Balancing EV/Pembro and Gem/Cis-Nivo: Selecting the Right 1L Therapy for Node-Only Disease

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 second segment of the roundtable, the panel highlights the role of enfortumab vedotin plus pembrolizumab as the preferred first-line therapy for bladder cancer and the potential need for consolidation with surgery or radiation after a strong systemic response. Experts also debate patient selection, alternative regimens like gemcitabine-cisplatin with nivolumab, and the balance between escalation and de-escalation strategies in the absence of definitive randomized data.

View the next segment on Post-EV/Pembro Progression: How Real-World Data is Shaping 2L Treatment Decisions.

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Dr. Grivas: Dr. Sonpavde, let me ask you a question. Of course, enfortumab vedotin plus pembrolizumab (EV/pembro) is the preferred standard of care. Can you describe which patients you may choose not to use EV/pembro for in your practice, if any?

Dr. Sonpavde: Yes, I believe EV/pembro is clearly the preferred first-line regimen based on the data. However, one group in which I have considered gemcitabine-cisplatin plus nivolumab (gem-cis/nivo) is patients with lymph node-only disease. The data we presented at ASCO last year showed that complete responses (CRs) in these patients are highly durable, with a median duration of CR of approximately three years. In cases of lymph node-only disease, the responses appear even more durable.

That being said, I was also impressed by the updated EV/pembro data presented at GU ASCO this year, which showed a median duration of response of around two years overall. More notably, approximately 75% of complete responses exceeded two years, suggesting promising durability. However, I do not yet see the same differential in response between lymph node-only disease and visceral disease with EV/pembro as I observed with gem-cis/nivo. For that reason, I still consider gem-cis/nivo in patients with lymph node-only disease.

Dr. Grivas: Understood. Thank you, and congratulations on your work with the trial you mentioned. That was an important study, presented in the same plenary session at ESMO 2023. Of course, EV/pembro generated significant attention, but if EV/pembro were not available, gem-cis/nivo would likely have received even more recognition.

May I ask, are there any medical comorbidities or specific patient profiles that would make you more hesitant to use EV/pembro, even at a reduced dose? Again, we all acknowledge that it is the strongly preferred regimen.

Dr. Sonpavde: Yes, it is important to remember that the EV-302 trial included very few patients with a performance status (PS) of 2: fewer than 5%. Patients with both poor renal function and PS2 were not eligible for the trial. Therefore, patient selection is critical when considering EV/pembro.

For frail patients with both PS2 and poor renal function or other significant comorbidities, I believe the JAVELIN paradigm remains a viable approach. In such cases, I prefer gemcitabine-carboplatin (gem-carbo), ideally using a split-dose regimen, followed by maintenance avelumab. I use pembrolizumab monotherapy in the first-line setting very sparingly, primarily for PD-L1 high patients. While it is approved for all platinum-ineligible patients, the concern is the potential for rapid disease progression in frail, sicker patients.

Dr. Grivas: That was a great discussion. Dr. Wallis, let me turn to you as the urologist in our tumor board today. How common is it to encounter patients with lymph node-only disease, as in Dr. Sonpavde’s example? Specifically, for patients with pelvic or possibly retroperitoneal lymph node involvement, if they achieve a strong clinical and radiologic response to EV/pembro, would you consider consolidation with radical cystectomy? In what scenarios would you entertain that option?

Dr. Wallace: That is a great question. I think we will return to different aspects of this topic later, but the key issue is how systemic therapy is improving and enabling us to clear low-volume metastatic disease. This evolution prompts a reconsideration of our local treatment paradigm and whether we should incorporate consolidation therapy.

Surgical consolidation is one approach, but we can also consider radiation-based consolidation. The first question to ask is whether there is a strong systemic response, as that is a critical factor. Once that is established, the next step is determining whether local consolidation offers additional clinical benefit.

We have performed cystectomies and pelvic lymph node dissections, including retroperitoneal lymph node dissections up to the renal hilum, though this is not common. These cases typically involve younger patients with excellent systemic responses. To be transparent, I have done this in the context of older perioperative cytotoxic paradigms, but I have not yet performed it in an immunotherapy-based systemic environment.

As we explore the perioperative use of EV/pembro, we must ask whether consolidation is necessary at all. On one hand, stronger systemic therapy may allow us to consolidate more patients who were previously not considered for local therapy. On the other hand, improved systemic therapy may reduce the need for local treatment, allowing for greater bladder preservation. Moving forward, we will see more nuanced, patient-centered decision-making rather than a one-size-fits-all approach.

Dr. Grivas: Before I turn to Dr. Galsky, I would like to ask Dr. Plimack for her thoughts. I know you have done extensive work in bladder preservation. Does this scenario come up in your tumor boards, particularly in cases of pelvic-confined lymph node disease where there is a strong response to EV/pembro? Would you consider consolidation with radiation or surgery?

Dr. Plimack: Yes, absolutely. This scenario arises in our tumor board discussions all the time. For locally advanced, unresectable disease, we typically start with EV/pembro because it has the highest response rate and achieves deep responses. However, I agree with Dr. Wallis that we do not yet know if consolidation offers additional benefit after a complete response. Some of these responses can be quite durable, as demonstrated in the EV-302 trial.

These patients would have been included in EV-302, and we often deliberate over whether consolidation is truly necessary. We acknowledge that some patients may already have long-term responses without additional treatment. It remains an open question, and I would be very interested to hear Dr. Galsky’s perspective.

Dr. Grivas: Dr. Galsky, what are your thoughts? You have done extensive work in this area, including leading the HCRN trial. How do you approach this scenario?

Dr. Galsky: I agree with Dr. Wallis’ perspective that it is not contradictory to consider both escalation and de-escalation with newer therapies. Some patients who were previously not considered curable may now be potentially curable with a strong response followed by surgical consolidation. Conversely, some patients with clinically localized disease may achieve long-term control with transurethral resection and systemic therapy alone.

Our challenge is identifying which patients fall into each category. However, we all have patients in our practice who fit this description. I have treated patients 10 to 15 years ago with clinical node-positive disease who received systemic therapy followed by surgical consolidation and remain disease-free off treatment a decade later. These patients are functionally cured.

Would they have achieved the same outcome without surgery? That remains unknown. However, we know that with surgery, they are cured. In situations where we lack randomized data, we understand what can be accomplished, but we still need to refine our understanding of what should be done for each patient using the treatment options available.

Dr. Grivas: Excellent point. As you mentioned, just because we can achieve certain outcomes does not mean we fully understand why they occur or what is driving them. This is an important area for continued investigation.