EV-103 Study by Dr. Jonathan Rosenberg led to the FDA Approval of Enfortumab + Pembrolizumab

EV-103: Study Design and Bladder Cancer Care Hello everyone I am Rahul Gosain. And I'm Rahul Gosain and we are oncology brothers. In the year 2023, as a practicing medical oncologist, a big issue has been the chemotherapy shortage, particularly when drugs such as carboplatin and cisplatin are the backbones of many treatment options. Any regiment approval in this space not using these chemotherapy agent is a great relief. More recently we've seen one such combination approval in metastatic bladder cancer and fortumab and pembrolizumab based on phase two study EV 103 cohort K and cisplatin in eligible patients. To better understand how we should be using this data in our day-to-day clinical practice, we're joined by Dr. Jonathan Rosenberg, one of the authors of this study that has led to the approval of this combination. Doctor Rosenberg, welcome. Speaker 3 Thank you so much. It's a pleasure to be here today. Speaker 2 Thanks for joining us, Dr. Rosenberg. Before we get started with EV103 cohort K data and study design, it is important to reiterate the current standard of care in advanced bladder cancer patient population. How we divide these treatment regimens is based on CIS eligible versus CIS ineligible and then PLATINUM ineligible for CIS eligible patient populations. We have CISGEM along with DOS, DES and WHACK. While CIS ineligible, we have carbogem. However, after that we have pembrolizumab for platinum ineligible patient population. Data from Javelin 100 study confirmed the role of eveloma maintenance after initial chemo. But now with infortumap and pembrolizumab combination which was recently approved based on phase two study we have that available for CIS in eligible patients as well. Doctor Rosenberg, to get started, can you please walk us through the inclusion criteria for this study? Speaker 3 Yes. So this patient population, or people who had metastatic or locally advanced unrestrictable urothelial cancer, who were not candidates to get cisplatin. And it was. Essentially the modified Golski criteria which focus on renal functions. So GFR in the trial was less than 60, although you know different people have different comfort levels on creatinine cutoffs and heart failure and poor performance status, although most patients had a pretty good performance status on the study. One thing that's important to remember is in Fortunevidentin causes peripheral neuropathy and so. So people with significant neuropathy who might otherwise be susplant and ineligible would not have been eligible for this study. And though and this study was really trying to understand how are the combination, how did the combination look in comparison to in fortumab monotherapy in this patient population. We know that in the second and third line setting, the response rate is in the mid to high 40s. And in the but the first line setting, it had never been tested. It really wasn't not a comparative study even though it was randomized but really to give an estimate of the activity of EV monotherapy as well as EV pembro. Distinguishing Platinum Ineligibility and PDL1 Biomarkers And the primary endpoint was objective response as you have listed here. And to get a sense, you know, is this, was it a fluke that the first study, you know, just happened to get lucky and have such a high response rate? Or was this actual, actual real? Speaker 1 Solid data, Doctor Rosenberg, you've mentioned cisplatin ineligible. I think that's important to reiterate because that is different than carboplatin or platinum ineligible criteria. You've also mentioned neuropathy something that we need to monitor for EV that is something that we also have to monitor for carboplatin as well because that is one of the criterias when we're saying these patients are platinum ineligible. So thank you so much for going over that. Speaker 3 Yeah. And platinum ineligible is is not really well defined. You know, really bad performance status, really bad kidney function. People who have, you know, severe comorbidities, people who might otherwise be sent to Hospice in many ways are the platinum ineligible patients because historically most of us have been able to get some gemcitabine and carboplatin into people, even if reduced doses. But a lot of patients and we, we saw this when the checkpoint inhibitors approved, a lot of patients who otherwise get no treatment are actually getting a checkpoint inhibitor. And while the majority didn't benefit, there were certainly some patients who did really well with that. And so the FDA and its wisdom, while it didn't define Platinum ineligible, left that approval in place, at least for Cumbrilism. Now. Speaker 2 When talking about immunotherapy in this setting, as a General Medical oncologist, it is very important to know in bladder cancer, we have seen approval of immunotherapy irrespective of PDL ONE score here in the United States, whether it be it in metastatic setting or adjuvant settings. Speaker 3 Right, right. So the data, the data in the adjuvant setting for nivolumab does suggest that the activity may be higher in the PDL 1 positive patients, but. Study wasn't designed specifically to say, it was actually designed in the entire population as well and all patients seem to benefit, although the benefit may have been greater in the PDL one population in the in Europe, the EMA only approved for PDL 1, PDL 1 positive patients for maintenance therapy, the same phenomenon occurs. It appears that the PDL 1 positive patients may get more benefit, but that doesn't mean the PDL 1 low patients get no benefit. And in the refractory setting where pembrolizumab is used in the post platinum post setting for resistant disease, it doesn't actually appear to correlate with much. It's actually you know not useful to check PDO one status in refractory disease in the first line setting. The biomarkers didn't perform properly in the as monotherapy in most of the first line trials like you know 361 which was negative. And the Danube trial. And so in the first line setting, we're not, we don't look at PDO one status anymore, at least in the United States. Interpreting EV-103 Data and Practical Toxicity Management Absolutely. And then coming back to EV103, what did this study show here? Speaker 3 Right. So this data was just actually published in Jco like within the last several weeks. So the response rate for EV pembro was 64.5%. Which was similar to the cohort a group which was the initial 45 patients which at 73% EV monotherapy was 45% which is you know in the in the range of what we've seen EV do in other disease states. Interestingly enough and we see here the progression free survival is about a year with EV pembro and the overall survival is about two years the. I think these are relatively immature data still. You see there's a lot of sensoring still going on and as time goes on, I think we'll see that these numbers look quite good compared to historical data with gemcitabine and carboplatin and the cohort A long term outcomes about 40% of people are alive at four years. That's like not something we've seen before in bladder cancer and metastatic disease with poor prognostic features, so. You know, smallish study. I don't want to hang too much on that, but these data are pretty promising for the future I would say. Speaker 2 No, these are some remarkable results have very very promising though this is phase two, but hoping that phase three will result into the similar. Speaker 3 Outcome there exactly. We're hoping to see those results within the year I would say from EV302 which randomized people to gem cytamine and platinum or to EV pembro. Many of the patients apparently got a Valiumab maintenance, but not all because the study was started before Valiumab was a thing as a maintenance therapy. And so this is the problem with our very rapidly changing field. I wonder if the same thing will plague other phase threes. We just heard that Checkmate 901 was positive and we don't know what the control arm was like in terms of getting maintenance immunotherapy. And so those are going to be important questions to ask down the road as we see the data from these large phase three trials. Speaker 2 Right, just back along the same point there, if you have a patient who's coming in where we now have two options available for cysts in eligible patient population, carbogen followed by velumab and now EV pembro. If we are not suffering with the current shortage, how would you decide amongst these two therapies to go with? Speaker 3 It's a great question. You know, first of all, I think about hyperglycemia as a risk of EV and EV pembro. And if the patients are poorly controlled or uncontrolled diabetics, I would not pick and fortemeb as a treatment in in the regimen. I would go towards trim cytabine and carboplatin. I think about neuropathy and what their baseline neuropathy is because carboplatin, while it can exacerbate neuropathy usually is, it's not a, it's not a big deal, it usually doesn't happen frequently and it's usually not severe. So those are two things that I think about and then I have a complicated discussion unfortunately with the patient. Talking about the risks of early toxicity with EV Pembroke, there are reports of TEN and Stevens Johnson syndrome with EV monotherapy and although they were not seen in the EV 103 cohort, K significant skin toxicity is a real thing and patients need early monitoring. And I encourage oncologists who use this regimen to see their patients each time they're getting treated, certainly for the first few months. Even on day eight, that may not be the practice for gem carbo for everybody, but catching these skin toxicities, catching the hyperglycemia which can very rarely be very severe and refractory to insulin, if you catch that early, oftentimes you can skip a dose, start them on topical steroids. I wouldn't necessarily give oral. I don't love giving oral steroids all the time for this, but high potency topical steroids for severe rashes if they get. You know estrif or what used to be called baboon syndrome, things like Silvadene under the, you know in in those regional regions and hold treatment until things get better to potentially resume at a dose reduction. If you don't see it, you're not going to do anything with a patient, you're going to end up with a disaster. And so I'm I'm pretty hyper vigilant about this with patients getting these regimens and I think it's very important for docs to be aware that they need to make a friend of a dermatologist. And hopefully they have some experience dealing with these skin toxicities, but you know it's it's no shame or crime to hold the dose with patients getting EV cumbr or EV monotherapy. Navigating New Treatments and Bladder Cancer's Evolving Paradigm And I think with all these new approvals, it's not only important to stay up to date on the data, it is important to get comfortable on how to manage these toxicities with different classes of drugs, Adc's we have seen different toxicities with or the fit to live with eye toxicity. So again, as a General Medical oncologist, I think that we have to continue to stay on top of this and keep a close eye on how this field is evolving. Speaker 3 And the one you know. The one analogy I use is that you know without modern anti medics and. Modern supportive care giving cisplatin is an unbearable experience for patients and we all have figured out how to do it as time has gone on. And I think in some ways while this is not cisplatin, obviously that experience and understanding the toxicities and toxicity management is key to what may be very prolonged survival for many of these patients. Speaker 1 And I, you know, I really encourage people to pay attention to these issues with their patients, absolutely. Speaker 2 Doctor Rosenberg at ASCO 2023, we've seen updated data from Thor study that was for FGFR mutated patient population with oral survival benefit with OR to fit Neb. Now if a patient presents who is SIS ineligible with FGFR mutation, do we have any knowledge in this patient population if we were to utilize EV Pembroke combination? Speaker 3 It's a great question that there's a little bit of data that's starting to come out. That does seem to suggest that at least with EV, it may not matter dramatically. With EV pembro, there's not enough experience yet because it's been used so rarely, but that it's not going to matter that much if you do EV or ERDA in the post platinum setting. I think they're both good options. In fact, if you look at the, you know the overall survival length. They're pretty identical between the two regimens in the refractory setting. It is important to note though that the ERDA Fitnib Phase three that was reported was post platinum and post checkpoint randomized to taxanes or VIN Fluenian if they're in Europe, whereas we haven't heard the data in platinum refractory IO naive where they're randomized to IO or or to Fitnib and that data. Maybe they're very similar or it may be different. And so just keep that in mind when you're thinking about who to give this to or if the the Thor update really is third line therapy. I would feel comfortable personally using it after EV pembro in an FGFR 3 mutant patient because they would have progressed on immunotherapy and a cytotoxic and the EV is a cytotoxic in in in very important ways and so I wouldn't necessarily have to have them have platinum. What we do second line right now though after EV Pembro is sort of not totally clear. Should we be giving them gemcitamin and carboplatin? I don't know. We're gonna have to try it and see what happens I think and and do some some oldfashioned retrospective analyses and or some small prospective trials to see, you know what the activity of that combination might be. What do we move right on to something like or to Fitnib or Cesitusemab or other or other refractory agents? Refractory disease agents? Speaker 2 Right. The treatment paradigm for bladder cancer is quickly changing. Doctor Rosenberg, congratulations as your work has led to another treatment option for our cysts in eligible patients, especially when we are going through this platinum shortage. And we hope to see similar confirmatory data in phase three for a listener. Stay tuned for a quick wrap up. Just before ASCO 2023 and Fort MAP and Pembrolizum map combination was approved based on EV103 cohort case study, Insys ineligible advanced bladder cancer patient population and Doctor Rosenberg, one of the authors discussed this study and his treatment approach with us today. Speaker 1 Upfront it is critical to know whose cisplatin ineligible as this is different than being carboplatin or platinum, Ineligible now insists in eligible patients we have two good options Carbogem followed by a value map as maintenance or Infertumab and Pembrolis map based on the recent approval that we've just covered. Speaker 2 It is important to keep the side effects of and Fort MAP and antibody drug conjugate in mind as you would be using this drug in either frontline or later lines. We will eagerly await to see phase three data from EB103 core K but for now this seems to be very good viable option in our selected bladder cancer patient population. Tune back in for more practice changing discussions. We are the on Quality Brothers.