Treatment Combinations in the Neoadjuvant Setting and Impacts to Potential Subsequent Surgery

A roundtable discussion, moderated by Thomas Powles, MBBS, MRCP, MD, covered the latest updates in bladder cancer treatment and research, including recent data from ESMO 2023. Dr. Powles was joined by Shilpa Gupta, MD; Sia Daneshmand, MD; and Petros Grivas, MD.

In the next segment of the roundtable series, the panel discusses the potential shift of new therapies to the frontline setting and how that will impact subsequent treatment decisions.

Watch the next segment in this series.

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Dr. Powles: Sia, what we’ve done as a community is we’ve moved these drugs very quickly into the neoadjuvant space, and there are a plethora of neoadjuvant trials. There are some chemotherapy/immune therapy trials, there’s cisplatin nivolumab for example, but there’s cisplatin/durvalumab… but there’s also EV [enfortumab vedotin]/pembrolizumab in both cisplatin-eligible and in cisplatin-ineligible, and durvalumab/tremelimumab/EV neoadjuvant triplets. In some of the trials you’re giving a period before and after the surgery, in other trials you’re only giving it before. What’s your take on this neoadjuvant space, whether or not these trials are going to be positive? We talked about pathologic CR [complete response] before, but DFS [disease-free survival] and OS [overall survival] are both I think crucial endpoints. Then I guess the last piece is how easy is it from a surgical perspective once we put these patients through these cycles to do the operations and is it safe?

Dr. Daneshmand: Loaded questions.

Dr. Gupta: You can handle it, Sia.

Dr. Grivas: And only a few, only a few.

Dr. Daneshmand: First of all, it’s super exciting. We see these data and immediately our minds are thinking this is absolutely going to move into the neoadjuvant space, and how is that going to impact what we do afterward? There are 2 ways to think about it. One is are we going to improve the CR rate and hence outcomes of the patients? The patients who have CR with chemotherapy do extremely well. They have 85%, 90% survival rate post-cystectomy. The question really is how many of them need a cystectomy? That same question is going to be posed once we move these agents into their earlier phases and do neoadjuvant chemotherapy. If we see very high CR rates, you’re going to see the next set of trials that are going to examine whether or not they need cystectomy.

Again, that’s going to take a while; we’re going to talk about again what does it mean for CR. We’re very excited. The first phase is of course we’ve had the PURE trial with pembrolizumab showing 35%, 40%, all the neoadjuvant for cisplatin-ineligible checkpoint trials show about that 35%, 40% CR rate, which is interesting and exciting, certainly more than the 20%, 25% we see with chemotherapy. Question is does it really make a difference on the other end? Do we still need the cystectomy and what component is that treating? Theoretically, it’s treating the micrometastatic disease. Do we have micrometastatic disease? Does every patient need neoadjuvant therapy? There are lots of these questions and I think part of it will be with biomarker assessments, and the ctDNA is super exciting to me to see whether we can actually select patients for…

Dr. Gupta: I have a question here. In these perioperative trials, even when patients do get CR, they continue EV/pembrolizumab. Is there really going to be a need for that in the adjuvant setting?

Dr. Powles: I think Sia’s points around ctDNA is going to turn out to be important. I also think the CR rate of 30% and the early response as you described, I can see those EV/pembrolizumab trials being positive for survival. The chemotherapy/immune therapy studies, I think there is a degree of antagonism. I’m involved in all sorts of bits… but I just don’t feel they’re perfect. Even cisplatin-based therapy, I don’t think the KETNOTE-361, the IMvigor130, and the study we’ve just talked about, the CheckMate 901 trial, they don’t seem to show a massive bounce in general response and the curves seem to go apart afterward. I’m a bit anxious about those trials because I don’t think the 2 are acting together in a synergistic way. But there does seem to be something additive at least around the EV/pembrolizumab and with a CR rate of 30%, I would expect those trials to be positive.

Dr. Daneshmand: I think bottom line, you have to think about this. With metastatic disease, you have disease that’s already out there, it’s outside the bladder. With localized bladder cancers we have a clinical T2 or T3, there are some patients who actually have localized disease. We’re over-treating a proportion of patients with systemic agents that really could have had a cystectomy, and then we’re under treating some because we only give them neoadjuvant chemotherapy and then cystectomy and plus minus adjuvant nivolumab, but it may not be enough. We really need to sort out who has localized disease, who has actual metastatic disease, and I think that’s, like you said, where the ctDNA comes in and other perhaps biomarkers to tell us exactly what’s going on before it becomes radiographically evident. Because once it does, I think we’ve lost our chance.

Dr. Grivas: On that note quickly, I think all 3 of us are part of the International Bladder Cancer Group, IBCG guidelines, trying to develop a framework, some guidelines of how can design optimal trials to enable the concept of bladder preservation with systemic therapy alone. How can we rely on a clinical complete response rate after we properly define it and correlate it with long-term time to prevent endpoint? Negative cystoscopy, cytology, negative MRI maybe or CT and potentially negative ctDNA, all of the above might help us select the patients who might be able to be eligible for bladder preservation with systemic therapy alone.

Dr. Daneshmand: You’re trying to put me out of a job is what you’re saying.

Dr. Grivas: Or help us achieve the bladder preservation cure.