Alternative BCG strains may help address ongoing supply challenges in NMIBC

BCG remains a cornerstone of treatment for patients with high-risk non-muscle invasive bladder cancer (NMIBC), but ongoing supply constraints have complicated the delivery of recommended maintenance therapy.

In this Q&A, Eugene B. Cone, MD, co-director of research and a principal physician with Urology of Indiana in Indianapolis, discusses the role of maintenance BCG, the potential of alternative strains and recombinant BCG, and recent data from the SWOG S1602 trial (NCT03091660). Cone also addresses how these approaches may affect BCG availability and the evolving role of BCG-based combination therapies in NMIBC.

Urology Times: To start, what do we know about the role of maintenance BCG in patients with NMIBC?

Cone: BCG has been a cornerstone of treatment for bladder cancer for decades. It's the original immunotherapy in the cancer world, and it's wonderful in that it's not systemically absorbed; you get excellent activation locally with an intravesical treatment. Classically, it's been the induction course plus 2 to 3 years of maintenance on the SWOG protocol. We know, and what's been reinforced with trials like KEYNOTE[-057], CREST, POTOMAC, and PATAPSCO, has been that BCG, when given on the SWOG protocol and adhered to, actually works very well. Response rates for BCG-naïve high-risk bladder cancer was in the 70% range on almost all of those trials for the BCG-only arm. We know that it works very well, but you have to give maintenance, and ideally you want to be giving the full 2 to 3 years. That just hasn't been possible in recent years for a lot of practices.

Urology Times: What are some of the current limitations of BCG therapy that have driven interest in alternative strains and therapy approaches?

Cone: Right now, there's only 1 strain of BCG that has true FDA approval in this country, and that's TICE BCG. There are other strains that are used more broadly globally. Tokyo[-172] is probably the most prevalent example, but more recently there's been recombinant BCG that has also come along. [However,] none of those have an FDA label in this country, so when you have significant supply-side constraints like we've seen with TICE BCG, [it can be challenging.] Merck only has 1 plant that produces it, and it's not able to keep up with the current demand. In theory, there's a second plant opening, but the date on that has gotten pushed [several times]. BCG has become extremely constrained in terms of its availability for urologists across the country.

Fortunately, there are some urologists who are not very affected by this and have as much BCG as they want. There are other practices that can't get it and have to look to other options, like intravesical chemo, that don't quite have the same level 1 evidence backing them but do seem to be acceptable alternatives. The supply-side constraints have really been very problematic over the past decade.

Beyond that, BCG is a treatment that does have a toxicity profile. Patients may develop predominantly grade 1 and 2 lower urinary tract symptoms. There is interest in newer strains that could potentially be slightly more targeted, more potent, and also [have a] less toxic [safety] profile.

Urology Times: SWOG S1602 is evaluating that Tokyo strain of BCG in high-risk NMIBC. What is the rationale and design of that study?

Cone: The rationale was the shortage. When TICE BCG was readily available, it wasn't a huge deal that we only had 1 strain available in the US. Now that we have significant supply constraints, it makes sense to try to expand the pool of BCG in the US. The Tokyo strain is widely used in the rest of the world, so the SWOG consortium came up with a trial that looked head-to-head at the Tokyo strain of BCG vs the TICE strain of BCG. It was a non-inferiority trial, so it wasn't trying to prove that Tokyo was better—it was just trying to [show if it] was at least as efficacious. That was a phase 3 trial that very recently read out.

Urology Times: What did the initial results from that study show, and how should urologists be interpreting these findings?

Cone: The study did reach non-inferiority; it showed a comparable efficacy profile between the 2 [BCG strains].¹ In terms of raw numbers, the Tokyo strain was slightly more efficacious, 64% vs 58% for 5-year recurrence-free survival. That didn't reach statistical significance, but it did demonstrate non-inferiority.

There was an arm of the trial that also looked at transdermal priming, so giving a BCG injection to prime the immune system to respond more vigorously against the BCG. That did not have any superiority compared with just intravesical delivery. The take-home [message] here is that if the Tokyo strain becomes available in the US, urologists can administer it interchangeably with TICE without concern about lack of efficacy or clinical benefit.

Urology Times: Recombinant BCG is another potential alternative in this space. How does its mechanism or manufacturing approach differ from conventional BCG?

Cone: The recombinant strain is, as the name implies, recombinant—it's crossbred BCG. The idea is to get both a more potent and a more targeted activation of the T-cell pathway. [This would] ideally [lead to] less spillover toxicity, fewer lower urinary tract symptoms from the cytokine storm that can come with indiscriminate activation of the T-cell chain, while also maintaining at least as much efficacy and, in theory, potentially better efficacy, although that is not currently supported by any data at this time.

Urology Times: The ResQ133A-NMIBC trial (NCT06800963) is evaluating intravesical recombinant BCG in patients with BCG-naïve NMIBC. What questions is the study hoping to answer?

Cone: This is a phase 1/ 2 trial. It's single arm; there is no head-to-head vs TICE or Tokyo or anything else, so it's more on the hypothesis-generating side of things than about whether it's truly as efficacious head-to-head. We're looking at the toxicity profile. We will get some good answers there and hopefully some hard data to back that up. [It's also assessing] efficacy, recurrence-free survival being the main thing that is being looked at.

Recombinant BCG is available in the US widely. Any urology practice can sign up for it through an early access program through the FDA. If there is any path to recombinant BCG getting a true FDA label, it's going to require trial data, which the early access program is not providing. It's providing some limited safety data, but definitely not on the efficacy side of things. So, ResQ133A-NMIBC is a great first step there. Whether the FDA would give a label based solely off phase 2 data or whether they're going to want a head-to-head, especially given that the Tokyo strain is going to have head-to-head data, remains an open-ended question.

Urology Times: Given ongoing BCG supply challenges, could alternative strains or recombinant BCG meaningfully improve treatment availability, or are there still logistical barriers that need to be solved?

Cone: It's definitely going to help improve supply. Recombinant BCG has already significantly alleviated some of the strain from the TICE shortage in the US. Locally, [in] our program, we heavily use recombinant BCG. Data from the global standpoint do seem to support that it's roughly as efficacious, even though there's no head-to-head data. Anecdotally, our patients, especially the ones who have prior experience with TICE BCG, do seem to think that there's a little bit less irritation of the urinary tract with recombinant BCG. We've been happy with that locally. I know of a number of practices across the US that have been able to fix their BCG shortage issue using recombinant BCG. So, adding new strains into the pool is definitely helpful. There is a little bit of extra paperwork under the early access program that would obviously go away if there's a label, so that would be nice. There were some packaging issues early on, but those have gone away. So, for the most part, I think it's primarily just making it available.

Urology Times: Is there anything else that you wanted to add?

Cone: As urologists, we've traditionally thought of BCG as the main treatment and the entry-level treatment for all patients with high-risk disease and most intermediate-risk patients as well. We're entering a world in which it's not just useful in that setting. There's also nogapendekin alfa inbakicept-pmln [(Anktiva)], the IL-15 superagonist that has to be paired with BCG, and we now have the PATAPSCO-POTOMAC protocol where BCG is paired up with durvalumab [(Imfinzi)]. So, BCG is being used in combination at this point. It has emphasized the need to secure a reliable and steady stream of BCG for our patients, and I think getting new strains on board is critical to making that happen.

REFERENCE

1. Svatek RS, Tangen C, Meeks JJ, et al. SWOG S1602: A phase III randomized trial to evaluate BCG strain differences and priming with intradermal BCG before intravesical therapy for BCG-naïve high-grade non-muscle invasive bladder cancer (NCT #03091660). J Clin Oncol. 2026;44(7). doi:10.1200/JCO.2026.44.7_suppl.LBA629