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Non–muscle-invasive bladder cancer: The revolution is here


In the last decade, there has been a revolution of sorts in the management of non–muscle-invasive bladder cancer (NMIBC). Enhanced methods of detection, improvements in surgical approaches, and new drug options, with many more in the pipeline, are changing the treatment landscape and addressing therapeutic challenges.

“The history of drug development for this disease had been bleak. Only 4 drugs had been approved by the FDA since 1959 until Keytruda [pembrolizumab] was approved in 20201,” said Colin P.N. Dinney, MD, chairman of the Department of Urology at The University of Texas MD Anderson Cancer Center in Houston.

“In 2012, the Society of Urologic Oncology [SUO], American Urological Association [AUA], and FDA launched a collaborative effort to address the deficiency of new agents being developed for bladder cancer. The initial focus was on defining a pathway for drug development in bacillus Calmette-Guérin [BCG]-unresponsive disease and stimulating activity in this space. Now, the majority of clinical trials in non–muscle-invasive bladder cancer include patients with BCG-unresponsive disease,” Dinney said.

Current state

Transurethral resection of the bladder tumor (TURBT) remains the standard for the initial management of NMIBC, according to Leonard G. Gomella, MD, the Bernard W. Godwin Jr Professor of Prostate Cancer and chair of the Department of Urologyat the Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, Pennsylvania.

“It is very important to get clear margins. What we have been finding is to get good margins there is a lot of variation in the technique and some limitations to standard white light detection,” Gomella said.

A major limitation of standard cystoscopy and TURBT when using white light is that it can miss 20% to 30% of flat, papillary, or carcinoma in situ (CIS) lesions, resulting in early recurrence,2 according to Badar M. Mian, MD, FACS, professor of surgery in the Division of Urology at Albany Medical College in New York.

“Two of the most commonly used modalities to improve the diagnostic and therapeutic yield endoscopic resection include photodynamic diagnostic, or blue light, cystoscopy and narrow band imaging. In single-arm studies,3 both modalities have demonstrated improved cancer detection rates and decreased recurrence rates. Blue light cystoscopy appears to be more efficacious, but there are no studies of direct head-to-head comparison of these enhanced imaging modalities,” Mian said.

Most low-grade bladder tumors do not need intravesical therapy. However, intravesical therapy is recommended for high-grade superficially invasive T1 bladder cancer with or without CIS. A repeat TURBT several weeks later is recommended in most settings with the presence of high-grade Ta or T1 disease. In the presence of any CIS, the patient is automatically classified as high risk. Guidelines always suggest that radical cystectomy or clinical trials be considered in these patients. However, in clinical practice it is reasonable to attempt to control the cancer with intravesical therapy initially, according to Gomella.

BCG remains today’s standard of care immuno-oncology agent for NMIBC. US clinicians tend to use BCG according to the Southwest Oncology Group (SWOG) regimen,4 which is an induction course of intravesical BCG for 6 weeks and then maintenance courses of 3 weekly doses at 3 months and every 6 months thereafter for up to 2 to 3 years, for both T1 and CIS disease, according to Gomella.

“There are many different variations on this schedule,” Gomella said.

Unfortunately, 30% to 40% of patients with NMIBC fail to respond to BCG therapy, and there is a need to better define BCG failure, according to Michael S. Cookson, MD, MMHC, FACS, professor and chairman of the Department of Urology and the Donald D. Albers Endowed Chair in Urology at the University of Oklahoma Health Sciences Center in Oklahoma City.

“Historically, patients treated with intravesical BCG who recurred were not properly identified, and so the decision as to when to discontinue BCG or move on to second-line treatments was difficult,” Cookson said. “Furthermore, the lack of a standard definition of BCG-unresponsive disease confounded results from these ‘salvage treatments’ and resulted in both overly optimistic response rates due to treatment of patients at lower risk and poor results sometimes due to delayed recognition of patients who were subjected to too many rounds of ineffective BCG. To be clear, patients identified as BCG unresponsive should not receive further BCG. So, it is important to clearly define BCG-unresponsive disease.”

It is defined in patients who recur with high-grade noninvasive disease who have persistent or recurrent CIS alone or with recurrent Ta/T1 disease within 12 months of completion of adequate BCG therapy, recurrent high-grade Ta/T1 disease alone within 6 months of completion of adequate BCG therapy, or T1 high-grade disease at the first evaluation following an induction BCG course. According to the FDA, adequate BCG is defined as at least 5 of 6 doses of an initial induction course plus at least 2 of 3 doses of maintenance therapy or at least 5 of 6 doses of an initial induction course plus at least 2 of 6 doses of a second induction course.5

“Non–muscle-invasive bladder cancer [that] has recurred or persisted despite intravesical BCG is destined to progress to more advanced disease,” Mian said. “Delay in identifying BCG-unresponsive disease and moving to radical cystectomy is associated with worse overall survival, especially when non–muscle-invasive cancer is allowed to progress to muscle-invasive disease. Radical cystectomy remains the only curative option for BCG-unresponsive non–muscle-invasive bladder cancer, but some patients are not optimal candidates for, or refuse, a major surgical procedure.”

Another consideration is the worldwide BCG shortage, which is expected to continue for at least the next year, according to Gomella.

SUO and AUA recommend not using BCG for low-risk disease and to consider using an alternative chemotherapy agent or reduced-dose BCG for intermediate or high-risk disease.6

“The suggestion right now of using a half dose for induction and possibly a third of a dose for maintenance appears to be very reasonable. So far, we have not seen any major changes in disease recurrence or progression, although this is an area of ongoing research,” Gomella said.

Intravesical therapy is not only used in the salvage setting but also postoperatively.

“Historically, we have found that a single dose of chemotherapy within 24 hours of a TURBT, with 6 hours or less being the optimum time, can reduce 5-year recurrence rates. Right now, gemcitabine used in a 2000 mg dose and mitomycin C used in the 40 mg dose7 are the preferred agents,” Gomella said.

Currently, the only FDA-approved intravesical chemotherapy agents are thiotepa and valrubicin. Thiotepa is no longer used due to toxicity concerns, and valrubicin’s label is specific for BCG-refractory CIS in patients who cannot undergo radical cystectomy, Gomella said.

“We are using many intravesical agents now mostly off label. Agents such as gemcitabine [and] docetaxel [are examples],8 and one of the mainstays that we have used for many years is mitomycin C,” Gomella said. “There are many trials using different methods seeking to improve the effectiveness of intravesical therapy. One of the biggest areas right now is the use of combination intravesical chemotherapy, and one of the most exciting areas that has been reported is the sequential use of gemcitabine and docetaxel. There have been some nonprospective randomized institutional studies that have shown using this combination of gemcitabine and docetaxel sequentially can have a recurrence-free survival [rate] at [approximately] 60% at 1 year and [approximately] 46% at 2 years in BCG-refractory disease.”

A big development last year was the approval of systemic pembrolizumab for BCG-refractory NMIBC.

“Pembrolizumab, a PD-1 immune checkpoint inhibitor, received approval9 after a single-arm study (KEYNOTE-057; NCT02625961) of high-risk, BCG-unresponsive non–muscle-invasive bladder cancer with carcinoma in situ,” Mian said. “It demonstrated complete response in 41% of patients for a median duration of 16.2 months. These patients were either ineligible for or declined radical cystectomy and required intravenous pembrolizumab for up to 24 months.”

Safety, however, could be an issue for some patients, as approximately 13% of those treated with pembrolizumab in trials reported 3 to 5 adverse events, according to Dinney.

“It is important to point out that the long-term disease control, or cure, rates of bladder salvage options such combination intravesical chemotherapy or PD-1 inhibitors are not comparable to radical cystectomy,” Mian said. “Thus, the treatment options for potential avoidance of radical cystectomy should be discussed with sufficient equipoise and in the appropriate patient population.”

Pipeline update

There is a tremendous amount of work being done in BCG-refractory cancer, with dozens of trials looking at novel intravesical agents, according to Gomella.

“These novel agents include things such as the Tokyo strain of BCG. The SWOG 1602 Prime trial10 is actually looking at intradermal BCG priming when using the Tokyo strain of BCG,” Gomella said.

The FDA granted priority review to Vicineum (VB4-845), a recombinant fusion protein that targets epithelial cell adhesion molecule antigens on the surface of tumor cells to deliver a potent protein payload, Pseudomonas exotoxin A.11

“A recent trial12 showed this is a very safe approach and that patients with non–muscle-invasive bladder cancer in situ had reasonable complete response rates of [approximately] 40% at 3 months and [approximately] 28% at 6 months,” Gomella said. “What is important in that trial, known as the VISTA trial13, is that 75% of patients were able to remain free of cystectomy at a period of over 2 years.”

In late-stage trials, the oncolytic adenovirus CG0070, which contains a GM-CSF transgene, selectively killed cancer cells through the cells’ dysfunctional retinoblastoma pathway. Developer CG Oncology announced in December that the first patient with BCG-unresponsive NMIBC was dosed in a phase 2 clinical trial of CG0070 in combination with pembrolizumab.14

The FDA also is reviewing the investigational gene therapy nadofaragene firadenovec. Investigators with the SUO Clinical Trials Consortium reported that in high-grade, BCG-unresponsive NMIBC, nadofaragene firadenovec resulted in a 46% complete response rate in CIS at 12 months, with or without Ta or T1 disease.15

According to Dinney, who is part of the team that developed nadofaragene firadenovec, the goals of the therapy are to alter the natural history of this disease and prevent recurrence and progression to provide bladder preservation with acceptable morbidity.

“If you look at the studies that have been reported, it seems patients have [approximately 1] year to try other therapies before their survival is compromised by avoiding cystectomy,” Dinney said. “If you look at Vicineum and nadofaragene, the clinical responses are similar. Vicineum has a more intense induction and maintenance schedule. Nadofaragene is a gene therapy that is given intravesically once every 3 months. And the safety profile of nadofaragene is favored over pembrolizumab.”

One other promising investigational agent for BCG-unresponsive NMIBC is the IL-15 super agonist known as N-803.

“The IL-15 is a super agonist antibody and cytokine fusion protein that targets and activates endogenous killing through NK cells and CD8 positive T-cells without inducing any type of T-regulatory stimulation,” Gomella said. “It was reported...that in an early trial,16 almost 60% of the patients with carcinoma in situ had a complete response at 12 months with a very reasonable safety profile.”

The landscape is going to change dramatically in the next 2 years, according to Dinney.

“[Patients with] non–muscle-invasive bladder cancer will have a lot more choices,” he said.

Disclosures: Dinney developed nadofaragene firadenovec. Cookson has done consulting with FerGene.


1. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. News release. FDA. January 8, 2020. Accessed April 7, 2021. https://bit.ly/3mpTTF9

2. Zlatev DV, Altobelli E, Liao JC. Advances in imaging technologies in the evaluation of high-grade bladder cancer. Urol Clin North Am. 2015;42(2):147-157. doi:10.1016/j.ucl.2015.01.001

3. Motlagh RS, Mori K, Laukhtina E, et al. Impact of enhanced optical techniques at time of TURBT with or without single immediate intravesical chemotherapy on recurrence rate of NMIBC, a systematic review and network meta-analysis of randomized trials. BJU Int. Published online March 8, 2021. doi:10.1111/bju.15383

4. Flanigan RC, DeLaurentis DA, Waters WB, Kunz K. Bacillus Calmette-Guerin. Is monthly maintenance an option for transitional cell carcinoma of the bladder? Urol Oncol. 2000;6(1):16-19. doi:10.1016/s1078-1439(00)00099-5

5. BCG-unresponsive nonmuscle invasive bladder cancer: developing drugs and biologics for treatment guidance for industry. FDA. February 2018. Accessed April 7, 2021. https://bit.ly/39O9dq4

6. BCG shortage info. American Urological Association. September 2020. Accessed April 7, 2021. https://bit.ly/39TtlqN

7. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 2.2021. Accessed April 7, 2021. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf

8. Li R, Li Y, Song J, et al. Intravesical gemcitabine versus mitomycin for non-muscle invasive bladder cancer: a systematic review and meta-analysis of randomized controlled trial. BMC Urol. 2020;20(1):97. doi:10.1186/s12894-020-00610-9

9. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. News release. FDA. January 8, 2020. Accessed April 7, 2021. https://bit.ly/3mpTTF9

10. S1602: different strains of BCG with or without vaccine in high grade non-muscle invasive bladder cancer. ClinicalTrials.gov. Updated February 24, 2021. Accessed April 7, 2021. https://clinicaltrials.gov/ct2/show/NCT03091660

11. Sesen Bio announces FDA acceptance and priority review of its biologics license application for Vicineum. News release. Sesen Bio. February 16, 2021. Accessed April 7, 2021. https://bit.ly/31Uh80y

12. Sesen Bio reports positive, preliminary data update from phase 3 VISTA trial for high-risk non-muscle invasive bladder cancer. News release. Sesen Bio. August 8, 2019. Accessed February 17, 2021. https://bit.ly/2OM9LEB

13. Dickstein R, Wu N, Cowan B, et al. Phase 3 study of vicinium in BCG-unresponsive non-muscle invasive bladder cancer: initial results. J Urol. 2018;199(suppl 4):e1167. doi:10.1016/j.juro.2018.03.099

14. CG Oncology announces first patient dosed in phase 2 clinical trial of CG0070, an oncolytic immunotherapy, in combination with Keytruda (pembrolizumab) for non-muscle-invasive bladder cancer unresponsive to bacillus Calmette-Guerin. News release. CG Oncology. December 9, 2020. Accessed April 7, 2021. https://bit.ly/2Y5Kh76

15. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107-117. doi:10.1016/S1470-2045(20)30540-4

16. ImmunityBio announces primary endpoint met of phase 2/3 trial for BCG unresponsive non-muscle invasive bladder cancer CIS with 72% complete response rate. News release. ImmunityBio. December 21, 2020. Accessed April 7, 2021. https://yhoo.it/31RM811

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