Narayan Discusses Bladder Preservation and the Role of Gene Therapies in NMIBC

Vikram M. Narayan, MD

The longest follow-up data on a gene therapy intravesical agent presented to date revealed that treatment with nadofaragene firadenovec-vncg (Adstiladrin) allowed for bladder preservation in approximately 50% of patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC), according to Vikram M. Narayan, MD, who noted that remaining questions with the agent are under evaluation.

Five-year follow-up data from a phase 3 trial (NCT02773849) presented at the 2024 American Urological Association (AUA) Annual Meeting demonstrated that the 60-month cystectomy-free survival rate was 43% (95% CI, 32.2%-53.7%) among patients with NMIBC who were treated with the nonreplicating adenovirus gene therapy in the carcinoma in situ (CIS) cohort (n = 103). Patients with high-grade Ta or T1 disease (n = 43) experienced a cystectomy-free survival rate of 59% (95% CI, 43.1%-71.4%) at 60 months. Additionally, the Kaplan-Meier high-grade recurrence-free survival rate estimates at 57 months were 13% (95% CI, 6.9%-21.5%) in the CIS cohort and 33% (95% CI, 19.5%-46.6%) in the Ta/T1 cohort (n = 43).

“There were very few progression events overall, only 5 patients over the course of 5 years at the time of last assessment [progressed to muscle-invasive disease], but the original study design did not allow for any retreatment [with nadofaragene firadenovec] if a patient had high-grade recurrence,” Narayan explained. “We did not allow retreatment with nadofaragene firadenovecin this trial, and many of the other drugs that have also been investigated for use in the space do allow for retreatment.”

In an interview with OncLive^®, Narayan highlighted key takeaways from the 5-year final analysis of the trial, next steps with nadofaragene firadenovec, and promising emerging therapies for patients with bladder cancer. Narayan practices at Emory University Hospital, serves as director of urological oncology at Grady Memorial Hospital, and is an assistant professor in the Department of Urology at Emory University School of Medicine and a member of the Winship Cancer Institute in Atlanta, Georgia.

OncLive: What are the key takeaways from this final analysis?

Narayan: We previously presented results with 12-months of follow up, but this [final analysis] provides 5-year follow-up data and the study is important for a few reasons. It is the longest follow-up to date of any gene therapy intravesical agent, which is a new drug class for patients with BCG-unresponsive NMIBC. There were no new safety events identified with 5 years of follow-up. Very few patients discontinued the therapy because of a drug-related adverse effect [AE] and there were no grade 4 or 5 study drug-related AEs.

[At 57 months], 11% of patients in the CIS cohort maintained a complete response [CR] if they had a CR at 3 months and that [rate] was 20% for those in the high-grade Ta or T1 disease cohort. [However], there were some patients who were lost to follow up. [Approximately] 25% of patients had an ongoing response—no disease recurrence at the time of their last disease assessment—in the CIS cohort, and 49% of patients in the high-grade Ta/T1 cohort fell in that category as well.

Another important takeaway is the percentage of patients who were able to keep their bladder. You can’t necessarily attribute bladder preservation to any one cause [and] many patients who may have [experienced progression on] nadofaragene firadenoveccould have gone on to get other treatments that may have contributed [to undergoing a cystectomy]. But at least from the perspective of is this drug safe to give as an alternative to cystectomy, of those in the CIS cohort approximately 43% had a cystectomy-free survival [at 60 months]. That’s very important and our patients may be excited to hear that. [Fifty-nine percent] of patients in the high-grade Ta/T1 cohort had bladder preservation at 60 months as well.

What questions remain on nadofaragene firadenovec in this patient population?

One important question that’s unanswered is related to what we can do to better augment the treatment responses and how we can offer patients even better [care] than what we were able to through this study. It is important to remember that this study was [initiated] at a time when we were very conservative about what we would offer our patients with BCG-unresponsive NMIBC. There was a lot of concern about using alternative treatments in lieu of cystectomy for fear of progression and [other concerns].

An unanswered question is if retreatment with nadofaragene firadenovec offers any benefit to patients and that’s being investigated in an upcoming study. Another question is can you combine nadofaragene firadenovec with other agents to see if that can potentially confer better outcomes? For example, the [upcoming] ABLE-22 study is designed to look at whether nadofaragene firadenovecwith gemcitabine/docetaxel/intravascular chemotherapy or nadofaragene firadenovecplus pembrolizumab [Keytruda] can provide [better] options for patients. We’re excited to see where some of those [trials] will lead.

What does the future hold fornadofaragene firadenovec in other patient populations?

There is an investigation ongoing looking at nadofaragene firadenovecfor low-grade upper tract urothelial cancer and that’s a bit of a different patient population altogether. The use of the drug in that setting involves administering the drug and then using a balloon catheter to help maintain it in the renal pelvis. Also, in intermediate-risk disease—the non-high-risk BCG-unresponsive patient population—that’s an area where there’s a lot of unmet need. Patients [with] recurrent low-grade disease also can potentially be an area of interest. There are other urothelial cancer spaces that this drug is being investigated in [as well].

We are [also] interested in understanding if we can better stratify patients for high-risk, low-risk, [and] intermediate-risk [disease] with a biomarker. We’ve looked at urinary biomarkers with the UroAmp test and recently presented data at the AUA Annual Meeting using phase 2 trial results with nadofaragene firadenovec. Can we replicate that with phase 3 data and validate that further so that in future clinical trials, we’re not just using, for example, patients who have CIS or papillary disease? [Then], we can drill down into what sorts of mutations they have or what types of minimal residual disease they have. That is going to be key to better isolating which patients are best for these treatments.

What data or trials in the future will be key in the bladder cancer field?

Exciting things to look at moving forward involve clinical trial designs looking at bladder preservation which are of increasing interest. We do have an understanding that there is a subset of patients who don’t need cystectomy, but our guidelines currently recommend cystectomy in lieu of all good alternatives and importantly, in lieu of good ability for us to be able to [determine who the] patients who don’t need cystectomy are upfront before surgery.

It’s very easy in retrospect after you remove someone’s bladder to say, ‘you had great pathology, and may have been somebody who could have avoided cystectomy.’ That’s not as easy to do before surgery and we know from a lot of previous studies that it is very difficult to clinically stage a patient with enough confidence that would allow you to tell upfront whether they truly needed a cystectomy. There are several clinical trials that are looking at using [technology such as] ctDNA in combination with either systemic agents [or] close surveillance to figure out [if] a patient can be watched safely, allowed bladder preservation, [and/or] allowed perhaps maintenance therapy with an intravesical agent [or if the] patient should undergo cystectomy to have the best outcome.

What emerging novel therapies or gene therapies have also shown promise?

This is a very exciting time to be a physician helping take care of these patients. When I was a resident, we had very few options for treating patients with NMIBC, particularly high-risk NMIBC; patients would either get repeat BCG, intravesical chemotherapy of some sort, or they would be offered cystectomy. It always struck me as somewhat unusual that we did not have more options for our patients, and I’m heartened to see that today there are dozens of trials in this space.

Very recently, nogapendekin alfa inbakicept-pmln [Anktiva] which is given with BCG was approved [by the FDA]. It remains to be seen [how aspects] such as cost and efficacy in the real world [are with that agent]. Also, what role do all these new drugs play as we try and think about sequencing of agents and which drug might be best for which patients? There are a lot of unanswered questions, but these are good problems to have, whereas previously we were in a situation where we didn’t have a lot of options for patients. There are a number of agents like this and others that are coming down the pipeline that we’re very excited about.

A gene therapy, cretostimogene grenadenorepvec [CG0070], is being investigated in several clinical trials. There were recent data presented at the AUA Annual Meeting from the phase 3 BOND-003 [NCT04452591] study looking at the agent in the BCG-unresponsive population that were very encouraging. We don’t have long-term data on it, but we did see fairly good 12-month follow up data which are exciting as well. Cretostimogene grenadenorepvec is dosed once a week every 6 weeks and has a similar gene therapy type of mechanism of action.

As we see those drugs and others emerge, it’s going to be important for us to figure out how to decide which of these options to offer a patient. A patient may ask which one’s better and being able to break down the differences between the study designs, whether retreatment was allowed, [and more] is going to be important.

Reference

Narayan VM, Boorjian SA, Alemozaffar M, et al. Efficacy of intravesical nadofaragene firadenovec for patients with Bacillus Calmette-Guérin-unresponsive nonmuscle-invasive bladder cancer: 5-year follow-up from a phase 3 trial. J Urol. Published online May 5, 2024. doi:10.1097/JU.0000000000004020