Tailoring Treatment for High-Risk Bladder Cancer: Beyond BCG

Stephen Williams, MD, MS, FACS

Personalizing treatment for patients with high-risk non-muscle invasive bladder cancer (NMIBC) can be challenging, especially for those patients who have been unresponsive to Bacillus Calmette-Guérin, the standard-of-care in this disease. Intravesical gemcitabine has shown to be a promising alternative, especially in the face of recent BCG shortages. Intravesical gemcitabine is also associated with lower costs, making it an attractive option for patients.

“One of the limitations of any agents to administer are costs. Bladder cancer is the [costliest] cancer of all cancer types. We need to be more judicious on how we allocate treatment but also to the availability. [Intravesical gemcitabine] is chemotherapeutic agent and does not need to be grown, such as what we see with BCG,” said Stephen Williams, MD, MS, FACS, in an interview with Targeted Oncology^TM.

At the 2024 ASCO Genitourinary (GU) Cancers Symposium, Williams presented data from a retrospective cohort study that showed that intravesical gemcitabine use was increasing across both BCG-exposed and -naive patients. Williams and his co-authors concluded that more research on intravesical gemcitabine vs BCG was warranted in both the BCG-exposed and -naive populations.

Here, Williams, associate chief medical officer at the University of Texas Medical Branch (UTMB) Galveston, chief of the Division of Urology Department of Surgery, and medical director for high value care of the UTMB Health System, discussed his presentation from ASCO GU, unmet needs in NMIBC, and exciting trends in the field.

Targeted Oncology: Can you provide an overview of the abstract that you presented at ASCO GU this year?

Williams: This is a retrospective cohort study from the SEER-Medicare database dating from 2007 to 2019. What we wanted to better understand is the utilization of intravesical gemcitabine, particularly in patients with high-risk non-muscle invasive bladder cancer.

This is an association-type study, not derivation. In addition, we did not account for induction and maintenance phase of the treatment cycles, [which are] very hard to parse out. This does provide the first large population-based analysis on utilization trends of gemcitabine. That informs future work that needs to be done that we're currently exploring, both in population-based analyses, but also in our trials.

Although it’s a [White]-predominant disease, it is not exclusive and does not necessarily represent the entire global scope of the population that we treat. As we embark upon understanding our treatments, we also need to pay respect to the populations that we identify and treat as well.

In your experience, what are the primary factors driving the use of intravesical gemcitabine for high-risk NMIBC vs other options?

With BCG, which is the gold standard of treatment for high-risk non-muscle invasive bladder cancer, unfortunately, we have had shortages in the United States and worldwide. This is also driving trends that we observed, particularly in this study, with increasing use of intravesical gemcitabine and other agents. An added benefit of the intravesical gemcitabine also are the costs associated with this. The cost of this medication is substantially lower than some of the alternatives and newer agents being developed.

Have any geographical trends influenced these factors?

We looked specifically at urban, metro [areas] vs rural. We know, historically, that urban and metro populations may have access to more experts that primarily deliver bladder cancer care and may find increased use of this agent, but as well as just treatments overall for bladder cancer.

Are there specific patient subgroups within the high-risk NMIBC population who seem to benefit most from intravesical gemcitabine? Are there any groups that you would be more cautious of with this regimen?

We looked at several factors. We looked at BCG-naive vs -exposed patients to better understand those 2 populations at large. [We also looked at] age, sex, race, and these tend to corroborate prior findings where bladder cancer is historically more common among males [and] decreased among non-Whites. There are certain patients that may, in fact, have increased benefit of gemcitabine, but this is a retrospective cohort study. It is associations, not causation. We are currently investigating several other studies [gemcitabine] in combination with other agents, such as docetaxel, to really understand the efficacy of these agents.

What is the importance of individualizing treatment based on patient factors and preferences?

What is critical, and what we are moving towards—although we extrapolate in large population bases, trying to perform precision-based medicine—is understanding patients who have been prior BCG-exposed or -unresponsive. We used “exposed” in this retrospective cohort study because it's challenging to pinpoint the definition for BCG-unresponsive disease. But patients who have failed BCG, then gemcitabine in combination with docetaxel, which is more commonly performed together. And we did identify that, particularly in this study, for those BCG-exposed patients, where gemcitabine, in combination with docetaxel, was more commonly performed.

Are there any potential limitations of gemcitabine, either that you identified through this retrospective study or through other research?

One of the limitations of any agents to administer is cost. Bladder cancer is the [costliest] cancer of all cancer types. We need to be more judicious on how we allocate treatment but also to the availability. This is a chemotherapeutic agent and does not need to be grown, such as what we see with BCG. That is not a limitation.

We also may come into shortages if there is an increased use. For instance, in 2020, utilization was about almost 18%. Historically, in 2008, 2013, [it] was 0.5%. One could argue that [if] the increasing use of it becomes more common, then we may experience shortages as well.

Also, we have a number of novel agents coming online [that] are being tested. Sometimes, some of these older agents, while they are less costly, lose [their] luster in regard to understanding in comparison with some of those newer agents. We need to do and perform judicial cost-effectiveness analyses to really understand and individualize these regimens, which I think do have a benefit.

Also, to the instillation technique. We did not analyze that, and particularly this cohort, all [were] intravesical. [There are] different types of instillations. We have gels, stents, [and] other devices that are currently being tested and or are currently on the market, which is exciting for this particular type of disease.

Looking ahead, what areas do you see as most promising for future research on optimizing intravascular gemcitabine for use in high-risk NMIBC?

A current very exciting arm of trials involves the TAR200 device, which is a device that uses intravesical gemcitabine [that have] been instilled within a pretzel-like device. This remains in the bladder. This allows a sustained release of this medication over time. This is currently being evaluated in several sunrise trials, both in the non-muscle invasive state but also muscle invasive disease. So once again, I think that is a wonderful illustration of this.

There is a gel-like platform that has currently been developed that is primarily used an upper tract urothelial carcinoma and has not really been robustly tested in the non-muscle invasive bladder cancer state.

Are there any other innovative approaches or emerging therapies that you think hold promise for future treatment in bladder cancer?

We are looking at gene therapy, precision technology, and current platforms that are waiting to be FDA approved. In addition, there are a number of other interleukin-type combination agents that are currently tested, and that's very exciting as well.

Although it has not gained a lot of traction, it is the use of the local [agents] and systemic. [There are] additional toxicities whenever you present a systemic agent, so our hope is more localized therapy. But really, the optimal goal is retaining one's bladder. Our hope is that in the future, removing someone's bladder, particularly for non-muscle invasive bladder cancer, will be obsolete. That should be our goal.