Perioperative Durvalumab FDA Approval New Standard for Muscle Invasive Bladder Cancer

Intro Welcome back to another episode of the Oncology Brothers podcast, their ongoing series of new FDA approvals. Yes, we've seen a few already in 2025. We just covered cabocentinib recently based off cabinet study in neuroendocrine tumor and today we're covering Niagara trial in receptible muscle invasive bladder cancer. For this, we're joined by the lead author of this trial, Doctor Tom Powells, a Gu Medical Oncologist from Parts Cancer Institute in England. Tom, you were with us to discuss EV3O2, which resulted in doubling of OS for metastatic bladder cancer with Yusuf, infertumab and pembro. And here we are again with another approval and change in our standard of care treatment. Thanks for joining us again. Speaker 2 Thank you for inviting me. Speaker 3 And welcome to back-to-back successes for you, your team and importantly for our patients. Congratulations, prior to Niagara trial are treatment for unresectable muscle invasive bladder cancer has been neo adjuvant chemo with cisplatin backbone followed by surgery. Now we have Niagara trial with the use of immunotherapy upfront followed by surgery, one with chemo and then also adjuvant dirvalumab. On March 28th, 2025 diralumab plus chemo was approved for resectable muscle invasive bladder cancer. Before we touch on the study design and talk more about the study itself, being a Canadian and we both live in upstate New York and are very close to Niagara Falls, I have to ask you this. Why the name of the trial? Why the name Niagara? Speaker 2 Let me tell you. So we started the bladder cancer series with duvalimab, named after rivers and water areas to be Fay. We have the Nile trial, the Danube trial, the Biscay trial, for example. We have the Volga trial, which has become quite controversial, of course. And finally we have the Niagara study. There are others as well. There's the Potomac trial. Now I've got to tell you that the Niagara study is the shortest river. It's only 40 kilometres long, and I don't know if we named it after the river or the falls. I'm guessing it was the falls. So strictly speaking, it shouldn't have been named after a river, but it has been the most positive of all of those, which just shows you that you can't judge a book by its cover. Speaker 3 Indeed, and just for our American friends, 40 kilometers will be 24.8 miles. Speaker 2 All right. Speaker 3 Can you start us off with the study design and also touch on the cisplatin dosing for the patients with the renal dysfunction used in Niagara trial please? Study Design Yeah, the. Speaker 2 Neoadjuvant chemotherapy, proactive cystectomy is associated with about a 5% improvement in overall survival. It has to be cisplatin based and GEMS SIS has become the standard of care, although other regimes are also used in that neoadjuvant space. But there's no clear consensus on the best regime and for that reason GEMS SIS, which is the most widely global regime, was chosen. We chose 4 cycles. There is also a debate about the number of cycles. Some people have given 3 cycles rather than four, and indeed some trials have three rather than four. There's some trials which give 6 cycles, but four, If you go around 200 centres around the world and try and do a big global trial, it's pretty much agreed 3 is too short for many centres so four were chosen. The global community feels that any platinum based chemotherapy is better than none. If you look at the update of Tuptake of neoadjuvant chemotherapy 20 years ago, only about 20% of patients were getting it. We've increased that percentage now. So the majority of patients from a global perspective are giving neoadjuvant chemotherapy. And what I say to people is I don't really mind which neoadjuvant regime you give, but it's better to give it than not give it. And I hope we've won that battle. Adjuvant chemotherapy has never had as robust data and carboplatin has never had as robust data. This trial is the first of a series of perioperative immune therapy trials. Perioperative Immune Therapy Trial It's not a neoadjuvant immune therapy trial. It's neoadjuvant chemotherapy, but perioperative immune checkpoint inhibition. 4 cycles given beforehand with the chemotherapy and then the remaining of the year 8 cycles given afterwards. Some people say why isn't there a third arm only exploring that neoadjuvant space and the answer to that question is this is 1000 patients study with survival powered for that. It's crucial we hit survival in these trials. We don't think other endpoints are fabulous. They're OK but not fabulous. We can't really do a much smaller 2 arm trial. You have to do for survival. You need about 1000 patients. We've never done 1000 patients neo adjuvant trial before anywhere near that bladder cancer. I was involved in some of the ertc studies where we only recruited 2 or 300 patients and closed early because of slow recruitment. So to put a third or a fourth arm with two or three thousand patients didn't seem practical at the time. So this doesn't answer all of the questions, but what it does tell us is early immune checkpoint inhibition saves lives and is associated with a significant survival advantage. There are other correlative endpoints, pathological CR, circulating tumour DNA that we can talk about in a minute. Essentially we included patients who were classic muscle invasive bladder cancer, T2 to T4A. We included a small percentage of patients with N1 disease. I would have liked to include more of those patients. At the moment, many of those patients are having surgery and being included with neoadjuvant chemotherapy. We allowed the creatinine clearance to go down to 40. Historically, there's always been a debate about the level if you split the dose of cisplatin and give day one and day 8 cisplatin, you can go down to 40 mils per minute and that's what we did in this trial. 20% of patients had split doses plaqued. In this study, we picked our endpoints and this is important, dual primary endpoints of path CR and event free survival. We had Oval survival with alpha control as a secondary endpoint. There was an interim path CR analysis that was not positive. It was an early analysis. Not all of the patients were included in that analysis and that was not positive. The first end point that read out was the significant and positive event free survival. When we retrospectively look back on pass CR with all of the patients, that would have been positive. Speaker 1 To Tom, thanks for touching on that. And again a few things to reiterate, cisplatin cannot be replaced with carboplatin in D settings. We know that cisplatin is superior and out in the community we're getting very comfortable with this sandwich approach of Peria post op immunotherapy. We've been using this for non small cell lung cancer, triple negative breast cancer and now in bladder cancer. We were actually awaiting trial to be read out for gastric cancer as well. Matter Horn study and you touched on this idea of this third arm. We'll take a dive into the results. The reason why we all continue to ask for that third arm is we still don't know how much is immunotherapy buying us in these post op settings, especially if you have complete pathological response. Overall survival advantage Tom, why don't you walk us through these findings and then let's touch on some of these nuances. Speaker 2 So the the overall survival, there was a significant overall survival advantage with a 25% reduction in the risk of death. The curves go apart at about four months and they stay apart. The hazard ratio of 0.75 is statistically significant. The landmark 24 month OS is 75% versus 82% for the combination arms. So A7 mile, a 7% increase in OS at two years, the curves go apart and they stay apart. There was also of the pathological CR rate of 37% and 27%. Pathological CR rate The primary endpoint event free survival hazard ratio was 0.86. It hit two of those endpoints and the third endpoint showed a 10% delta in pack CR. When you look in detail at pack CR, we've done some subsequent analysis and we've shown it doesn't matter if you had a pack CR or not. The Duvalium album tracked above the standard arm. Two things about pack CR, it's not a perfect endpoint in the control arm. At two years, 15% of patients relapsed. Even if you had a PAT CR, just showing it's not perfect. And then there was a 7% increase from event 3 survival in those patients who had the addition of duvalimab. Event 3 survival And in those patients who did not achieve pat CR, only 50% of those patients remained event 3. And again, there was about a 5% increase in the addition of Duvalimab. What this tells us, which I think is relevant, is #1 pass CR's not a perfect endpoint. If it had been perfect and no one would relapse, you could say, well, maybe if no one's going to relapse, you don't need to give the Duvalimab, then you've cured them, but you haven't 15% relapse and the Duvalimal. So it doesn't resolve that issue around pass CR. We have to keep going. I think it's also worthwhile saying in the subset analysis of these two trials in the forest plot analysis, the benefit was across broad subgroups of patients. So whether it was pure urothelial or had a component of other non urothelial components to it, whether it was T2 or it was more advanced, whether it was split dose or non split dose geographical regions, both for EFS and OS, they were broad subgroups, both benefit against broad subgroups of patients. And then finally and maybe most relevant, can you give the combination safe? Combination Safety What we discovered surprised me a little. Number one is more patients in the duvalimab arm got surgery that in the control arm. One of my great fears was that as we gave therapy to patients, we may get some immune related toxicity and that immune related toxicity might make surgery more complicated. We could have lots of patients on steroids at the time of surgery because of immune related adverse events and we may delay surgery because patients recovering from these immune related adverse events. And Matt Gauski presented the past CR data very nicely at ASCO. Gu and Jim Cato at Eau just presented the surgical safety data which showed that there were no increase in delays. There were more surgeries in the Giovanni arm. There were no increase in surgical toxicity or adverse events by CTCT in the neoadjuvant period and there were no more treatment related deaths or postoperative complications. So #1 is that it's improving survival #2 is it's not having a detrimental effect on the incidents or performing surgery. Speaker 1 Thankfully, we are not compromising any surgical outcomes here. When it comes to side effects, Gem says we're very comfortable with what to expect. Side effects of dIRVALUMAb Dirvalumab, again out in community, we used this day in day out. We're very comfortable with that when we're combining GEM says dirvalumab, anything unique that we have to worry about? Can you just touch on the side effects that we're seeing in NIGRA trial? Speaker 2 So let me tell you what I think about this. I don't think CTC criteria were designed to assess adverse events associated with immune therapy. With immune therapy, you can get the weird and the wonderful. You can get interstitial lung disease, you can get chronic colitis, you can get pneumonitis. You can get other adverse events, endocrine, neurological and cardiac advent events. In this trial you said if you're getting into trouble with immune therapy on cycle 1/2 and three, don't keep pushing it in. The important thing is you get the patient to the surgical operation safely. If on cycle 2 you need steroids, you might not want to give cycle 3 and 4 of immune therapy. You want to get the operation done, do it safely, and then maybe you reintroduce the immune therapy in the adjuvant phase. The important thing is not to be pushing and this is true for platinum based chemotherapy. You get really bad neutropenic sepsis on cycle three. I wouldn't give cycle 4. Let's not compromise. Give the patients some time or get them back to baseline. If you're saying what would I be encouraging people in the community to do? Don't force in the immune therapy if you run into trouble, you know, on cycle 4, if you've got transaminitis grade 3 on cycle 3 and the patient's still got a grade 2 transaminitis, if you push in cycle three, you're going to end up delaying the surgery. So it really is classic good medicine, you know, when being pragmatic about problems, prioritising the important things in this case is the surgery and making sure you're getting that patient to the surgery effectively because the all surgical colleagues we have to work in parallel. Speaker 3 With them. Speaker 2 And they'll stop referring as patients if each one arrives on 16 milligrams of pregnancy alone with a Grade 3 humanisers. Speaker 3 Thanks for covering that, Tom. Raul, as you alluded to not just here but also in breast, lung and now in gastric, we will be utilizing this periop approach when using post op IO. Role of CTDA in adjuvant therapy The question always is which is that patient who is deriving this benefit of post op immunotherapy. Tom, outside of clinical trials, any role of CTDNA to dictate who should in fact get immunotherapy in adjuvant? Speaker 2 Settings. I don't know the answer to that question. I could talk about it for a long, long time because I like to meander when I don't know the answer to the question. Let me tell you what I think at the moment. I think CTDNA is going through a really rapid evolution. I can tell you from other neoadjuvant trials, Abacus, tombola and other adjuvant trials in vigor and leather that the proportion of patients. Speaker 3 At. Speaker 2 Before surgery who are CTDA positive it's about 60%. So it's quite a high proportion pre surgery. Now that doesn't necessarily represent micro metastatic disease. It may just represent the primary T2 or T3 tumor. Post surgery, it's about 10% of unselected patients. But if you go for high risk patients such as Invega 11, that goes up to about 40%. So if you pick the high risk post operative patients, about 40% are CTA positive, about 60% are baseline. Immune therapy alone is associated with about a 20% clearance in CTDNA and chemotherapy we think is associated with about a 30% clearance. This is predominantly with Notera technology, which is the informed technique. There are other techniques which have less robust data. If you are CTDA negative post neoadjuvant immune therapy and chemotherapy, does that mean you can stop therapy? Well, there are two parts to that. Number one is it might be the immune therapy that's actually cleared your CTDA because we know that's about 20%. If that's the case, 3 months feels too short for me. In metastatic disease, you wouldn't give three months of immune therapy. In my world, I think you get one good go at immune therapy. If I had a patient who cleared their CTDNAI would say we need to keep going to consolidate this benefit. I think 3 months of immune therapy is too sure. One of the key questions would be what about those patients that don't clear their CTDNA and remain positive? Should we keep going or does this define treatment failure? And that also an interesting issue, my gut feeling is if you remain CT DNA positive, we should keep going with this. But you might say, well, if they're a main CTA positive, they're going to become a radiological positive. We know that CTA positivity tends to predate radiology positivity by about four to six months. So I would keep a really close eye on that patient. And then there's an issue about whether they should become an EV pembro, more immune therapy or EV by itself. Right now I don't know the answer to that question either. Speaker 1 CTDNA is a moving target. The data is intriguing, but out in the practice. We should not be using this to dictate or treatment. The standard of care as of now should be all comers getting immunotherapy if there's no other contraindication and whatever we're keeping these patients on immunotherapy longer, we have to manage those side effects. Speaker 3 All the fine balancing yacht, Tom, before we close this, we will see in community or academic setting if this patient was to progress or recur, are you going to use infortumab with pembro or infortumab alone? The future of immunotherapy How is that sequencing going to look like if the patient is on durvalumab in post op setting or has completed durvalumab? Speaker 2 I've given this question a great deal of thought and there isn't any data at the moment and I've got 2 answers. If I may, 1 is a scientific answer and the second is a pragmatic answer. The science that's available to us as it stands suggests immune therapy patients or patients who receive immune therapy have one good go at responding to it. We haven't shown that sequencing PD1 inhibitors or indeed LAG 3, Aqua 40 and CSO and R, We haven't shown that in nivolumab, refractory disease or the other immune therapies suddenly work brilliantly. It looks like the tumours are predisposed to either respond or not. Drugs like a tetalizumab cause an immune infiltrate, but that seems to be associated with with with a potentially response. But it doesn't seem to be associated with when you would give it a second time. You get that occurring again. Again #1 #2 is we've done randomised trials in kidney cancer where we've re challenged with immune therapy and it's done absolutely nothing. This principle of giving it a second go doesn't make a lot of sense. There is the caveat in the adjuvant or the perioperative setting. If a patient was to relapse a year or two afterwards, it will be reasonable for a clinician to say that's different from the metastatic trials that you've done. It may be that they will always a responder and need in a longer period and we're more comfortable giving 2 rather than one year of immune therapy. So I'm happy to entertain the possibility if there is a gap between immune therapy. But if it's within six months, you're still on immune therapy as far as I can see. And so I'm not super keen on rechallenge. Let me though come to EV Pembro. EV Pembroke There are people who believe that EV Pembro has a synergistic interaction. We haven't seen CR rates of 30% before. We haven't seen OS of 36 months. And with so few attractive options remaining for these patients, particularly in Niagara who will have had platinum based chemotherapy and immunotherapy, the thought of going on to something like single Asian taxane therapy is really unappealing. So clearly EV for me is definitely the right treatment. The question is, is that addition of Pembroke going to be associated with something unusual that we don't know? Is the EV disrupting the tumor microenvironment and letting the T cells in? We haven't shown that's not the case yet. I've got a group or Amigos group that we do, my friend Brian Rooney and we've we've generated A scoring system where we've asked, you know, around 30 experts around the world what they think of re challenge with Eden Pembro. The majority of experts are comfortable with it, but I think that's not because of the luxury of choices in this environment. It's because you're almost in the last chance saloon here and I think people feel that patients who have relaxed disease can you go with Eden Pembro? Makes sense. Another big question will be, you know, Edie Pembro will move into the neoadjuvant setting. And when that happens, what do we do next? And I'll tell you, that's a podcast for a different day. Speaker 1 You know, this is all data free zones, how we come up with sequencing. It's important because patients living longer in the last year we've seen bladder cancer overall survival doubling in metastatic disease thanks to your study. And now in muscle invasive vasectable disease, we're again seeing it proved pathological complete responses improved overall survival with use of immunotherapy and chemotherapy. Tom, thanks for taking the time to cover NIGRA study with us today, which has led to the approval of dirvalumab with chemotherapy and resectable muscle invasive disease. Summary and Conclusion For our listeners. Let us go over a quick recap from today's discussion. Speaker 3 Today in our discussion with Doctor Tom Powells, AGU Medical Oncologist and lead author for the. Speaker 2 Niagara Trial. Speaker 3 We had a chance to break down the recent approval of dirvalumab and chemotherapy in resectable muscle invasive bladder cancer. We touched on improved overall survival of 82% versus 75% at a two year mark with dirvalumab and cisplatin based chemotherapy in combination and then continuing dirvalumab for leading that total of 1 year after surgery. Speaker 1 Well, not just today, but even during our non small cell lung cancer and triple negative breast cancer, we've touched on this stand ditch approach and use of immunotherapy in resectable cancer. It remains unclear if all patients are driving equal benefit from post op immunotherapy, but the given clinical trial design this should be part of our treatment. Thankfully, we're not seeing significant toxicities with the combination of their value MAP when we're comparing this to chemotherapy alone. Given this recent approval to value MAP with cisplatin based chemotherapy should now be the standard of care treatment for resectable muscle invasive bladder cancer. Thanks for joining us. Make sure to check out our other conference highlights, FDA approvals and toxic discussions. We are the oncology brothers.