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 shared their thoughts on the EV-302 study, which showed that the enfortumab vedotin and pembrolizumab combination had “unusually expected good results.”
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Dr. Powles: Shilpa, you were on the EV-302 publication and that story, which has generated a huge amount of momentum, really was 1 around enfortumab vedotin (EV), a Nectin-4 antibody drug conjugate with MMAE as a payload microtubule-disrupting agent, which has shown in platinum-refractory disease to be associated with a 30% reduction in the risk of death.
Pembrolizumab we all know. If you don’t know if pembrolizumab, you’ve been on holiday for a long time, but it’s a PD-1 inhibitor and it’s an active agent. When you combine those 2 drugs together in a phase 2 study, we showed I think unusually expected good results. We showed response rates of about 70% and a toxicity profile, which we’ll talk about, which was manageable. We did this big study EV-302. Do you want to talk a bit about EV-302 and what we showed?
Dr. Gupta: EV-302 was the landmark study, phase 3 study, of platinum-based chemotherapy gemcitabine/cisplatin or gemcitabine/carboplatin based on the cisplatin eligibility criteria, not investigator’s discretion, unlike IMvigor130 versus EV/pembrolizumab. While avelumab was not a part of the treatment in the control arm per protocol amendment midway, it was allowed for patients who needed avelumab. I think around 30% patients ended up getting it where it was accessible and needed. As you showed, Tom, the overall survival (OS) doubling with EV/pembrolizumab, the response rates, the durability of response, the PFS [progression-free survival] doubling, all those really are outstanding results and everybody here knows what the data is. I think the data, there is no gray zone there and one might say 70% of patients did not get avelumab. But I think when you look at the hazard ratio of less than 0.5, that tells you that even if patients would’ve received avelumab, it’s probably the hazard ratio wouldn’t have been 0.8 or more than that.
I think that’s my take on it, that it’s certainly the better regimen. But I do have concerns about indefinite use of EV, which in my opinion is not needed. The median number of cycles patients got was 9. In our experience, we got a lot of patients on this study, the toxicity can get very distressing if we are not really asking patients about it. That to me is a big concern. Over 50% patients getting bad neuropathy and if left unchecked can be very disabling.
Dr. Powles: The study showed a 55% reduction in risk of progression, progression above 12 months, which we haven’t seen before. A 53% reduction in the risk of death with a median survival above 30 months. As you said, a response rate, a CR [complete response] rate of 30%, which is impressive. I think the proportion of patients who get maintenance avelumab is probably… in the real-world data, it’s actually about 25%. Now I think in a clinical trial, it’ll be higher than that because patients have been told at the beginning and they won’t know. But people talk about 10% primary progression rate, that’s the first scan. Well, to get maintenance avelumab, you could have 3 scans to that progression. You’ve got at the first scan mid between therapy, the second scan toward the end, and then the final. I can see about half of the patients not getting that. I would say about 50% is a tailwind number and you could get up to 60% I guess, and 20% feels a bit low to me and so that feels about right.
As I said before, I think the overall benefit, it might be about 10% overall in unselected patients because remember, the avelumab only starts the completion of chemotherapy. That’s where you hazard ratio starts. You go right back to the beginning of the start of the journey. It probably might dilute a hazard ratio by 5 or 10 points as I said for the nivolumab piece and that would bring it down to 0.55, which is still a 45% reduction in risk of death. It does seem to have swept away all the castles on the sandy beach, and we have a new standard of care.
Petros, there was in grade 3 or 4 or more adverse events; 70% for chemotherapy, 56% for EV/pembrolizumab. Toxic-related deaths were only 0.9%, no consistency, and skin toxicity, hypoglycemia, and peripheral neuropathy were all adverse events associated with EV/pembrolizumab.
Just talk a bit about that adverse event management. When you see a patient, what are you saying to them about what’s likely to happen? Shilpa is correct in that we keep going, and what does that conversation look like?
Dr. Grivas: First of all, I totally agree. I think the degree of benefit, the magnitude of benefit with the hazard ratio of 0.45 for PFS, 0.47 for OS is impressive, it’s transformative. The doubling of median OS is a huge transformational, not incremental improvement. I agree that the caveats may include the not ideal proportion of patients getting maintenance avelumab, but I agree with you, Tom, that this does not subtract on the impact of the trial. I think this is standard of care and should be in patients who can tolerate EV, which is the vast majority of patients. Hopefully in as many countries as possible because of the reimbursement issues. Think about the implementation of the new standard of care, which is very important. I think toxicity optimal management is key for the optimal experience of the patient and the provider. As you point out, Tom, in the EV-302 trial, 56% of patients had grade 3 or higher treatment-related adverse events, lower compared to chemotherapy. It was about 69% I think with chemotherapy.
Dr. Powles: 70%.
Dr. Grivas: 70%. That I think is a relevant point that you rarely see trials that have such huge improvement of survival and less toxicity. Now, what are those toxicities? I think peripheral neuropathy in about half of the patient, 50%, and those patients may have grade 1/grade 2. Grade 3 is less common, but you can argue that grade 2 neuropathy is impacting daily activity so it’s a relevant thing to keep in mind. I think all of us should keep a very low threshold to dose reduce and adjust enfortumab; that is happening in their world already, even in the context of pembrolizumab/EV or with EV monotherapy. Extra attention to neuropathy, and there are multiple questions and physical exam that needs to be done with the patient. We call the shower test. I ask the patient when they take a shower, when they close their eyes, do they need to grab into something, hold onto something to avoid falling.
Dr. Powles: You don’t encourage people to close their eyes in the shower?
Dr. Grivas: I do not. I do not. I do not. Keep your eyes open, that’s ideal.
Dr. Gupta: I ask them if they can button their shirts or feel the ground.
Dr. Powles: Yes, yes. A shower just sounds very risky to me.
Dr. Grivas: It is risky. Keep your eyes open overall, regardless of this conversation, keep your eyes open including the shower, I agree. But if they end up closing their eyes, do they need to hold them to something? That may tell us about proprioception and neuropathy. The point is, do a very good, detailed history, physical exam. Buttoning the buttons, tying the shoelaces, all the things that Shilpa, you mentioned are important questions. Skin rash, about half, maybe 60% of patients have skin rash, mostly grade 1/grade 2, managed with topical products, topical steroid creams and…
Dr. Powles: The skin rash is bad at the start of the journey and that’s important the first 3 cycles. What do you say to your patients when they leave the room for the first time on this drug about the skin rash? Do you say that don’t worry about it, we’ll treat through it, or what’s the conversation?
Dr. Grivas: I’m over-emphasizing, over-educating the importance of recognizing and reporting early and timely side effects, including the skin rash. Skin rash can be potentially life-threatening. Rarely, you see Stevens-Johnson syndrome with this drug so we cannot ignore it. I tell the patient to please immediately report as soon as possible any potential skin change, even if it’s mild; we need to evaluate, examine, and manage it. I think, Tom, and you and me have discussed this, that oncologists should take ownership of the management. It would be ideal when the resources are available to have additional resources like dermatologists that we have the luxury of having in academic centers, and we need more information of course and education to them. But I’d overemphasize the need to not ignore and not minimize skin rash or any other side effects.
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