Sam Chang: Hi, my name is Sam Chang, and I'm the luckiest person in the world today. Why? Because I am with a true superstar. Dr. Leslie Ballas is a radiation oncologist, full professor at Cedars-Sinai, and has really been actually at the forefront of different treatment strategies, but we're going to focus on one, specifically looking at bladder sparing. This is SWOG 2427, which is a phase three trial.

Leslie Ballas: Phase two.

Sam Chang: Phase two trial, sorry, looking at immunotherapy with radiation therapy, following a response after neoadjuvant chemotherapy.

Leslie Ballas: Who's the superstar now, Sam?

Sam Chang: I think I got that right. But really, I think hitting on the question that we all have, what happens after a patient gets what we think is a complete response after neoadjuvant therapy? So, I'll leave it at that. So, if you could tell us the details and the exciting things that you're presenting or have presented at ASCO GU 2026, we're all ears.

Leslie Ballas: Thank you so much, thank you for having me today. So, this trial was really driven by patients that I had seen in clinic over the years, patients who got neoadjuvant therapy and who had what they believed to be a good response to that, and then asked their urologist, "Can I save my bladder? Do I really need a cystectomy?" And there was really no paradigm for those patients. There's been a lot of advances in systemic therapy for bladder cancer. And so building on that, there have been a lot of single-arm phase two trials looking at whether or not patients need any sort of local therapy following a complete clinical response to neoadjuvant therapy. And those trials have been remarkable in what they've shown, in that the bladder-intact distant mets-free survival is somewhere in the sort of 60, 70% range on Matt Galsky's Hoosier trial and a little bit less than that on the RETAIN-1.

Obviously, we're going to see Dr. Ghatalia present RETAIN-2 during this meeting, but there are still patients that are failing and then having to go on to get cystectomy and/or developing metastatic disease, which really points to what we know from SWOG 0219, which is that a complete clinical response is not a pathologic complete response. 60% of patients that had what they thought was a CCR on 0219 ended up having disease at cystectomy. And I think the importance of local therapy needs to be evaluated. And so, we are taking patients who've had any form of neoadjuvant therapy, which after this meeting might be a standard EV pembrolizumab, certainly it could be GC-durvalumab as per the NIAGARA protocol, could be standard chemotherapy. They have a TURBT following the completion of that neoadjuvant therapy.

Sam Chang: So, okay. All right, great, because I was going to ask you in the trial, how are you determining the complete clinical response?

Leslie Ballas: Yeah. So we're doing TURBT, as well as imaging, which can be CT, MR, or PET-based. And we're allowing patients to enroll on trial who have either complete clinical response or, and this is a very understudied population, but a T1 after neoadjuvant therapy. And then they go on to get radiation and immunotherapy, getting rid of the radiosensitizing chemotherapy in that setting using the immunotherapy for that and the full dose neoadjuvant therapy. And then they get radiation to the whole bladder, 20 treatments, 55 Gray, and then they will go on to get observed. If patients have this trial in mind or providers have this trial in mind and they do not have a T1 or better response to neoadjuvant therapy, they could then go on to either get cystectomy, or they could go on to other TMT trials. NRG has one open that they could qualify for as well.

Sam Chang: So, patients get enrolled then after the TUR, and it's what I like about is, it's very practical. Your systemic therapy upfront, your neoadjuvant therapy is neoadjuvant therapy. Your evaluation, you have to have a TURBT, that makes sense. But then the evaluation in terms of, okay, CT, MRI, there's no question we're changing, we're trying to get better. Your initial points of, you had a significant proportion of patients that require therapy because we really don't know who clearly is pathologic CR. I love all of that. In terms of the dosing, specific questions, the 55 Gray of radiation therapy to the bladder, is that a standard dose? Is that something that we, if we had a standard TMT type of protocol, is that a normal dose?

Leslie Ballas: It is, yeah.

Sam Chang: Being radiation dosage somewhat ignorant.

Leslie Ballas: I'm actually impressed that you're asking about the dose.

Sam Chang: So the dosing, and are you going whole pelvis or just focusing on the bladder?

Leslie Ballas: Just whole bladder. So we know from the 55 and 20 is a dose that was used on the BC2001 trial and has been used in the UK for many years, used in the US as well. There has been an analysis looking at the classic RTOG 64 Gray and 32 treatments, versus the 55 and 20, and showing general similarity-

Sam Chang: Roughly equivalent, okay.

Leslie Ballas: ... between the two dosings. Obviously, it's nice to be done in 20 days as opposed to 32 days. And so, that is a very standard option that is being delivered. We are doing whole bladder, not whole pelvis, mostly because the most recent trial from the UK, the RAIDER trial, that looked at modern day radiotherapy to the whole bladder, had a pelvic failure rate or failure in the lymph nodes of the pelvis less than 7%. And so, we feel that it is reasonable to omit treatment to the pelvic lymph nodes, especially in these patients that were N0 upfront and have continued to be N0 and have had such a robust response in the bladder.

Sam Chang: And then the follow-up to that, the immunotherapy is pembrolizumab for a year, is that right?

Leslie Ballas: It is, that's exactly right.

Sam Chang: Okay, okay. And so, tell me the thought process behind including, because I love this too, is including the T1 patients, T1 or less. The rationale behind that is what?

Leslie Ballas: Well-

Sam Chang: That you're worried that something may happen or it may be a signal that we need to treat, so.

Leslie Ballas: So, there's a lot of work that's been done in the complete response patients in terms of an active surveillance or immunotherapy maintenance kind of treatment. But there are these patients that have minimal residual disease, T1 disease, and to have them undergo a cystectomy, even though they've been downstaged by their neoadjuvant therapy, begs the question, if we're going to give local therapy and local therapy that has been shown to be effective in T2 to T4 disease with TMT, why not include them? We initially looked at, should we allow for T2 in lower patients? The urology colleagues that were involved from SWOG and that are the urology PIs on the trial felt a little nervous about down-staging only to T2. And so, T1 felt good all around and we know that radiation certainly can eradicate disease in those patients.

Sam Chang: Right. So then that begs a second unrelated question, maybe the fourth or fifth question I have, but what do you think of radiation therapy for T1 disease? Let's get BCG out of it, T1 tumors that we know are T1. What do you think about radiation therapy for those?

Leslie Ballas: We, in the past year or two had a publication, RTOG 0926, which looked at chemo radiation for patients with T1 disease whose next step was cystectomy.

Sam Chang: Cystectomy, okay.

Leslie Ballas: And they had a three-year cystectomy-free rate of 88% on that trial, which is basically a huge wow. That's amazing, and save these patients their bladder. And so from that, through the NCTN clinical trials planning meeting, another concept was developed, a much larger concept that is being run by Brian Baumann through the NRG, the PARRC trial, which is looking at T1 patients whose next step would be cystectomy, and randomly assigning them to either chemo radiation or radiation IO, in order to better ascertain how we can use and if we can use radiation in these patients. Ananya Choudhury is going to give a talk at this meeting discussing the role of radiation in non-muscle-invasive bladder cancer, and they have a trial in the UK that's also going to open a phase three trial in this space.

Sam Chang: Yeah. I think the higher quality evidence we get in that space, I think it's really going to be really important because clearly despite our attempts, urologists still are under-staging a significant number of these patients. It's becoming increasingly difficult to persuade patients to proceed with cystectomy in T1 disease, even though we really feel like that's their next best step. And so to have an alternative that would be effective, both long-term as well as being able to then keep the bladders intact, I think is something that we need to get a better handle on for sure.

Leslie Ballas: And I think that the great thing about these upcoming trials is they are so pragmatic. I mean, the non-muscle-invasive bladder cancer space on the urology side has so many options. There's so many different treatments that are available to patients. This is, radiation would be after patients had tried-

Sam Chang: Sure.

Leslie Ballas: ... failed, any of those things. And so, it's a really exciting additional treatment option.

Sam Chang: Yeah, next step, because I mean, these patients, and I really do think this is going to be the case, we're going to do more and more to try to keep the patient's bladders. And how we increase the degree of treatment, what we do, those are the questions we're going to help answer with superstars like you. So now, every time I spend time with you, I learn so much and really appreciate taking the steps through the cooperative group trials and figuring out what to do next. Tell me then, last question, timeframe here. What are we looking at at the SWOG 2427 trial?

Leslie Ballas: Yeah. So we activated the trial to accrual at the end of 2025, and so it has been opened at a number of centers nationally. Because patients don't register for trial until after they've had the neoadjuvant therapy and the TURBT, there's a long lead-in before we get patients, but we do have four patients on trial thus far. We're just starting.

Sam Chang: Oh, great. Oh, wow.

Leslie Ballas: But open it at your centers, enroll patients on this trial. It's exciting, it's a great trial. We've got multidisciplinary involvement and buy-in, and I'm so excited to be part of this group.

Sam Chang: Well, I mean, to have... There's obviously a huge group of urologists, medical oncologists, radiation oncologists led by you. I think it's going to be obviously a really, really important trial, and look forward to seeing the results, and look forward to talking about them.

Leslie Ballas: Thank you so much.