Sam Chang: Hi, my name is Sam Chang. I'm a urologist at Vanderbilt University Medical Center, and I have the real pleasure and honor of actually spending some time again with Dr. Sarah Psutka, who is an associate professor at the University of Washington. She really doesn’t need an introduction.

She’s also the associate director of urologic oncology there and is truly a rising star in GU oncology—kidney cancer, urothelial carcinoma, you name it. She has so many interests—high-level care, geriatric care—I can’t even list them all.

But today, she’s going to focus on an expanded access program and a presentation that she gave at ASCO GU in 2025, looking at an expanded access program for cretostimogene. I know it as CG0070. And Sarah, thanks for spending some time with us. Obviously, people are very excited about this medication, but I think they’re just as excited about the opportunity it presents for different patients and different disease states.

Sarah Psutka: Yeah. Well, Sam, thank you so much for having me. I'm thrilled to be here. I’m going to go ahead and present the slides that we shared with our poster presentation at ASCO GU, and then I’m excited to talk to you about what this program really offers for our patients with high-risk BCG-unresponsive bladder cancer.

Cretostimogene is a novel oncolytic immunotherapy that’s being evaluated for non-muscle invasive bladder cancer. It has a dual mechanism of action. This drug selectively replicates in and lyses bladder cancer cells that express the RB, or retinoblastoma, E2F1 pathway alteration. The subsequent release of the virus and tumor-specific antigens initiates an anti-tumor immune activation pathway or cascade that ultimately allows for innate-to-adaptive immune switching.

The way I explain this to patients is that not only is the drug toxic to the cancer cells, but it also turns the cancer cells into a bit of a bioreactor, releasing more drug and creating a cascade that ultimately results in bladder cancer cell death.

Based on the preliminary efficacy and safety results of the BOND-003 study, which were presented at the SUO at the tail end of last year, cretostimogene has received both Fast Track and Breakthrough Therapy designations by the US FDA for BCG-unresponsive non-muscle invasive bladder cancer with carcinoma in situ.

As we all know, this agent addresses a critical disease space, given that our current guidelines endorse radical cystectomy as the frontline strategy for managing BCG-unresponsive non-muscle invasive bladder cancer. However, many patients are unwilling to undergo this morbid intervention or are unfit due to numerous competing medical risks.

Therefore, we have a significant unmet medical need for clinically effective and well-tolerated therapeutics that allow patients to spare their bladder with a durable, objective response. This expanded access program was developed to meet that need.

What we have here is an open-label expanded access clinical trial designed to provide cretostimogene to a diverse population of real-world patients with BCG-unresponsive non-muscle invasive bladder cancer with carcinoma in situ who otherwise are not eligible for enrolling clinical trials in this space or who don’t have access to other agents that permit a bladder-sparing strategy.

The eligibility criteria are designed to be extremely pragmatic, reflecting the at-risk patient population we see in real-world practice. This includes higher performance statuses such as ECOG 0 to 3, and patients with pathologically confirmed BCG-unresponsive carcinoma in situ with or without papillary disease—high-grade Ta or T1—after completing adequate BCG treatment, with maximally feasible resection of visible tumor prior to study entry.
We’ve previously amended this protocol to improve its flexibility and allow patients who have received other bladder-sparing therapies, including investigational therapies for high-risk BCG-unresponsive non-muscle invasive bladder cancer, to enroll.

After trial entry, patients undergo intravesical instillation of cretostimogene, preceded by an excipient, or DDM, which enhances adenoviral delivery, for six weekly doses during the induction phase—very analogous to what we do with BCG—with permission for reinduction for a partial response. I’ll explain that more in a moment.

Induction is then followed by maintenance dosing: three weekly maintenance cycles given quarterly through month 12, then every six months through month 24.

The primary disease assessments mirror what we do in clinical practice, including serial cystoscopy, cytology, axial imaging, and directed biopsies if clinically indicated, with local review of pathologic samples. The co-primary endpoints are safety and efficacy, with efficacy measured by complete response at any time and at 12 months.

Secondary endpoints include duration of response, high-grade recurrence-free survival, progression-free survival, and cystectomy-free survival. We also have exploratory outcomes, including health-related quality of life, overall survival, and biomarker assessments.

This slide provides additional details about key protocol features, including the study’s administrative schedule and maintenance dosing, as previously described. Notably, patients with persistent CIS or high-grade Ta at three months are eligible for reinduction. However, patients with high-grade T1 at that time would not be eligible to continue receiving cretostimogene on this protocol.

Sam Chang: Sarah, great overview of the expanded access program. I love the real-world aspect of it. Is there a target enrollment goal or a specific follow-up period of at least a year? What’s the thought process behind how many patients we’re actually going to study in this program?

Sarah Psutka: I think the objective is to enroll as many patients as we can. The goal is to go beyond what we typically see in a clinical trial setting and enroll the kinds of patients we see in clinical practice.

That means including patients with worse performance status who wouldn’t qualify for a standard clinical trial due to restrictive inclusion criteria. But also, access is a major issue—many clinical trials fail to enroll socioeconomically diverse patient populations.

This program aims to generate real-world data on efficacy and safety in a broader, more representative group. We're opening sites across the country, and enrollment is already underway. I don’t have the most up-to-date numbers, but we should have a better idea by next year.

Sam Chang: I think, excitingly, there are so many of these patients we talk about who may or may not have access to trials, including those with disease characteristics such as prostatic urethral involvement, disease in a diverticulum, or those who may have received other therapies that would exclude them from many of these trials. Gathering information on these patients will be increasingly important because the field is starting to get crowded.

We've got different options, and we're trying to determine—OK, what's the best option? But we really don't know much about sequencing. This trial, in itself, probably gives us information way ahead of the game in terms of understanding whether something is effective in these different clinical situations. So I think it’s really, really important.

Sarah, how do you fit this into your algorithm for considering treatment options for patients? Clearly, we’ve identified those who are ineligible for or unwilling to undergo cystectomy, but how do you stack this against other trials? Are you primarily basing it on exclusion criteria or other specific factors?

Or, for example, I have patients asking me about this medication. They’ve heard about it but may not have access to the currently open trials we have. How do you factor that into your treatment algorithm?

Sarah Psutka: Well, I think, as you said, Sam, it’s an abundance of riches. We suddenly went from having very limited options for patients who didn’t want to or couldn’t undergo cystectomy for their BCG-unresponsive disease to now having multiple options.

However, there are still challenges with drug availability. Although several drugs have already received FDA approval or are expected to within the next calendar year, many of them are not widely available yet. Speaking from my own experience, we have only one novel agent available at our site on formulary. It takes time to get these drugs onto formularies, particularly given the administrative protocols that each institution follows. So despite having new FDA-approved drugs, actually obtaining them remains a challenge.

I think this expanded access program is a great option for sites looking to provide bladder-sparing therapy, especially as newly approved agents become available. This drug is anticipated to receive full FDA approval within the next calendar year for BCG-unresponsive carcinoma in situ, with or without papillary disease.

The key question then becomes: How do we sequence these drugs? One exciting thing is that we’ve really raised the bar with novel agents. Here, of course, we’re talking about options like nadofaragene, N-803 (NIA), which is available but not yet accessible at all sites, cretostimogene, and TAR-200, which has received approval and will hopefully become widely available in the coming year.

The factors that will ultimately influence sequencing decisions include a few things. First, treatment burden—and that’s something I’m particularly interested in. One of the reasons I got involved in this study was my focus on understanding the burden of treatment on patients.

When this company offered me the opportunity to participate in this trial, I was particularly excited about the patient-reported quality-of-life outcomes that would be collected. These are the data points our patients want to know about when choosing between different agents.

Looking at efficacy, we’ve raised the bar. The complete response (CR) rate across these novel agents now appears to be in the 60-80% range, and the median duration of response is also being pushed further out. For example, in BOND-003, the median duration of response has not yet been reached as of the last report—now exceeding 27 months.

That’s a game-changer. Having a therapy for BCG-unresponsive non-muscle invasive bladder cancer with a median duration of response where more than half of the patients remain disease-free for over two years is a completely different landscape than what we had previously.

However, an important consideration is treatment burden—how many times is a patient coming into my office, sitting for 1 to 2 hours, receiving therapy, and managing potential adverse events?

While this is a well-tolerated agent—like many of the newer options, it is generally better tolerated than traditional BCG or even intravesical chemotherapy—this is the kind of data we need to help patients make informed choices. Which therapy should I choose first? If my disease comes back, what should I choose next?

For patients with heavily pre-treated bladders, how many bladder-sparing therapies can we rationally go through before we start worrying about distant disease? That remains an unanswered question, and it’s something many of us are concerned about. But ultimately, we need real-world data to help guide these decisions.

I’m particularly excited about this study because of the quality-of-life data that will be collected. I think that will be key in advising patients and helping them make priority-aligned treatment decisions.

Sam Chang: Yeah, I totally agree, especially with how this study is structured. As you mentioned, we already have a patient population that has undergone treatment and received different types of therapies.

Gathering post-treatment data—particularly around different sequencing strategies—and evaluating patient-reported outcomes to assess how well patients tolerate these treatments will be very important. As you said, the bar keeps getting higher, which is great for our patients, but ultimately, we need a framework for making the best choices.

I think your work on treatment burden will be especially valuable. We've made this major shift away from cystectomy, but now the question is: What do we do with an intact bladder? How do we weigh these different therapies? That’s going to be very, very important.

As you look at the next steps for this medication, people are now exploring systemic therapies for invasive disease, potentially combining local control approaches like radiation or surgery, and maybe even integrating intravesical therapies. Where do you see the next big step or area of focus for these novel non-muscle invasive intravesical treatments?

Sarah Psutka: I think one of the biggest unanswered questions in bladder cancer is how to manage locally advanced disease. Can we get to a point where we can spare the bladder in that situation? That’s the Holy Grail that many people are focused on right now.

But another area seeing a lot of activity is earlier-stage disease—specifically, intermediate-risk disease. There’s a big debate in that space: Do we escalate care for non-lethal disease, or do we de-escalate care?

For example, the PIVOT-006 study is currently investigating cretostimogene in intermediate-risk bladder cancer. We have this trial open at the University of Washington, and we’re actively enrolling patients. This is a randomized controlled trial comparing cretostimogene vs. observation in intermediate-risk disease.

That’s a completely different question. Here, we’re not talking about whether the patient will lose their bladder. Intermediate-risk disease—recurrent low-grade Ta tumors—is not considered lethal bladder cancer, so the oncologic potential is very different.

So then the treatment burden question becomes even more—

Sam Chang: —Even more important.

Sarah Psutka: Exactly. And this area used to be somewhat of an orphan space within bladder cancer research. Historically, all the focus and funding were in high-risk non-muscle invasive bladder cancer and BCG-unresponsive disease.

But now, we’re seeing a tremendous amount of activity focused on reducing recurrences in intermediate-risk disease.

Sam Chang: Yeah, that’s a really important shift. Previously, the dominant concern was bladder loss and disease progression, but now we’re also focusing on the burden of intermediate-risk disease—the frequent recurrences, repeated resections, patient anxiety, and the need for repeat cystoscopies.

That’s why patient-reported outcomes will be critical. They’ll help us understand the true impact of managing this disease—whether it’s better to monitor and treat as needed or proactively prevent recurrences with novel therapies.

Your point about escalating care when needed and de-escalating when we don’t is something we’ve all struggled with for years. But in a way, it’s a good problem to have—because it means we finally have effective treatments, and we don’t have to overtreat as often.

Sarah Psutka: Absolutely. I always tell my residents, "It’s not just about whether we can treat—it’s about whether we should."

Sam Chang: No question. I think our treatment paradigm could look dramatically different in just a few years.

Sarah, as always, I really appreciate your time and insights. We’re looking forward to seeing more data from these trials. Hopefully, we’ll get you back on soon with results!

Sarah Psutka: Thank you so much.