How Will Gemcitabine Intravesical System Impact BCG-Unresponsive NMIBC?

Gary Steinberg, MD, highlights the FDA approval of the gemcitabine intravesical system and what this means for patients with BCG-unresponsive NMIBC.

For patients with high-risk, Bacillus Calmette-Guérin (BCG)–unresponsive non-muscle-invasive bladder cancer (NMBIC), the traditional standard of care has been radical cystectomy. However, with the newly FDA-approved regimen of gemcitabine intravesical system (Inlexzo; formerly TAR-200), there may be another option.¹

CancerNetwork® spoke with Gary Steinberg, MD, a professor in the Department of Urology at Rush University, who noted results from the phase 2 SunRISe-1 trial (NCT04640623), which led to the approval. A complete response was observed in 82% (95% CI, 72%-90%) of patients, and 51% had a response for at least 1 year.

Steinberg also highlighted how this approval presents a pathway for patients who have limited options and how this could fit into the treatment paradigm for NMIBC.

CancerNetwork: How do you see the gemcitabine intravesical system fitting into the current treatment algorithm for BCG-unresponsive NMIBC?

Steinberg: There’s a tremendous unmet need for patients with BCG-unresponsive, high-grade disease. Traditionally, the standard of care has been radical cystectomy. Patients would like to avoid losing their bladder, especially if they don’t have any evidence of muscle-invasive disease. Over the past few years, we’ve seen new treatments that have been FDA-approved in this space. The first was pembrolizumab [Keytruda], which is a checkpoint inhibitor, which was approved by the FDA in [January] 2020.² We’ve also seen [nadofaragene firadenovec; Adstiladrin], which is an oncolytic immunotherapy, which was approved in [December 2022].³ Then, in the spring of 2024, we saw the combination of intravesical—that's medication put inside the bladder—BCG plus [nogapendekin alfa inbakicept-pmln; Anktiva], which is an IL-15 agonist.⁴

We’ve got 3 drugs, all with different mechanisms of action. One is a combination. Now, we have a fourth treatment that’s been FDA-approved with a different mechanism of action. The patients and the physicians that take care of them for their bladder cancer are truly benefiting tremendously. Having said that, it is an older chemotherapeutic drug that’s put into the [intravesical system] device. It is a better way to deliver intravesical chemotherapy. Many urologists today, because of BCG-unresponsive disease, the BCG shortages, and their unfamiliarity with some of the new products, are shying away from using intravenous pembrolizumab, which is associated with its 11% to 12% grade 3 or greater immune-related adverse events. [They] have been using gemcitabine and docetaxel, an intravesical chemotherapy combination, [without] any FDA approval or any prospective data. With the prospective data we have from the [gemcitabine intravesical system] in the phase 2 SunRISe-1 trial, that will probably replace gemcitabine/docetaxel because the numbers we see from the recent trial are, I believe, superior to what we see from intravascular gemcitabine/docetaxel.

The product's prescribing information includes warnings about the risk of metastatic bladder cancer with delayed cystectomy. What is your recommended approach for patient counseling to ensure they understand the importance of surveillance and the potential for disease progression while on this therapy?

When you look at the older data vs the newer data, the risk of progression is not as high as we once thought. As we see in the [gemcitabine intravesical system] data, 8% of their patients progressed to muscle-invasive disease within 12 months. We do need to be very careful and make sure that we follow up with patients with cystoscopies, urinary cytologies, CT [scans], or MRI imaging as needed. We do have room to try 1 to 3 additional therapies once patients become BCG unresponsive. We saw in the trial that led to pembrolizumab’s approval in BCG-unresponsive carcinoma in situ, the KEYNOTE-057 trial [NCT02625961], that there were a fair number of patients who did not respond to pembrolizumab, did not undergo cystectomy, and were followed with multiple different other therapies, and that the progression rate was still very low.

I was one of the co-authors of a retrospective review. We took retrospective data from 10 different medical centers on patients who were deemed BCG-unresponsive and looked at their additional treatments that they got over time. We saw that patients were able to get a second treatment. Once we start getting into the third and fourth lines of therapy after BCG, we then begin to see more progression to muscle invasion. Patients are going to want at least 1 attempt, if not 2 attempts, with different mechanisms of action once they become BCG unresponsive and still have NMIBC.

The most common adverse effects included urinary frequency and dysuria. How do these adverse events compare to other intravesical therapies, and what practical measures do you recommend for mitigating them to improve quality of life?

There’s no question that with the [gemcitabine intravesical system], it’s a foreign body that’s put in the bladder and stays there. Interestingly, for every 3-week installation of [gemcitabine], it’s only delivering the drug for one of those 3 weeks. [The reason] why you keep a foreign body when it’s only delivering a drug for 1 week out of 3 is something that needs to be investigated. There’s no question that the number of serious adverse effects, about 24% with the [gemcitabine intravesical system] and a discontinuation rate of about 7%—some of the presentations were as high as 9%—is of concern. The other thing that we saw was a higher incidence of [urinary tract symptoms] with the [gemcitabine intravesical system] vs other trials. Symptoms of the urinary tract infections [include] frequency and urgency, and treating older patients with multiple rounds of antibiotics does lead to antibiotic resistance. Treating patients in their 70s and 80s with multiple medications or an overactive bladder does lead to other [adverse] effects such as dry mouth, constipation, blurry vision, and so forth. Many older patients don’t necessarily tolerate the overactive bladder medications very well. It is a fine line.

One of the things that I’ve been told anecdotally is that there are some, especially female patients, who will void out the [gemcitabine intravesical system]. There are some [therapy] delays and needs to have a catheter put back in, but having a cystoscopy every 3 weeks for 6 months, and then every 6 months for up to 18 months, is something to consider.

Looking ahead, what are the next crucial research questions that need to be answered for the gemcitabine intravesical system?

In the SunRISe-1 trial, they randomly assigned patients to 3 arms. One of the arms was the [gemcitabine intravesical system] plus cetrelimab, which is a checkpoint inhibitor. That cohort was closed early. We haven’t seen all the data from that cohort, but the preliminary reports were that the complete response rate and the durability were inferior to the [gemcitabine intravesical system] alone. The concept of any intravesical chemotherapy is that you’re causing tumor lysis and immune cell death. If you create immune cell death, you upregulate interferon gamma, which turns off the T cells. In general, a checkpoint inhibitor helps reverse that. Why that didn’t occur with the [gemcitabine intravesical system] is unclear.

People believe that the [gemcitabine intravesical system] is not just a chemotherapeutic drug, but that when it’s given in a low dose continuously, it also has some immunologic effects. They’ve seen that in some animal models for pancreatic cancer. We clearly haven’t seen human data to support that, and so at the end of the day, the [gemcitabine intravesical system] may function as intravesical chemotherapy alone, albeit given in a better way. In terms of the pharmacokinetics, [when] putting it in somebody’s bladder and having them void it out in an hour or 2 [later], there should be more topical absorption. As we know, cancer is smart. Cancer figures out ways to become chemotherapy-resistant and evade chemotherapy in the cells. We know that when we stop chemotherapy in general, that’s when cancers can come back, which is the whole reason why the whole oncology community is enthralled with immunotherapy because with immunotherapy, we believe that we can create a T cell memory. We do know that when you look at checkpoint inhibitors of all classes and all comers, we have anywhere from an 18% to about a 25% durable complete response in all different types of tumors. That 25% we see is in the melanoma population, and we clearly need to do better. We’re looking at combinations. That’s what enfortumab vedotin-ejfv [Padcev] and pembrolizumab have in common in terms of metastatic bladder cancer. We need to think about additional combinations down the road. The fact that gemcitabine in the bladder in the [intravesical system] plus a checkpoint inhibitor did not show any additional benefit is of interest and something that needs to be addressed.

Most importantly, one of the key questions that we all need to ask with all our treatments is not about the patients who respond, but about the patients who don't respond. We can begin to understand mechanisms of resistance so that we can begin to target those mechanisms of resistance and treat them better. One of the things about cretostimogene grenadenorepvec is that it’s replication selective in patients with bladder cancer who are retinoblastoma pathway deficient, which is about 70% to 80% of all patients with high-grade NMIBC. It has a selective treatment response. It should cause viral killing only in the bladder cancer cells and not in normal cells. What we see in the phase 2 CORE-001 trial [NCT04387461] is that in the combination of cretostimogene grenadenorepvec plus checkpoint inhibitors such as pembrolizumab, there were some additional complete responses and durability.⁵ Having said that, we don’t want to give everybody checkpoint inhibitors because of the systemic [adverse] effects of checkpoint inhibitors, but cretostimogene grenadenorepvec alone clearly has demonstrated best-in-class durability, at least [in what] we’ve seen in the phase 3 BOND-003 trial [NCT04452591] at 24 months.⁶

References

1. U.S. FDA approval of INLEXZO™ (gemcitabine intravesical system) set to transform how certain bladder cancers are treated. News release. Johnson & Johnson. September 9, 2025. Accessed September 9, 2025. https://tinyurl.com/4zjz22z7
2. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. News release. FDA. January 8, 2020. Accessed September 12, 2025. https://tinyurl.com/29rsyr8m
3. FDA approves first adenoviral vector-based gene therapy for high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer. News release. FDA. December 16, 2022. Accessed September 12, 2025. https://tinyurl.com/4mx7vn23
4. FDA approves nogapendekin alfa inbakicept-pmln for BCG-unresponsive non-muscle invasive bladder cancer. News release. FDA. April 22, 2024. Accessed September 12, 2025. https://tinyurl.com/3m3kben9
5. Li R, Shah PH, Stewart TF, et al. Oncolytic adenoviral therapy plus pembrolizumab in BCG-unresponsive non-muscle-invasive bladder cancer: the phase 2 CORE-001 trial. Nat Med. 2024;30(8):2216-2223. doi:10.1038/s41591-024-03025-3. Erratum in: Nat Med. 2024;30(8):2372. doi:10.1038/s41591-024-03137-w. Erratum in: Nat Med. 2024;30(8):2377. doi:10.1038/s41591-024-03157-6.
6. Tyson M. BOND-003 cohort C- a phase-3, single-arm study of intravesical cretostimogene grenadenorepvec for high-risk BCG-unresponsive NMIBC with CIS. Presented at: American Urological Association Annual Congress; April 26-29, 2025; Las Vegas, NV. P2s.