Hannah Clarke

A shift in the management of BCG-unresponsive non–muscle invasive bladder cancer (NMIBC) has been the inevitable culmination of over a decade’s worth of work.

Traditional approaches to the management of NMIBC were limited to intravesical immunotherapy or chemotherapy––relying primarily on BCG, with the only other approved alternative being valrubicin. With the BCG shortage taking hold in 2012, urologists found themselves grappling with an even more constrained set of options. Considering this reality, pharmaceutical companies, investigators, and the FDA itself recognized the need for new therapeutics in this space, thus beginning the arm’s race for novel innovations.

In recent years, the fruits of this effort have become apparent, with 3 new approvals in the NMIBC realm and many more agents in phase 3 development.

However, even after the BCG shortage resolves, the need for agents in the BCG-unresponsive setting will remain.

“In the future, we are going to probably have other BCG strains, but this concept of BCG failure or BCG refractory disease is not going to go away,” said Siamak Daneshmand, MD, a professor of urology and director of clinical research at the University of Southern California, in an interview with 

®. “Not everybody responds to BCG. There's a global need for patients who don't respond to BCG, and then there's a small percentage of patients who don't tolerate BCG very well. We're so used to it because we've been using it for so long, but there are some patients who have a really difficult time with BCG.”

As 2024 comes to a close, the excitement for these new agents could not be more apparent. The BCG-unresponsive NMIBC space has gone from a dearth of options to a wave of new treatments, and now urologists are faced with an encouraging challenge: choosing the best one.

Siamak Daneshmand, MD
Credit: Keck School of Medicine of USC

The wave of new treatment options began in January 2020 with the approval of intravenous pembrolizumab (Keytruda), an anti-PD-1 therapy for patients with high-risk, BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Although this approval offered a new bladder-sparing option for patients, long-term outcomes showcased its downsides. Pembrolizumab was the first approved agent in the space with a 3-month complete response (CR) rate of 41%, but only 18.8% of the initial treatment cohort (n = 96) remained disease-free at 12 months.

Daneshmand noted, “Pembrolizumab has been around for several years now for [NMIBC], but the efficacy is not very high, especially when you start to look at 3 years. That safety-profile-to-benefit ratio is just not quite there.”

It wasn’t long before a new option rivaled the efficacy seen with pembrolizumab. In December 2022, the FDA approved nadofaragene firadenovec-vncg (Adstiladrin), an oncolytic adenovirus for patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary disease.

The approval was supported by data showing a 3-month CR rate of 53.4%.

 At 2 years following its initial approval, the therapeutic continues to demonstrate tolerability and safety in these patients, with promising cystectomy-free survival outcomes.

 The dosing schedule is also convenient for patients, as nadofaragene is dosed every 3 months as opposed to once per week like many of the other treatments that are available.

Vikram Narayan, MD
Credit: Emory University

However, this drug comes with its own set of challenges, primarily in its storing and handling. Nadofaragene arrives frozen and needs to be thawed before use, making it challenging for hospitals to manage in a busy environment.

Vikram Narayan, MD, an assistant professor of urology at Emory University in Atlanta, Georgia, explained, “The company has provided some additional guidance on how to make that piece easier, but I think in a lot of urology practices, being able to do that in an efficient way in a busy clinical practice remains a challenge.”

This year saw the approval of a third new agent––the interleukin-15 (IL-15) superagonist nogapendekin alfa inbakicept (N-803; Anktiva). Anktiva is indicated for use in combination with BCG for the treatment of patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors. The approval was based on data showing a CR rate of 55% at 3 months and 71% at any time point.

 However, real-world outcomes with this agent remain to be seen.

Although all 3 novel therapies have served as catalysts in bringing renewed hope to the BCG-unresponsive NMIBC space, there is optimism for further advancements in the near future.

Narayan noted, “I think it's fair to say that we haven't been as excited about the durability of a lot of these agents. So, we want to see better durability.”

Fortunately, it appears the wait for this progress will not be nearly as long as the decades leading up to these new options. Several agents already having demonstrated encouraging results in phase 2/3 studies, including TAR-200, cretostimogene grenadenorepvec, and TARA-002. Impressively, these agents boast CR rates at any time point of 83.5%,

Moving away from the BCG-unresponsive setting, there is even more potential with TAR-210, UGN-102, and combination regimens with BCG.

These agents are ushering in a new era of intravesical treatments, which appear to have comparable efficacy to systemic agents with less toxicity.

 Such treatments are anticipated to provide an additive impact to the profound progress that has already been seen in the BCG-unresponsive setting.

Sarah P. Psutka, MD, MSc
Credit: University of Washington

Thus, with a dizzying amount of activity in the management of NMIBC, urologists are now faced with new questions. The current treatment options were approved based on single-arm trials, so there are limited data on comparative efficacy. In the absence of head-to-head data, patient selection and treatment sequencing remain a challenge. As Sarah P. Psutka, MD, MSc, explains, these factors are a “black box,” and more data are needed to be able to make more informed decisions.

“Real-world data hopefully will help us to start to be able to use a data-driven approach to intelligently guide patients towards the therapies that they are most likely to respond to, but we're obviously not there yet. In the absence of comparative trials, it's just really challenging to know,” said Psutka, an associate professor of urology at the University of Washington in Seattle.

Patients will also face some considerations of their own.

Mark D. Tyson, II, MD, MPH
Credit: Mayo Clinic

“My understanding of the data is that most of these agents are about the same in terms of their efficacy. So, I think what it's going to boil down to, for the most part with patients, is going to be tolerability,” said Mark D. Tyson, II, MD, MPH, a urologic oncologist at Mayo Clinic in Phoenix, Arizona. “I also think there's going to be some other drivers of utilization. I'm sure the payers going to have something to say about this when the costs––for all of these agents––come out into full view. For the most part, I think patients are going to look at convenience, administration methods, tolerability, those sorts of things.”

Despite all of these unknowns, one thing remains clear: the future for NMIBC is bright.

Undoubtedly, this shift––deciding which agent to choose from–– is a welcome challenge in consideration of the previous era where bladder-sparing options were limited. This year has been a marked reflection of the past decade’s worth of progress in this space, and 2025 is poised to provide even more practice-changing advancements.

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Chamie K, Chang SS, Kramolowsky E, et al. IL-15 Superagonist NAI in BCG-Unresponsive Non–Muscle-Invasive Bladder Cancer. 

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Daneshmand S, Zainfeld D, Pieczonka C, et al. Safety and tolerability of TAR-200 monotherapy in patients with bacillus Calmette–Guérin (BCG)-unresponsive high-risk non–muscle-invasive bladder cancer (HR NMIBC) in SunRISe-1. Presented at: Society of Urologic Oncology 25th Annual Meeting. December 4-6, 2024. Dallas, Texas. Abstract 135. Accessed December 5, 2024. https://suo-abstracts.secure-platform.com/a/gallery/rounds/21/details/3800

Tyson M, Uchio E, Nam J-K, et al. Topline results from BOND-003: a phase-3 study of intravesical cretostimogene grenadenorepvec for the treatment of high-risk BCG-unresponsive NMIBC with CIS. Presented at: Society of Urologic Oncology 25th Annual Meeting. December 4-6, 2024. Dallas, Texas. Late-breaking abstract.

Mazzarella B, Jayram G, Shore S, et al. ADVANCED-2: phase 2 open-label study to evaluate safety and anti-tumor activity of intravesical instillation of TARA-002 in adults with high-grade non-muscle invasive bladder cancer. Presented at: Society of Urologic Oncology 25th Annual Meeting. December 4-6, 2024. Dallas, Texas. Abstract 119. Accessed December 5, 2024. https://suo-abstracts.secure-platform.com/a/gallery/rounds/21/details/3637

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Articles

The management of BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) has evolved significantly due to a decade-long effort to develop new treatments. Traditional options were limited, but recent years have seen the approval of three new therapies: pembrolizumab, nadofaragene firadenovec, and nogapendekin alfa inbakicept. These advancements offer new hope, though challenges remain in terms of treatment durability, patient selection, and real-world efficacy. Future developments are promising, with several agents in advanced trials, potentially transforming the therapeutic landscape for NMIBC.

The BCG-unresponsive non-muscle invasive bladder cancer space has gone from a dearth of options to a wave of new treatments.