With the increasing availability of circulating tumor DNA analysis, we may soon be able to personalize adjuvant treatment decisions more effectively.

Finally, while these trials focus on surgery-based approaches, there is growing interest in bladder-preserving strategies such as trimodal therapy. The optimal integration of systemic therapy in the setting of chemoradiation remains unclear, and further research is needed to refine peri-radiotherapy systemic treatment strategies.

Dr. Grivas: Those are excellent points. We all share the goal of increasing bladder preservation and identifying patients who could achieve long-term remission with systemic therapy alone. Ongoing trials, including those led by Drs. Galsky and Plimack, will be critical in advancing these efforts.