Enfortumab vedotin + Pembro FDA Approval in Muscle Invasive Bladder Cancer (MIBC): Dr. Thomas Powles

Groundbreaking EV Pembro Approval and Keynote-905 Study Findings Thanks for joining us for another bite sized update on the Oncology Brothers podcast. As community medical oncologist, we know how fast bladder cancer is evolving, be it in non muscle or muscle invasive bladder cancer. Earlier this year, in March 2025, duvalumab with chemotherapy in peri op settings followed by additional duvalumab after cystectomy became the new standard of care for resectable muscle invasive bladder cancer. But in the second-half of this year, we have yet another approval in this space, EV pembro based off Keynote 905, EV 303 study. Good morning everyone. I'm Rahul Ghosain here with my brother and Co host Rohit Ghosain. Speaker 2 Rahul, we've covered quite a few FDA approvals. This one has to be the most profound study of 2025, especially when you tie in event free survival and overall survival with hazard ratio of 0.5 bearing the EV pembro arm. We have quite a bit to cover here. And to walk us through the study, we're joined by world renowned Gu medical oncologist, Doctor Tom Powells. Tom, thanks so much for joining us. Speaker 3 Thanks for inviting me, it's nice to see you both. Speaker 1 Tom, welcome on the world of bladder cancer. This is a third home run in a row from EV3O2 in metastatic settings to nigra trial. And we covered that with you back in March of this year. And now EV3O3, you know, it's overwhelming to keep up with all this, but at the end of the day, this is good news for our patients because they are indeed living longer because of these advances. All right, let's get started with EV3O3. Tom, can you touch on the study design and its findings? Speaker 3 So actually it's Keno nine O 5 as well because the study was run by MSD and the investigator did a brilliant job. It's a randomized phase three study. It's for muscle invasive bladder cancer. That's for T2 to T4N1 test that group of patients. But importantly it's for those individuals who weren't previously getting neoadjuvant platinum based chemotherapy. So it's distinct from that population that we talked about previously that have a good kidney function and are able to get GEM cyst duvalumab. And as we know in the Niagara study that had a survival advantage. And so those patients are getting GEM cyst you've and Perioptia duvalumab. But what about those patients who at the moment are not able to have neoadjuvant chemotherapy? At the moment, we're doing cystectomy alone and that's the control arm of this trial, but we're comparing that to perioperative EV pembro 3 cycles before surgery, 5 cycles after surgery with a total of a year of immune therapy. Now in the trial design, there was originally a duvalium abalone arm. We didn't see the results of that. And I think that's really exciting and important because it'll give us some idea of component parts. The trial was modest in size. Niagara had 1000 patients, this had 350 patients, but the results were overwhelmingly positive. There were two striking features. Firstly, you just talked about a doubling in overall survival, but we also saw a pathological complete response rate of 57%. And that high pathological CR tells us that systemic therapy is having a profound effect on these patients. And indeed, if you look now, the control arm performs in this trial, the control arm performs really poorly. The event free survival, most patients are relapsing within two years. So what this tells us is 2 things #1 systemic therapy is really effective at getting in control of disease. But #2 those patients who are having cystectomy alone, most of them already have advanced disease. You just can't see it yet on CT. And therefore doing upfront surgery is actually not the right choice. The right choice is get control of the systemic disease. So effective systemic therapy, in this case in the cisplatin ineligible population, EV pembro with a path CR 8 of 57% and a doubling in Oval survival is really good at that. And so that becomes the new standard of care. Managing EV Pembro Toxicity and Patient Selection Considerations Now of course, there are issues around toxicity that we need to address. EV pembro in my experience is no more difficult cycle per cycle than platinum chemotherapy. Indeed, I think cycle per cycle it's easier, but there is an early skin rash that needs attention. There is some transaminitis as well. And as treatment goes on, you get a neuropathy. My experience is 9 cycles, maybe between 6:00 and 9:00 it begins to occur. The neuropathy is more of a problem with more prolonged therapy in advanced disease. So how do I summarize this trial overall? In fortune of avodosin and pembrolizumab is an antibody drug conjugate with an immune checkpoint inhibitor. It was transformative in advanced disease, curing probably 30% of patients. It's now gone into the perioperative testing with a shorter period of therapy, only 9 cycles. And essentially it's doing the same thing. It's probably curing lots of patients as well. We're doing surgery in these patients at the moment, but I can see a future where we'll stop doing surgery on some of these patients because we've got such effective therapy. The last bit I wanted to say before I hand it back to you is this isn't the end of the story. There are other trials out there. There's B-15 and there's Vulgar. They're both EV pembro trials. They're robust studies, one in the cisplatin eligible population where EV pembro is going head to head the genesis in the neoadjuvant setting. So we're going to end fairly soon with this regime being transformative and I think it already is in this study, but we've got more data to come. Speaker 2 Tom, what we saw was rather strict clinical trial criteria with regards to who's CIS eligible versus CIS ineligible. But when we tie this data to Niagara study for renal dysfunction patient, there was use of CIS split dosing. If you have a patient who presents with renal dysfunction, who does qualify for Niagara study and also for EV3O3 Keynote nine O 5 study? How are you going to pick amongst the two options here? Speaker 3 So let me tell you what I think at the moment, because I think it's a really good question. The evolving field with the data in front of us and the positive randomized phase three trials tells us the following #1 cisplatin eligible patients should get GEM CIS with perioptiduvalumab. And there's level 1A evidence for that. The cisplatin ineligible patients 9 cycles of EV pembro with surgery in the middle of that. And there is creep from both of those trials because the duvalumab trial Viagra allows split dose and the EV pembro trial allows some patients who are cisplatin eligible who refuse therapy. The proportion of these patients is relatively modest. Personally, I would say if you you don't need to do split doses platinum chemotherapy, you probably in that population when the crackling clearance is between 50 and 60, you can say, listen, we're going to give Evie Penro to those patients. These data are in front of us this keynote nine O 5 data is compelling enough to say, look, this data looks really good. After all the path CR rate in Niagara, it's 37% in nine O 5 is 57%. And you can't make cross trial comparisons directly. But it would be wrong to say because this is in the CIS path ineligible population, it looks inferior. It doesn't. So it's very reasonable in those patients who are not eligible for Genesis. You don't have to split dose. You can give EV Panbro. And I think the other issue which is relevant is you don't have to wait too long because the next trials vulgar trial, the B-15 trial looking at EV Pembro versus Genesis or looking at 3 rather than 9 cycles of EV Pembrokes, it's probably only a year or so away. We don't know when those trials are going to read out. So this is not a permanent fixture. This is a moving field. My personal feeling is keep us close to the randomized phase three data as we can. I wouldn't currently let EV pembro pinch for those CIS packs in eligible patients yet. That's my personal opinion. And I don't think you need to split the dose of GEM CIS with Niagara because I think EDP looks a perfectly good alternative and then you don't need to worry about the renal function in those patients. Speaker 1 You know, on social media we ran a poll saying someone who potentially could qualify for that split dosing cisplatin or EV pembro. What would you do? And 80% ended up going with EV pembro, which is likely what I envision will happen in our clinical practice because again, that has a ratio of 0.50 for overall survival is very impressive. But let's be honest, you both brought this up. This is coming at a cost of side effects, right? We always worry. Speaker 3 About can we get there, Can I just interrupt that because I would like to say one thing is the control arm of this trial performed really poorly. So while the hazard ratio in Niagara for OS maybe only 0.75 versus 0.5 O the landmark analysis of the control arm in Niagara because they got neoadjuvant gems CIS performed much better. The control arm in 905 performed really poorly. So I would not be doing personally at this stage. Don't get me wrong, I think EV Penrose transformative, but I just feel that those people who saying, you know, we can already translate this into the CIS plan eligible space because the hazard ratios are amazing. I don't I'm not bought into that. I am bought into the past yard 57%. I think that's a more compelling argument, but I'm not quite there yet. Speaker 1 Yeah, because again you brought that up, right. The comparator arm here for Keynote nine O 5 is taking them through surgery, whereas in sys eligible you're still giving them chemotherapy. So they're getting their fair share of systemic chemotherapy there. ctDNA's Role and Practical EV Pembro Side Effect Management So that point is absolutely valid. But one thing that I do want to touch about when we're talking about side effects, be it in Niagara trial or even Keynote nine O 5 in this periop post op settings, Tom ends up being over treatment in that post op settings with that PCR you presented the I'm vigor 01/1 study. Can we extrapolate is there any role of CTDNA in guiding who potentially might get EV pembro or that post op treatment for these patients? Speaker 3 So it's a difficult question. In VIGOR 11 is a trial for the adjuvant setting for patients who have not had neoadjuvant immune therapy. So they're immune therapy naive and they've had a cystectomy. And in those patients that are positive, we can show that starting immune checkpoint inhibition is associated with an Oval survival advantage. That's a somewhat of an oversimplification, but that's essentially what we showed. We also showed the negative patients, almost none of those patients die of bladder cancer and they therefore can be spared therapy. The problem with that is it does not translate into the perioctic spec setting, because Niagara tells us when we can start immune therapy in the adjuvant setting for those people who have not had prior immune therapy. It does not tell us when we can stop immune therapy for those patients who have previously had immune therapy in the neoadjuvant setting. If you think about it in the neoadjuvant setting, let's say the patient had GEM CIS Derva or they had EV pembro, If they've cleared their CTD and A and had a dramatic response, that could be because of the immune therapy. And we know that immune therapy has long term durable remissions, but we don't yet know if three months of immune therapy is enough to generate that. So if you were positive and become negative, that could be driven by the immune therapy and therefore stopping that at three months could be harmful. So as much as I don't want to give overtreatment to patients, I don't think the in VIGOR 11 trial translates into this neoadjuvant. Can we stop early phase, we're going to have to look at that differently. I realize that's frustrating. Speaker 2 Rahul, overtreatment as you're stating is certainly a concern and that's what we are seeing in breast cancer or lung cancer and now in bladder cancer as well. But at this point in time, sticking to the clinical trials as Tom mentioned is the way to go until we have more clarity whether utilization of CTDNA or not. All right, Tom, you've touched on the side effect profile of EV pembro. When you're especially tying in that neuropathy rash, how are you managing and any particular clinical pearls around? Speaker 3 It I describe EV pembro as a treatment to patients saying it's an individualized journey. There are almost No2 patients treated in advanced disease or perioptic disease that have been exactly the same. Most patients will require an interruption or a reduction at some point, and the key is when to do that. My message to treating physicians is education and training for patients is really important. Early skin rash requires dose interruption. What I have discovered in my team is that we had a steep learning curve. If you interrupt an earlier Grade 1 skin rash after one or two cycles, the skin rash occurs early. If you interrupt the dose, you wait for the skin to go back to normal and you dose reduce. Patients seem to be getting all fine. The times we get into trouble is when we see a Grade 1 skin rash. We don't ask the patient, we don't examine their skin. They think it's just a minor rash. We give them day 8 of cycle 2, and then they come back with a rash 2 weeks later. Then there's a grade 3 rash. So I strongly recommend to you to speak to your patients and say the skin rash is something that we can intervene successfully on, but we need to intervene early. Pills and potions and lotions don't work for the skin rash. It's about interruption and dose reduction. That point is really important. And then #2 the second point, which I think is relevant is it can sometimes be difficult to distinguish between immune therapy toxicity and ADC toxicity. But immune therapy tends to have a much longer half life. If you stop the ADC, you should see things like liver function and other bits and pieces getting better quite quickly. If they're not getting better, you might want to start steroids. Under those circumstances, I do not recommending starting steroids in every patient that has toxicity with this regime because some of it will be will be independent of the pembrolizumab. And of course, once you've started steroids once, you'll never really know what's going on. So it's about really careful management during those first 3 cycles. But remember, if you have that careful management, it's going to be easier to give those longer periods of therapy #1 and #2 is we're curing a lot of bladder cancer. This is a lethal disease. And if we can cure, and I think we're going to be curing 60 or 70% of patients with this, if we can do that, we have to learn how to give these treatments safely. And my experience is the learning curve is steep and I'm very confident that we can give the full line cycle if we get it. Speaker 2 Right. Exciting Future Directions and Key Takeaways from EV Pembro Approval Indeed, educating our patients and then managing these side effects is a very, very important, especially when we are using EV pembro in metastatic space already, but also now in localized space. Tom, Gu ASCO 2026 is right upon us. Anything exciting that you're looking forward to at Gu, ASCO or even in the next 12 months in bladder cancer space? Speaker 3 Let me start by saying also to congratulate the the team, the Keynote 905 study, this was a difficult study to do in a cisplatin ineligible population. We didn't think we could do these sorts of trials. And the team did an amazing job to get this study out of the line. The data was really clean. If you look at the capital markers, the sensoring is low. It's a really well conducted trial. We talk about randomized phase three trials being the truth and this is it. But actually if you look, some trials are conducted better than others. And this trial was a really robust, well conducted study, which is why I think the results are so clean. So congratulations to the team on that. I'm excited about ASCO Gu. I always love ASCO Gu. I think it's a great time to get together. You know, the things that I would like to see in the upcoming 12 months in your serial cancer. I would like to see more of these perioctic EV Pamborough trials. As I said, there were two out there. We don't know when they're coming out, but we'd like to see them sooner rather than later because both of those studies will add to where we are at the moment. One of the trials gives a shorter period of EVP will tell us whether we can give shorter periods of therapy. The other, the trial goes against platinum chemotherapy. I'm super excited about that, number one. Number two, I'd like to see some more data on ADC's. I'd like to see more data outside of China on the city of Avidotin because I think we've just seen the Chinese data. Wouldn't it be great if we could see more data, a global data? I think that's really important. Of course, they're randomized trials ongoing with that. And then there are other studies which are exciting. We've just had a new study announced EV pembro plus an FGFR 3 inhibitor versus EV pembro alone, Forager 2. That's a really exciting study as well. I think we need to be talking about this new second generation of trials where guess what, we're using EV pembro as a control arm. Isn't that incredible when you go about 5 or 10 years and we thought of these patients all being dead in a short period of time, outcomes really poor toxicity high. We've moved into a new era of ADC immune targeted triplets in randomized prospective studies, improving the outcomes of our patients. So it's an incredibly exciting time in your cellular cancer. I'm very lucky to be involved with it. And again, congratulations to those people who got this particular study over the long. Speaker 1 You know, truly what an exciting time as practicing medical oncologist because our patients are indeed living longer. And I'm hoping that moving forward we'll see these new approvals as control arms via Niagara or EV pembro so that we can continue to push this field forward. Tom, thank you so much for sharing your thoughts around this new approval, which is now the new standard of care for CIS ineligible resectable muscle invasive bladder cancer. For our listeners, let's go over a quick recap from today's discussion. For those listening, here are the big key takeaways from Keynote 9-O5EV3O3 which led to the approval of enfortumab. Vidotin plus primrolizumab insist in eligible muscle invasive bladder cancer based off improved event free survival and overall survival. Speaker 2 When we're talking about the overall survival, this has not matured yet an EV pembro arm, but the hazard ratio is 0.5. This is very impressive, but let's make sure we keep side effects of enfortumap such as rash, fatigue, neuropathy and in mind when we're trying to combine this with pembrolizumab. Immune related side effects as well should be on our radar. Speaker 1 Wrote it absolutely when we were talking about side effects. This also led to the discussion around over treatment and the role of CTDNA to guide post op therapy. You know, as of now the approval and recommendations is for all comers to receive that post op treatment, but we would love to see who we could selectively spur this additional treatment for. Thanks to everyone who tuned in. We'll be back soon with more practice changing updates in oncology. We are the oncology brothers.