Exploring NMIBC Options in the Face of BCG Shortages, Failure

Clinicians continue to consider and research the best options for patients in light of the ongoing unreliability of BCG.

Bacillus Calmette-Guérin (BCG) has been a standard-of-care treatment in high-risk non-muscle-invasive bladder cancer (NMIBC) for close to 50 years. An intravesical immunotherapy, BCG is likely one of the most effective immunotherapies in existence for any cancer, according to Ashish M. Kamat, MD, MBBS, a professor of urologic oncology and director of bladder cancer research at the University of Texas MD Anderson Cancer Center.

“There is always a lot of talk about newer agents for bladder cancer, but no agent hits the success rate of BCG,” Dr. Kamat said. “If used appropriately, with appropriate recognition of disease and instillation, less than 10% of patients will progress at 5 years.”

Unfortunately, many patients will not be able to complete the ideal treatment schedule. In the United States, there are more patients in need of BCG than Merck, the sole provider of the US Food and Drug Administration (FDA)-approved strain of BCG—the Tice strain—can keep up with.

GU Oncology Now recently spoke with several urologists about BCG, its current role in the treatment of NMIBC, how the field is adjusting to BCG shortages, and strategies to effectively treat BCG-unresponsive or BCG-exposed disease.

Realities of the Shortage

The Society of Urologic Oncology (SUO) and the American Urological Association amended their 2016 joint guideline in 2020 to reflect the realities of BCG shortages. The new guideline did not recommend use of BCG in low-risk NMIBC. Patients with high-risk, newly diagnosed carcinoma in situ (CIS) NMIBC should receive a 6-week induction course of full-dose BCG followed by BCG maintenance for 3 years. In patients with intermediate-risk disease, 1 year of maintenance was recommended.¹

“The reality is that most of us do not have access to that amount of BCG,” said Joshua Meeks, MD, PhD, an associate professor of urology, biochemistry, and molecular genetics at the Northwestern University Feinberg School of Medicine. “There are times where we have to tell a patient we can only give them a year’s worth of BCG, but the clinic across town could give them more than that,” Dr. Meeks said. “That disparity in access makes it more challenging for patients to navigate their diagnosis.”

A study looking at BCG utilization rates during the shortage—defined as ongoing from July 2012—showed that usage has decreased anywhere from approximately 6% to 33%, with a significant decrease in the proportion of patients who completed a full induction course of BCG.²

Availability of BCG is definitely variable, Dr. Kamat agreed. A large cancer center like MD Anderson has a different level of buying or negotiating power than a smaller community cancer center would have.

“We may have less of an issue procuring the drug,” Dr. Kamat said. “However, there are certainly parts of the [United States] where patients may have to travel 3, 4, or 5 hours to get to any place with a supply of BCG.”

Studies of the shortage also reflect an increase in bladder cancer recurrence and progression, as well as increased use of cystectomy,³ although data on the effect of the BCG shortage on cystectomy are conflicting.⁴

In 2021, Merck announced plans for the construction of a new facility to expand manufacturing for Tice BCG, but the company estimated that construction would take up to 5 or 6 years, after which the facility would need to complete regulatory reviews and approvals.⁵ In the meantime, clinicians and patients have had to look to alternatives.

Alternatives to BCG Therapy

According to Gary D. Steinberg, MD, a professor in the Department of Urology at Rush University Medical Center, one alternative is using other varieties or strains of BCG. “When we talk about the BCG shortage, we are talking about the Tice strain made by Merck,” Dr. Steinberg said. “There are plenty of other BCG strains—there are Chinese strains, Russian strains, and there is a BCG vaccine laboratory in India that can make a lot of BCG.”

Currently, the FDA has not allowed non-FDA-approved BCG strains to be used for treatment in the United States; however, Dr. Steinberg noted the FDA has allowed the use of different strains in ongoing international studies. “For example, Japanese patients can have the Tokyo strain or patients can get whatever local BCG strain they have as part of the clinical trials,” he said. “That is a big change for the FDA.”

There are currently no randomized clinical trial data comparing the efficacy of different BCG strains in NMIBC. However, the results of S1602, which compared different strains of BCG (Tokya-172 vs Tice) with or without vaccine in high-grade NMIBC, are eagerly awaited.⁶

There have also been efforts to modify the traditional BCG regimen. Abbreviated protocols have been developed using 1 year of maintenance instead of 3 years or using full-dose induction followed by reduced-dose maintenance. Dr. Kamat said that outcomes with these modified regimens are not nearly as good as outcomes with the recommended schedule.

BCG has been rigorously evaluated against single-agent intravesical chemotherapy in bladder cancer, explained Vignesh T. Packiam, MD, formerly of the University of Iowa and currently an associate professor in the Section of Urologic Oncology at Rutgers Cancer Institute of New Jersey. Particularly in Europe, there have been many high-quality, randomized clinical trials comparing BCG with mitomycin-C, doxorubicin, or gemcitabine. Almost all of those studies showed BCG to be equal if not superior to single-agent chemotherapy, and BCG tended to be less toxic.

“Another option with a lot of excitement right now is sequential doublet chemotherapy,” Dr. Packiam said. “About 10 years ago at the University of Iowa, Dr. Michael O’Donnell developed a sequential regimen of chemotherapy that involved instillation of gemcitabine immediately followed by docetaxel. This [approach] was very well-tolerated, with good efficacy for patients who have recurrence of cancer after BCG.”

As the BCG shortage continued, though, this combination was used more in the first-line setting as an alternative to BCG, Dr. Packiam explained.

Earlier this year, Dr. Packiam and colleagues published results of a retrospective study comparing sequential intravesical gemcitabine and docetaxel with BCG for high-risk NMIBC. Results showed less high-grade disease recurrence and treatment discontinuation with gemcitabine/docetaxel. The 24-month recurrence-free survival (RFS) was 81% for gemcitabine/docetaxel compared with 69% with BCG.⁷ However, it should be noted that the BCG induction dose was altered to one-third during times of BCG shortage, and BCG maintenance was also at a reduced dose.

Dr. Kamat said the use of gemcitabine/docetaxel is a “very reasonable” alternative to BCG. The ongoing phase 3 BRIDGE study evaluating intravesical BCG compared with intravesical docetaxel and gemcitabine in BCG-naive NMIBC should provide more guidance on its use.⁸

BCG Response

As with many first-line cancer therapies, a large percentage of patients treated with BCG will either progress or recur. “Before, we didn’t necessarily have strict criteria for defining these groups,” Dr. Steinberg explained. “BCG refractory was a patient with high-risk NMIBC who got BCG and despite that never achieved complete response; BCG relapsed was a patient with high-risk NMIBC [who] got BCG, had a complete response, but then recurred.”

Many older studies grouped these two categories, but Dr. Steinberg said that clinicians knew there were some differences in terms of prognosis. In order to better define these groups and conduct more accurate clinical trials, the terms BCG unresponsive and BCG exposed were developed.

“If a patient is BCG unresponsive, we know that more BCG is not going to help,” Dr. Steinberg said. “These are patients [who] had an induction-plus-maintenance course of BCG and recurred within 12 months of the last BCG dose, if they have CIS, or within 6 months if they have high-risk papillary disease.”

If a patient is BCG exposed, they did not receive the full course of induction and maintenance therapy. Dr. Steinberg conducted a retrospective analysis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program’s Medicare data, which showed that only 28.4% of patients with early-stage bladder cancer received “adequate treatment.”⁹

In 2018, the FDA adopted the term BCG unresponsive, allowing for the possibility to do open-label, single-arm trials “with complete response rate and duration of response as the primary end point” to “provide primary evidence of effectiveness to support a marketing application.”¹⁰ In contrast, in patients with BCG-exposed disease, randomized prospective clinical trials are best, although disagreement remains about what the appropriate control arm should be, Dr. Steinberg said.

Additionally, there is still ongoing discussion about and research looking into methods to predict what patients will have unresponsive disease.

“You would think that with a drug we have been using for about 50 years we could pick those patients out, but we can’t,” Dr. Meeks said.

Dr. Kamat and colleagues presented the results of a novel nomogram to predict BCG response in patients with high-grade NMIBC. The nomogram used a variety of patient and tumor characteristics and was able to provide a personalized prediction of recurrence and progression. Specifically, recurrent tumors, larger tumors, and diabetes predicted a higher risk of recurrence or death; prior BCG and older age were associated with higher risk of progression or death.¹¹

A patient’s immune make-up may also be involved, Dr. Kamat said. “If you do tumor profiling to see what the immune make-up is of a particular tumor, you may be able to predict who will do better and who won’t do as well, but those, like many other markers, are still more research tools and not clinically validated,” he said.

Post-BCG Options

In patients who have not responded to BCG, the guidelines suggest discussing radical cystectomy.

“If the tumor is noninvasive, we try to do multiple lines of therapy to save patients from having to lose their bladder, but we also don’t want to get to a point where the tumor has spread and is incurable,” Dr. Kamat said. “The issue is to make sure we don’t lose the window of opportunity for cure.”

Often, if a patient has very aggressive disease before or after undergoing treatment with BCG, clinicians will recommend radical cystectomy to avoid risk of the disease metastasizing. However, there may be a window of opportunity to try different agents in patients who don’t yet have metastatic disease.

“Radical cystectomy is not a bad option, if it is the only option, because it does have a cure rate of more than 95%, but we do try to avoid it where we can if we can safely save the bladder,” Dr. Kamat said.

There are several FDA-approved options in patients with BCG-exposed or BCG-unresponsive disease who desire bladder preservation. Intravesical valrubicin is approved for BCG-refractory CIS¹² but has a poor durable response rate of less than 10% at 2 years, Dr. Packiam said. BCG rechallenge is also an option in patients who do not respond to the first course of BCG.

In 2020, the FDA approved the immune checkpoint inhibitor pembrolizumab for BCG-unresponsive, high-risk NMIBC with CIS with or without papillary tumors. This approval was based on KEYNOTE-057, which yielded a complete response rate of 41%, with 46% of responses lasting at least 12 months.¹³

“In my opinion [pembrolizumab] has relatively modest results and is pretty rarely utilized,” Dr. Kamat said. “In addition to a relatively limited efficacy, there was somewhat significant toxicity compared with intravesical regimens.”

Gene therapy is another new option. In late 2022, the FDA approved the first gene therapy for BCG-unresponsive, high-risk NMIBC, nadofaragene firadenovec-vncg (Adstiladrin), a nonreplicating adenoviral vector-based gene therapy.¹⁴ A multicenter clinical study of this therapy yielded a complete response rate of 53.4%; response was maintained at 12 months in about half of these responders.¹⁵

In June, Ferring, the manufacturer of Adstiladrin, received FDA approval of its manufacturing scale-up for the drug. According to Ferring, the US rollout is expected in the second half of 2023, with supplies increasing in 2024.¹⁶

Alternative salvage intravesical regimens have also been explored as options post-BCG. A post-hoc analysis of intravesical gemcitabine/docetaxel after a single induction BCG failure showed similar oncologic outcomes to BCG plus interferon a-2b, with no significant differences in adjusted 2-year RFS rates.¹⁷ Additional retrospective data presented at the 23rd Annual Meeting of the Society of Urologic Oncology in 2022 also supported the efficacy of sequential gemcitabine and docetaxel in high-risk NMIBC after BCG failure,¹⁸ and long-term retrospective follow-up of 97 patients treated with gemcitabine/docetaxel after BCG failure yielded a 75% 5-year bladder preservation rate and a 91% 5-year cancer-specific survival rate.¹⁹

According to Dr. Packiam, sequential gemcitabine/docetaxel seems to be a preferred regimen in “real-world” settings.

“A survey sent by the [SUO] showed that a majority of people looking for options for patients after recurrence of BCG were using gemcitabine/docetaxel,” Dr. Packiam said. “The positive is that gemcitabine/docetaxel is widely available, well-tolerated, and urologists are getting more comfortable with it.”

The next most popular option is likely enrollment on a clinical trial, Dr. Packiam suggested.

One exciting trial in progress is BOND-003, a single-arm study of the oncolytic adenovirus CG0070 in BCG-unresponsive NMIBC. CG0070 targets bladder tumor cells through their defective retinoblastoma pathway.²⁰ Preliminary results of the open-label, phase 2 CORE1 study, which combined CG0070 with pembrolizumab, showed a complete response rate of 85%.²¹

Dr. Steinberg said there is also a lot of interest in superagonist N-803, a mutant IL-15 based immunostimulatory fusion protein complex that promotes proliferation and activation of natural killer cells and CD8+ T cells. One study of 160 patients with BCG-unresponsive NMIBC showed a 99% bladder-cancer-specific overall survival at 2 years and a 71% complete response rate in patients with CIS.²² The FDA accepted the Biologics License Application for N-803 in 2022 but announced earlier this year it could not approve the application due to deficiencies related to manufacturing.^23,24

The TAR-200 drug delivery system has also garnered excitement. An investigational intravesical drug delivery system, TAR-200 is a pretzel-shaped device that is inserted into the bladder and floats there, delivering gemcitabine pellets over a prolonged period of time. Results of the SunRISe-1 study presented earlier this year indicated that about three-quarters of patients with BCG-unresponsive disease had a complete response.²⁵

Questions Remain

As many as 5 new drugs for NMIBC could be approved in the next 12 months, and clinicians may be left with questions about how best to take advantage of these new tools.

“What do we recommend when it comes to selecting therapies? How do we sequence these drugs?” Dr. Kamat asked. “If we have 5 new options, not all of them are going to be appropriate for every patient. Do we have a way to identify which patients do better with which drugs?”

Another big question is whether or not there will be a step up in the manufacturing and availability of BCG. A variety of trials are looking at combining BCG with immune checkpoint inhibitors like pembrolizumab, but Dr. Packiam questioned the utility of these strategies given the ongoing issues with obtaining BCG.

Finally, Dr. Kamat mentioned a recent survey from the World Bladder Cancer Patient Coalition that attempted to capture the experiences of patients and those who care for them. One important finding is that it is important to patients to save their bladder, but not at the cost of their lives. “Options that work for patients after they have BCG-unresponsive disease or BCG failure feels like the next big step in meeting that goal,” Dr. Kamat said.

Part of that, Dr. Packiam said, will be better identifying the optimal time window to try these alternative bladder-sparing options. “Do we have 6 months or a couple of years? Overall, I think we tend to have 1 to 2 years to try intravesical therapy before it is most safe to proceed to radical cystectomy, but that is yet to be determined.”

References

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23. ImmunityBio announces FDA acceptance of Biologics License Application for N-803 in BCG-unresponsive non-muscle-invasive bladder cancer carcinoma in situ. ImmunityBio. July 28, 2022. Accessed August 7, 2023. https://immunitybio.com/immunitybio-announces-fda-acceptance-of-biologics-license-application-for-n-803-in-bcg-unresponsive-non-muscle-invasive-bladder-cancer-carcinoma-in-situ/
24. FDA declines to approve ImmunityBio’s bladder cancer therapy, shares slump. Reuters. May 11, 2023. Accessed August 7, 2023. https://www.reuters.com/business/healthcare-pharmaceuticals/immunitybio-slumps-fda-declines-approve-bladder-cancer-treatment-2023-05-11/
25. Daneshmand S, van der Heijden MS, Jacob JM, et al. LBA02-03 First results from Sunrise-1 in patients with BCG unresponsive high-risk non–muscle-invasive bladder cancer receiving TAR-200 in combination with cetrelimab, TAR-200, or cetrelimab alone. Urology. 2023. doi:10.1097/JU.0000000000003361.03