Breakthrough in Bladder Cancer: FDA approval - Enfortumab Vedotin + Pelbrolizumab with Dr. Tom Powles

Intro Hello everyone I am Rahul Gosain. Speaker 2 And I'm Roy Gosain. Speaker 1 And we are the oncology brothers. In the year 2023, Nature Medicine recognized 10 key influential individuals for advancing the science. That list includes one of the ChatGPT Co founder, another being an engineer who played a pivotal role in moon landing for India, and also a medical oncologist, Doctor Todd Powells, whose work has led to the doubling of the overall survival benefit for bladder cancer patients. And today we're here to take a deeper dive in that study, EV3O2. Tom, thank you so much for joining us. Speaker 3 That's quite an introduction. I, you know, it really is to be involved in the moon landing sort of been cool. I've got to say I don't even, I don't even know how to work chat, PGPT. So but I'm, I'm told that's amazing. So yeah, I was very lucky to be part of that group. It's a huge team effort, 10s, literally 10s, of thousands of people, and I just happened to be the person talking about it. And there would have been a lot of other people who would have been equally equally justified in that task. So I represent a huge clique of people and I'm very lucky to be involved. Speaker 2 Absolutely. Well, Tom, congratulations. This is no less than any other moon landing either we are and you're saving patients lives and making it much longer which is the key on why we are in oncology today. Tom Ivy was approved as a single agent in 2019 in relapsed refractory setting for bladder cancer and then phase two study EV1O3 cohort case showed promising data for CIS in the ineligible patients, but EV3O2 study was mainly for all comers. Here we have the study design, and if you don't mind going over the study design with us today. Apodotin vs. chemotherapy Yeah, it's relatively straightforward. So you're absolutely right. In fortune of Apodotin as a single agent in heavily pre treated patients have a 40% response rate. When you combine it with pembrolizumab in the frontline setting in a single arm trial that response rate goes up to about 70%. Chemotherapy historically response rates of about 45%. So we were quietly confident we could beat chemotherapy, but we weren't, we weren't confident we would get the results we did which I'll talk about in a second. So this is a frontline randomized trial. It's an all come a population gem, CIS gem carbo, you know PDL 1 positive, negative and all comers actually varied testology as well. So it's a, it's a Big Sur 80 patients because of dual primary endpoint of PFS and OS and EV pembro until progression chemotherapy 6 cycles and then maintenance of valiumab allowed 31% of patients had maintenance and valiumab which is you know probably in the real world about the same number, maybe in a trial it should be slightly higher, but I don't think that's massively in wrenching results. Speaker 1 Tom, thank you for covering that. You brought up that 31% of the patients got maintenance of Valiumab. To be honest, if the results were similar, we would have honed into that a little more saying, Oh my God, what's the cross trial comparison here? But clearly there is a significant synergy that we're seeing with this antibody drug conjugate and immunotherapy and these results are phenomenal. EV3O3 What did this study show? What are the findings of EV3O3? Speaker 3 So you know synergies were that it's a it's a complicated word and I think in pre clinical terms you know it's 1 + 1 = 3 and and and we've never really shot, I mean maybe intestis cancer, but the way I look at synergy in a clinical perspective is to have you know results much better than you're getting with either of the single agent drugs without the without apparent cross resistance. So I think 1 + 1 = 2.1 or 2.2 that's probably good enough for me to sit and it's a word. The other word we don't like using which is also being used for this trial is cure. You know we had a a 30% or 29% CR rate. We've never really seen anything like that in your feet or cancer before. But I think that's why some people you know are using these very these very high bar terms. Look the results were better than I thought. I I had, I I had dreams before this oil that hasn't. I do it quite a lot I should get out more but you know, but I would have bought 0.710.75 would have been you know. But here we got results of PFS of 0.45 hazard ratio and OS 0.47, so a more than a 50% reduction in the risk of progression or death. We also showed, I mean the control arm performed well. It performed very much in line with what you'd expect for a mixed gem, CIS gem carbon population. In fact, it performed better than we've seen from most of the previous control arms and the trials I've done maintenance of Valium have may have had a role to play in some of that. And and and I think that if you look at the OS curve, the tail of the curve looks a bit immature at the moment. And and I think when that does mature, we're going to steam the in the vials in the region for about 3 years. And that you know when we started doing these trials, when we started doing this study you know median OS between 12 and 14 months. So that bar has now been moved close to three years and and that is a big difference and it's and I think that is transformative and obviously we've not seen that with the chemotherapy GEM, CIS, gem CARBO immune therapy trials. We've not seen those sorts of results with maintenance of Valium AB. With the Valium AB you've got to get through that chemotherapy period and that's quite challenging. Many patients don't get through there and the durability of the immune responses, while they're good, many patients don't respond to single agent immune therapy and that's part of where that sort of synergy conversation comes in. Speaker 2 Oh, this is impressive to say the least. As an as you stated, transformative. Tom, again, congratulations. You rightly received the standing ovation. Definitely well deserved. Speaker 3 And I think the dates have received the standing ovation. Speaker 2 Yes, that's fair. No thanks to certainly our patients and their families and everyone involved in this trial. So now this is. Speaker 3 Approved. Speaker 2 Here in the US already as a new standard of care, but is there any particular patient that you would not consider this as a first line treatment option? Who should not consider this as a first-line treatment option? Yeah, that's a really good question. So the field is transforming and that's why I use transformative because we've been using Cisplatin eligibility for GEM CIS and GEM Carver for generation. And we also will recently be using Platinum eligibility to say well then you can't have platinum and if you can't have platinum, you can get single agent pembro. And quite a lot of patients were getting single agent pembro because platinum's pretty hard to give and it has doesn't have great results. And some people, some friends of mine say GEM carbo, you know it's a bit of a waste of time PFS four and a half, five months OS nine months and most of that times on toxic chemotherapy, this is very different from that. And my clinical, my personal experience we'll talk about toxicity in a second is that you can give and you're putting patients into quite durable remissions and some of those patients are not don't continue on EV penro, some of those patients can stop some of the therapies and and you can and reduce or change the drugs around. So it's a very different clinical phenotype is be treated patients. I don't think there are any patients who I would want to give gem sis or gem carbo to. You know, if you've got uncontrolled diabetes, well you wouldn't want to give chemotherapy to an uncontrolled diabetic. You want to control their diabetes. The same with EV pembro. There's some contraindications to immune checkpoint inhibition absolute. You know, if you, I don't know you're on immunosuppressive drugs for a transplant, although some I don't, I don't give those patients immune therapy. You might say they're better off with dysplatin. I'm happy to have that discussion. Some friends of mine disagree with me on that issue. Active autoimmune disease requiring immune suppression. If you had a really bad skin lesion, but you know if you've got psoriasis, you might say less than immune therapy problem. I don't think there was skin rashes as such that currently overlap with this skin rash. And I don't think that having existing skin rash never necessarily predisposes to a skin rash associated with this combination. So I sort of look at it and say, no, I don't think there is. And actually I think the pie gets a bit bigger of patients. And the reason why that's the case is even myself, every now and then I see a patient and say you know you're a bit borderline platinum based, chemotherapy is not that great. You might be better off just having pembro or having nothing honestly. And you have a conversation with the family and you talk through it. Whereas here when you talk about well, you know there's a 30% chance of CR and there's this issue around durable remission that we didn't see before. I think more people say actually I want to have a go and so I think the pool gets bigger. Then the next question which I suspect you're going to ask is, well, what about toxicity and how do we make, how do we give this as safely as we possibly can? Toxicity Yeah, actually let's take that as a good segue. Let's talk about toxicity because yes, it's approved, but in the community not only approval, I need to get very comfortable in managing this skin toxicities, neuropathy, hyperglycemia from infortumab, you've mentioned immune related toxicities from pembrolizumab. So can you share some clinical pros in managing some of these toxicities? Are you going to skip day A dose reduce? What is it looking like in your clinic today? Speaker 3 This is the most important issue for me because we can actually, we can. Pretty much everyone agrees this is a transformative regime and and the question then comes not about should we give this regime or that regime is how do we give this regime most effectively? How do we give this regime most safely. And that I think has to be and that's I'm, I'm flying around the world trying to describe that at the moment with friends and colleagues because the adverse event profile here you can see is is is higher for chemotherapy, the grade 3 or 4 adverse events at 70%, but that's high now that's very high and that underlines how difficult chemotherapy has been given has been. And that comes back to that patient who I talked to Jem Carbo about with the performance status of two who's not feeling great, who decided not to have it because when you talk through chemotherapy, some patients just say it's not for me. So actually saying it's better than chemotherapy which it might be is not actually the solution to our issue. Our issue is what toxicity can we expect? Have we been trained in this type of toxicity and how do we manage this safely? And the reality is we haven't been trained in the adverse events associated with all of the antibody drug conjugates. And this drug unlike chemotherapy which has got the nausea, the fatigue, the kidney function dysfunction, the neutropenic sepsis, the bleeding, all of those, it doesn't have any of those things. Actually what it does is two or three key adverse events that require education and training. The 1st is a skin rash. It can cause a skin rash in the first three or four cycles. If you get a skin rash in the first three or four cycles, stop the drug, even if it's a mild rash. Because what happens is the skin rash can escalate with time. And if you interrupt the drug and you let the skin rash settle and you bring the dose down one level, what you'll find is the skin rash probably doesn't come back. And under those circumstances you can treat these patients safely. What we did and I can tell you I've made every mistake you can imagine in life and in oncology. And you know what we did in in this is we actually I saw one of our first three or four patients single agent EV, not the combination but single agent EV we treated you know day 1815 we gave day 15 on cycle two of a patient with a grade one rash and they came back and their skin was blistering and it was difficult. So when you see rash, particularly in the first three or four cycles, dose, interrupt, close observation, rechallenge went back to normal at a lower dose, what you'll find is the drug is very active. You don't need to worry about pouring more and more drug in. I think we feel under pressure to give the drug because it's working and I don't think that's the right advice. My advice to people is don't pour in more and more drug, actually the drug is really active. Take your foot off the accelerator. When you've got toxicity, put your foot on the brake because that will stop permanent discontinuation. So that's the first thing. Peripheral neuropathy The second one is peripheral neuropathy. It's actually a motor and a sensory neuropathy. We're used to just sensory neuropathy with platinum. This can be some coordination as well if you better get too serious. And again it tends to accumulate between cycle 6 and cycle 12 in my experience. And if you dose interrupt on Grade 1 tox, you give three or four weeks off, you bring down one dose, you'll actually find you can keep going for much longer with that. And then there are other teases transaminitis, it does, it's not associated with very much interstitial lung disease, but it is and the and the rest of the adverse events actually quite similar to what you'd expect with immune checkpoint inhibition or dare I say it chemotherapy. You know, there's some nausea, there is a little bit of alopecia and other bits and pieces, as you can see. Speaker 2 Tom, thank you so much for going over with that though EV pembro as we can see and as you stated is certainly better tolerated than chemo. But as a community oncologist, we definitely need to get more familiarized with these side effects because impact is on quality of life. Tom, number of these patients about 30% as you stated earlier had a complete response with this regimen which is remarkable in stage 4 setting. Now with this hot topic of CTDNA, outside of clinical trials, would you be utilizing or are you utilizing this to avoid over treatment or thought when you might want to stop and Portumab at all? Using CTDNA to avoid overtreatment Yeah. So circulating tumour DNA is being used in the United States now. I think in urethelial cancer, it's currently continues to be an experimental tool. There is a study post adjuvant setting called Invigor 11, which is randomizing patients after a cystectomy who are CTDNA positive, just the positive population, the 40% of the positive to a tezalizumab or placebo and that's a really important study. I think in the adjuvant setting we're treating too many patients who don't need therapy. We know the relapse rate is only about 40 to 50%. That means we're putting half of the patients potentially in harm's way who don't need it. In the future, we will be selecting these patients. It's not fair on those patients who don't need adjuvant therapy to put them through a year of potentially 10% chance of life changing toxicity. So in the adjuvant setting, CTDA has got a really important role to play in this Senate team where we're monitoring disease progress. I'm not sure CTDA has a big role to play. I think we're going to see some data in the not too distant future in advanced disease at CTDNA clearance rates and what that means. And I think that that clearance may actually end up being more predictive than radiology response and I'd be excited about that. I think that moving away from radiology response, I think radiology will always have a role to say where is the disease, are there local therapies required, is there radiotherapy Saber. But once you know what you're doing, I'm not sure regular CT scans are that helpful. In the academic community. We were measured by RESIST 1.1. It's quite complicated. I don't love it to be honest. And I think that in the community, I'm sure we're just getting radiology reports saying that it's a bit better. I'm not sure that's as helpful as it could be. And I think we're going to develop more accurate tools in the future. But I think that's five or ten years or I don't think it's just here today or tomorrow. So I wouldn't be using CTDNA, but those patients that have had a complete response to therapy, once they get to the two year mark, that two year pembrolizumab mark which is stopped, there is a question about whether they need to continue on EV and actually some of those patients may be stopping EV earlier for adverse events. I think it's going to be really exciting to look at those complete responders to see if they continue on EV. My personal experience is we've managed to stop the PET, the drug in many of those patients who have done really well and they continue to do well. So it doesn't, I don't think it is a drug which you have to be giving to maintain that response and I think it's changing the disease. I think it's pushing patients in durable remission. I think it's hitting the cancer really hard at the start and that's allowing us for those patients to get some of their quality of life back as well. Speaker 1 The treatment algorithm for bladder cancer has not changed because of EV3O2 study and our patients are living longer with this disease. Tom, congratulations and thank you for taking the time to cover this data with us today for our listeners. Stay tuned for a quick recap. Summary On December 15th, 2023 and fortumabitotin and pembrolizumab as a combination was approved in first line for advanced or metastatic bladder cancer based off of EV3O2 study. In this discussion, we got a chance to focus on the study with Doctor Tom Powells, who led this effort. Speaker 1 When compared to chemotherapy and fortumab resulted in significant improvement in overall survival benefit with medium survival of 31.5 months versus 16.1 months with chemotherapy. Speaker 2 It is important to keep side effects of enfortumab and antibody drug conjugated mind as this is now our standard of care in frontline for metastatic bladder cancer patients. Make sure to check out our bladder cancer algorithm discussion with Doctor Karine Tuaji and Dr. Sia Danishment where we get a chance to put all our treatment options in context. Thanks for joining us. We are the oncology brothers.