Bladder Cancer Care Shifts as BCG Shortage Lingers, With Investigative Combinations and Tools at the Forefront

As the effects of the BCG shortage are still prevalent, several key considerations, such as which patients to administer full doses of BCG, to are at play when selecting therapies for patients, according to Vikram M. Narayan, MD.

The April 2024 FDA approval of nogapendekin alfa inbakicept-pmln (Anktiva) plus BCG for adult patients with BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors represented a notable advancement, but the trial supporting the approval administered full dose BCG with up to 37 months of BCG maintenance.1 Narayan noted that at his institution, Emory University Hospital, split doses of BCG are given, which is a notable consideration when selecting therapies for patients.

“Convenience is another consideration,” Narayan said in an interview with OncLive®. “Most patients are used to coming in once a week for 6 weeks followed by a maintenance period. However, the more lines [of therapy] you go through, the more weary patients get of this. Perhaps one of the best things about nadofaragene firadenovec-vncg [Adstiladrin] as a treatment option is it’s given [via] quarterly dosing. Now, in some of these clinical trials when we add additional treatments to try and improve efficacy and durability [of the agent], that competitive edge goes away.”

In the interview, Narayan detailed updates in the bladder cancer field, including the effects of the BCG shortage on practice and upcoming therapies/tools of interest. 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: How has the approval of nogapendekin alfa inbakicept plus BCG changed care for patients with BCG-unresponsive NMIBC?

Narayan: Nogapendekin alfa inbakiceptis a very exciting development [because] we love to see new drugs in this space and we’re expecting to see even more. This agent is given with BCG, it does not work as monotherapy, but when combined with BCG and given with induction/maintenance appears to offer patients with BCG-unresponsive disease an additional option. For me, the biggest challenge has been that in the US we still deal with quite a bit of issues around BCG shortages and nogapendekin alfa inbakicept, at least when it was investigated, required full dose BCG. Many practices have limited supply of full dose BCG, or in accordance with AUA and SUO guidance, do split dose treatments and that’s something we do at Emory.

That results in a challenge for us [in terms of] knowing whether there’s any efficacy in giving nogapendekin alfa inbakiceptwith half dose BCG and limited maintenance because the trial, FDA approval, and label are for full dose BCG with a full 3-year course of maintenance. Being able to offer that [combination] if you have a BCG shortage can be a challenge, and then it becomes this question of equity for patients who might be awaiting BCG. For example, do you upfront prioritize a BCG-unresponsive patient to get nogapendekin alfa inbakicept plus BCG? Then that means that a patient who has a new diagnosis of high-risk disease can’t get full dose BCG. Those are some difficult questions.

The company that manufactures nogapendekin alfa inbakiceptis working on clinical trials to secure supply for potential additional strains of BCG, although that’s probably several years away. Some practices do have access to full dose BCG and for them it’s a great option to have available.

Is there anything else that’s changing or coming that could help to combat issues with the BCG shortage?

There’s an additional facility that is in the works that should come online. I don’t know the time frame for that, but I’ve heard anything from 6 to 12 months as a potential way to mitigate this [shortage]. The way I understand BCG manufacturing to work is [that] typically the vendor spins up the production for BCG—it’s a bacteria—all at once with a guesstimate as to how much supply is going to be needed for the subsequent 2 years based on the preceding 2 years. The reason it’s done in that way is to help maintain the homogeneity of [the] manufacturing process because it’s a live organism. That means that as you get closer to the end of that 2-year cycle you’re going to have shortages as the demand for BCG fluctuates. Then, there’s allocations [of it] for each hospital.

We only have one vendor in the US with one facility, and at least [one] additional [facility] is planning to come online, so we’re hoping to see that. The other [consideration] is this interest that remains in terms of clinical trials that are looking at comparing different strains [of BCG], including non-US strains. If we can demonstrate noninferiority and show similar efficacy [with the new strains] then those can potentially receive FDA approval. It’s one of those things [where] it’s not an easy short-term fix unfortunately.

What is most important to highlight on the shifting treatment paradigm for bladder cancer right now?

Now more than ever patients need to have a thoughtful discussion with their provider about the treatment options that are available. Historically and still to this day, at least [per] the guidelines, radical cystectomy is recommended because it does offer the highest chance of complete response and durability [of response]. The durability picture seems to be improving with some of the emerging data on other treatments that have been under investigation, including the gemcitabine pretzel, the erdafitinib [Balversa] pretzel, cretostimogene [grenadenorepvec], and so forth.

There are also trials in progress, including nadofaragene firadenovec trials that are looking at combination strategies. The phase 2 ABLE-22 study [NCT06545955] is looking at combining nadofaragene firadenovec with chemotherapy or immunotherapy as an option to improve durability. The question that a patient and their physician usually have is which is the best treatment option that’s going to cure the cancer long term. We have that discussion with them [and] still talk about cystectomy, but we also give patients a menu of options. The way I usually have this conversation is I talk to them about the FDA-approved agents. Currently, that’s pembrolizumab [Keytruda], nadofaragene firadenovec, nogapendekin alfa inbakiceptplus BCG, clinical trial options, and gemcitabine/docetaxel, which remains a very efficacious treatment even though it’s being used off label.

You have that conversation, and then the question that is still on all our minds is, how do we sequence these treatments? A patient [might] say, ‘I don’t know, you decide for me––which one do you go with first?’ That’s a challenging question we don’t have answers to. It would be interesting to see how people are doing that. I suspect a lot of [clinicians] are prioritizing clinical trials, which makes sense, and then for the highest-risk patients such as those who have T1 disease or recurrence of CIS, still pushing towards cystectomy.

The other piece of this that is worth considering now is the cost of these drugs. A lot of the newer drugs are very expensive and financial toxicity as it relates to the lifetime of treatment for bladder cancer has always been high, but this continues to add to that. We need good cost effectiveness studies to help us inform which of these treatments patients should choose.

What new tools/tests could help push the field forward?

I am personally interested in some of the newer tools that have come out in the market, such as the Vesta product from Valar Labs, which essentially looks at pathology slides and can use artificial intelligence and machine learning to discern patterns in the pathology that a pathologist may not be able to see with the naked eye. Then [we can] look at that to consider BCG-unresponsive treatment options. Incorporating something like that as a tool into clinical trials is potentially very valuable and may be very insightful.

Another thing that I’ve reported on at previous congresses and we’ve published [findings] on as well has been looking at urinary cell-free DNA. For example, the UroAmp test is a way to look at minimal residual disease at the molecular level in cells within the urine. That’s an additional data point that you can potentially use to figure out how aggressive a cancer is. As it relates to divergent differentiation, we’re getting at this idea that all these tumors to some extent may have some non-urothelial component. Does that contribute to some of this nonresponse or diminished response? Probably. How do we figure that out in advance and how do we add that to the equation when we are having a conversation with the patient about what treatment they should get?

Reference

FDA approves nogapendekin alfa inbakicept-pmln for BCG-unresponsive non-muscle invasive bladder cancer. FDA. April 22, 2024. Accessed February 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nogapendekin-alfa-inbakicept-pmln-bcg-unresponsive-non-muscle-invasive-bladder-cancer