Long-Term Data Supports Nadofaragene Firadenovec in High-Risk NMIBC


Vikram Narayan, MD, discussed the durable clinical activity observed with nadofaragene firadenovec in the CS-003 trial for patients with non-muscle invasive bladder cancer.

Vikram Narayan, MD

Vikram Narayan, MD

A long-term analysis of the phase 3 Study CS-003 trial (NCT02773849) continues to support treatment with nadofaragene firadenovec-vncg (Adstiladrin) for patients with high-risk, BCG-unresponsive non-muscle invasive bladder cancer (NMIBC).

Nadofaragene was approved for use in this setting in December 2022. The approval was supported by previous data from this phase 3 study.

The trial included 157 patients who were enrolled in 1 of 2 cohorts. Cohort 1 included patients with carcinoma in situ (CIS) ± Ta/T1 (n = 107) and cohort 2 included those with high-grade Ta/T1 without CIS (n = 50).

In the 5-year efficacy analysis, which included 103 and 48 patients from each cohort, the overall survival (OS) rates were 76.3% (95% CI, 64.6-84.5) and 85.9% (95% CI, 70.9-93.5) in each cohort at a median follow-up of 50.8 months (IQR, 39.1-60.0). In each cohort, the cystectomy-free survival rates at 60 months were 43.2% (95% CI, 32.2-53.7) and 58.7% (95% CI, 43.1-71.4), respectively.

The agent represents a new treatment option, particularly of interest for those unable or not willing to undergo cystectomy, as it utilizes a convenient dosing pattern given once every 3 months.

“[M]any patients either are unable or unwilling to undergo cystectomy for various reasons, such as medical comorbidities, or for concerns over quality of life, etc. As a result, it is nice to have this drug available in addition to some of the other ones,” explained Vikram Narayan, MD, in an interview with Targeted OncologyTM.

In the interview, Narayan, director of urological o\ncology at Grady Memorial Hospital and an assistant professor in the Department of Urology at Emory University School of Medicine at Winship Cancer Institute, discussed the durable clinical activity observed with nadofaragene in the CS-003 trial for patients with NMIBC.

Targeted Oncology: Could you elaborate on the significance of the 5-year overall survival and cystectomy-free survival rates of nadofaragene firadenovec?

Narayan: This was, as you probably know, the 5-year follow-up data from our clinical trial, the phase 3 trial that was conducted, and we reported out 1-year results several years ago, which led to the FDA approval of nadofaragene firadenovec for BCG-unresponsive, non-muscle invasive bladder cancer. This provides 5 years of follow-up data for this kind of new class of drug, this gene therapy that is delivered in the bladder for patients who have this condition that has historically been very difficult to treat outside of something like radical cystectomy or some kind of intravesical chemotherapy. The significance is that it provides long-term follow-up, so 5 years of data.

With respect to cystectomy-free survival, the main topline takeaways are that nadofaragene seems to allow bladder preservation in nearly half of patients in the CIS cohort, and about two-thirds of patients in the Ta/T1 cohort. Now, I will say that it is hard to necessarily attribute the fact that these patients avoided cystectomy completely to nadofaragene. As you are probably aware, patients who recurred were allowed to go on to other treatments at the discretion of their treating physician, but it does provide some information as to the safety of offering alternatives to cystectomy in this patient populationin well-selected cases.

What can you discuss regarding the recurrence-free survival data?

When you look at the 5-year recurrence-free survival, there actually are not a lot of other treatment options that you can compare it to head-to-head. What we found in patients who had CIS was that at 5 years, if you had a complete response at 3 months, only about 11% of patients had high-grade recurrence-free survival at that 57-month time point. In the Ta/T1 cohort, it is only about 20%. But this does not capture the fact that there were not a number of patients who were lost to follow-up. If you include everybody who had ongoing response, meaning no recurrence at the time of their last assessment at whatever time point that was, or at that 60-month time point, that is about 25% of patients in the CIS cohort and about 49% of patients in the Ta/T1 cohort.

In terms of comparing this to other treatments and other options, a couple of things to highlight are that in this trial, when it was originally designed and conceived of, there was not a lot of understanding as it related to how well these patients would do with these sort of cystectomy alternatives. There was a lot of concern that delaying cystectomy could lead to progression, etc. We only saw 5 progression events in the entirety of the study, at least at the time of last disease assessment. So that is the first take home.

The other is that the trial itself was designed to be conservative. No patients were given retreatment at any point, meaning that if they recurred, they were not given a second course of the same drug. A lot of the other drugs that are currently being investigated in this space do allow for that, in part because we now understand that that is something that you can do reasonably and safely, given some of the things that were shown in this trial, but it is hard to make head-to-head comparisons. The other thing is we required all patients in the study to have a mandatory biopsy. So, there were some patients that were picked up as having recurrence even though clinically they may appear to not have a recurrence on cytology alone.

What were the most common adverse effects observed and which were the most significant?

Importantly, there were no grade 4 or 5 study drug-related adverse [effects]. The most common types of complications that were seen were those that you expect with many other intravesicular agents, including things that patients are already familiar with, such as BCG, so discharge around the catheter, fatigue, bladder spasm, urinary urgency. Those are common things that [patients] saw. Only 2% of patients discontinued therapy because of an adverse [effect], and that there were no new safety signals seen with any long-term.

What are the next steps for evaluating this agent?

It would be great to have some additional data on those who did undergo cystectomy. We have some data on those patients, but we do not have detailed data for those who went on to have cystectomy later on. Knowing the pathology of those patients at the time of cystectomy, I think would be important for us to know truly what our progression rate was.

The other thing is, with the efficacy data being what it is at 5 years, while many patients are able to avoid cystectomy, it is not the holy grail. There is still a lot of work that needs to be done in this space. Patients expect better efficacy than 11% or 20% at 5 years, depending on which cohort they are in. In the interest of us trying to figure out what other treatments can we offer our patients or what additives or combinations or things we can do, there are a few trials in development in this space… so those are some of the areas that we are continuing to explore.

How do you foresee nadofaragene being integrated into standard clinical practice for NMIBC?

The [American Urological Association] has included nadofaragene as an option for patients with BCG-unresponsive disease. It is another drug in the menu of options that we can offer our patients. I still think that radical cystectomy offers the best opportunity for cure for patients with this condition. When I am in the clinic, I still discuss that as sort of the first option for those patients. But as you know, many patients either are unable or unwilling to undergo cystectomy for various reasons, such as medical comorbidities, or for concerns over quality of life, etc. As a result, it is nice to have this drug available in addition to some of the other ones.

Other things that we discuss are intravesical gemcitabine/chemotherapy, gemcitabine, docetaxel, and chemotherapy. There are trials looking at that. Pembrolizumab [Keytruda] is discussed as well, and there are several drugs that are now available in this space that we go over with our patients so that they can choose in an informed way. With nadofaragene, the big advantage, in my mind or at least in the way I present it to patients, is that from a dosing perspective, it is convenient in that it is once every 3 months. That is why a lot of patients find it favorable. It is delivered through the bladder and delivered in the bladder so they can avoid some of the systemic [adverse] effects that you might otherwise see. For those reasons, patients find it appealing. But there are some logistical issues that you have to deal with in terms of freezers and things like that when setting your office up to be able to give it. It is also expensive. That is something that we have to think about with all of these new therapies, the cost of these drugs and how our patients and the healthcare system have to bear that burden.

It is an exciting time for those of us who have been kind of involved in this area of research because we are seeing so many new drugs finally being available for our patients. I think there is still a lot of work left to be done. What I tell my patients is that having bladder cancer is 1 of those things where there are a lot of twists and turns, and it is all about coming up with a plan that can help them take them to the next step, whatever path that might be for them. It is nice to see these agents now being available. It is heartening to see a lot of the work that has been done by countless folks. I represent just 1 person amongst all of the coauthors on the project that we presented, and the research that we presented, and credit really goes to all of the participants and patients that that were in the study, and of course, the various investigators across the 33 clinical sites that the trial was run at.

Efficacy of nadofaragene firadenovec-vncg for patients with Bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer: final results from a phase 3 trial. Presented at: 2024 American Urological Association Annual Meeting. May 2-6, San Antonio, Texas. Abstract PD48-01.
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