Filling the BCG Shortage Hole for Patients With NMIBC

A panel discussion during the American Urological Association’s (AUA) Virtual Experience highlighted ways to treat patients with non–muscle invasive bladder cancer (NMIBC) in the face of a shortage of standard-of-care Bacillus Calmette-Guerin (BCG) treatment.¹

The panel discussion was moderated by Seth P. Lerner, MD, and the panelists included Stephen A. Boorjian, MD; Ashish M. Kamat, MD, MBBS; James M. McKiernan, MD; and Chad R. Ritch, MD, MBA.

Previously there were 2 manufacturers of BCG, Sanofi Pasteur and Merck. However, Sanofi Pasteur went off line in 2012 and permanently closed in 2017. Merck manufactures Tice BCG from a single plant for distribution to 70 countries. Despite increasing production more than 100%, Merck is operating at full capacity, but the demand has exceeded the supply, and since January 2019, the manufacturer began an allocation distribution, leading to the shortage.

Merck has noted that production of Tice BCG is a top priority for the company, but it is also exploring alternatives to increase production capacity. The FDA and other health authorities have been working with Merck to try to maximize access to BCG and bring new strains to the market.

For example, Kamat, a urologist at Mayo Clinic, noted that BCG is being studied in a SARS-CoV-2, which would hopefully open the drug up for further production in the United States.

In response to the BCG shortage, a joint statement was released from several urology organizations, including the AUA, in February 2019 for strategies to use in the care of patients with NMIBC if BCG is in limited or no supply.²

The organizations stated that BCG should not be used for patients with low-risk disease, and intravesical chemotherapy should be the first-line treatment option for patients with intermediate-risk disease, thereby prioritizing the use of BCG for patients with high-risk disease. The statement recommended that patients with high-risk disease received full-strength BCG if available, and if not, they could receive one-half to one-third the standard dose. Additionally, if there is enough BCG supply for maintenance therapy, physicians should aim to give their patients with NMIBC a one-third dose of BCG limited to one year. However, in the event that BCG is not available, induction therapy should be prioritized over maintenance therapy for patients with high-risk disease.

Lerner, the Beth and Dave Swalm Chair in Urologic Oncology, director of Urologic Oncology, director of the Multidisciplinary Bladder Cancer Program, Baylor College of Medicine, explained that urologists can give reduced doses of BCG since an appropriate cytokine response can still be achieved with as little as one-hundredth of a standard dose. He did note, however, that urologists should be careful about billing for split dosing of BCG as coverage may vary by region.

Appropriate Selection and Usage of BCG

Kamat advised that patient selection for BCG therapy is key even when there is no shortage of the therapy.

Among patients with low-grade, intermediate-risk disease, if they present with 3 or more risk factors—multiple tumors, tumor size >3 cm, early recurrence (<1 year), and/or frequent recurrences (>1 per year)—they should be treated as if they have high-risk disease with transurethral resection of bladder tumor (TURBT) and BCG induction and maintenance therapy.

When giving BCG maintenance therapy, administering on a 6+3 schedule (SWOG protocol) leads to the most benefit without wasting the treatment. Kamat also explained that the duration of treatment with BCG seems to matter more than the dose of the therapy.

In the EORTC 30962 study, which examined the use of full-dose and one-third dosing of BCG maintenance for 1 or 3 years in patients with intermediate- and high-risk NMIBC, those who received 3 years of maintenance therapy at either dosing demonstrated better 5-year disease-free rates than those who only received 1 year of therapy. The patients who received 3 years of the full dose had a 5-year disease-free rate of 64.2% and those who received the one-third dose for 3 years had a 5-year rate of 62.6%. Comparatively, those who received 1 year of maintenance therapy had a 5-year disease-free rate of 58.8% with the full dose and 54.5% with the one-third dose (P= .09).³

Ritch, from the Department of Urology, University of Miami Health Center, explained that the one-third dose can be split up by taking a full dose of 1 vial of 50 mg BCG and reconstitute it to 50 mL and then split that into 3 syringes that are all then reconstituted to 50 mL. These can then be administered to 3 patients within 2 hours.

Kamat recommended that new high-risk patients should receive BCG induction for 6 weeks at one-third of the dose so that more patients can be treated, even though the AUA recommends the full dose at induction. He also recommended that patients with Ta tumors who are at lower risk of progression could hold off maintenance therapy unless they have recurrence at 3 months.

BCG Alternatives

As an alternative to BCG, single-agent intravesical chemotherapy can be used in patients with NMIBC, and Ritch offered that mitomycin C is a readily available option. Although, overall BCG may reduce the time to recurrence compared with mitomycin C (HR, 0.88; 95% CI, 0.71-1.09),⁴ one review has shown that when no maintenance therapy is given, mitomycin C may delay the time to first recurrence over BCG.⁵

Other single-agent chemotherapy alternatives to BCG include valrubicin, gemcitabine, and taxanes including nab-paclitaxel (Abraxane), which have all shown modest benefit in single-arm studies in patients with NMIBC.

McKiernan, the John K. Lattimer Professor of Urology, chair of the Department of Urology, director of Urologic Oncology, Columbia University Irving Medical Center, focused on patients who have recurred on or following BCG; in this case, additional BCG does not have a high probability of response for these patients. In this setting, gemcitabine has been one of the most studied single-agent chemotherapies showing a disease-free survival rate of approximately 15% to 30%.

In one such study, intravesical gemcitabine was compared with BCG administrated following BCG failure in patients with high-risk NMIBC and gemcitabine showed a 2-year recurrence-free survival (RFS) rate of 19% compared with 3% with BCG (P <.008). Both treatments were considered to be well tolerated.⁶

“You may be surprised to realize that gemcitabine actually worked better than a second induction of BCG,” McKiernan said. “So in the setting of BCG shortage, there’s some pretty strong evidence here to suggest that you should not waste your vital resource of BCG on a patient in that setting if you do get access to single-agent gemcitabine.”

McKiernan added that single-agent gemcitabine is probably the most practical in terms of time in the clinic and ease of use for the practitioner.

Sequential treatment with intravesical gemcitabine followed by docetaxel rescue therapy was found to be beneficial and provide durable response in patients with recurrent NMIBC following BCG. At 1 year, the RFS rate in this patient population was 60% with sequential gemcitabine and docetaxel and 46% at 2 years. The rate of cystectomy-free survival was 84% and only 3.6% of patients progressed on transurethral resection.⁷

“I think this is quietly becoming a standard, non-FDA approved doublet regimen [against] which many other things are being compared,” McKiernan commented.

McKiernan also pointed to a recent phase I study from the Columbia University Medical Center assessing the combination of cabazitaxel (Jevtana) with gemcitabine and cisplatin (CGC) in patients with BCG-unresponsive or recurrent/relapsing NMIBC who were ineligible for or declined cystectomy. Among patients who had received a mean of 3.3 prior courses of induction therapy and had failed at least 2 induction courses, CGC induced an overall complete response (CR) rate of 89% and an RFS rate of 83% at 1 year.⁸

Looking to Newer Treatments for BCG-Unresponsive Patients

Boorjian explained that BCG-unresponsive NMIBC is defined as persistent/recurrent high-grade Ta or T1 urothelial carcinoma within 6 months of completion of an adequate quantity of BCG or persistent/recurrent carcinoma in situ (CIS) (±Ta or T1 disease) within 12 months of completing an adequate course of BCG. Adequate BCG was considered to be 5 of 6 instillations of induction BCG and 2 of 3 maintenance treatments or 2 of 6 courses of the second round of induction. The only exception was patients who presented with high-grade T1 disease at their first evaluation after induction BCG.

He noted that this definition helps frame future treatment decision making for these patients as further BCG shows a lack of significant efficacy in these patients and instead increases their risk of progression.

“This is of particular relevance in the current era that we’re talking about of the BCG shortage where allocation is critical. We don’t want to waste BCG on patients not likely to respond to BCG,” emphasized Boorjian, professor of urology and director of Urologic Oncology Fellowship at The University of Texas MD Anderson Cancer Center.

Guidelines from the AUA and Society of Urologic Oncology (SUO) from 2016 advised that patients with high-risk, BCG-unresponsive should receive radical cystectomy, and Boorjian noted that this is still the gold standard in 2020. For those who are unfit for or unwilling to undergo cystectomy, clinical trials are recommended. If a trial is unavailable, intravesical chemotherapy is suggested, although there is no robust evidence to recommend one treatment over another.⁹

Kamat noted that rates of radical cystectomy increase dramatically in the setting of a BCG shortage; while urologists should not subject their patients to unnecessary surgery, there is a time for cystectomy. He noted that patients with highest-risk features, such as high-grade T1 disease with extensive CIS, prostatic involvement, or variant histology, would benefit from discussions of radical cystectomy.

Checkpoint inhibitor pembrolizumab (Keytruda) was approved by the FDA at the beginning of the year for the treatment of patients with BCG-unresponsive, high-risk NMIBC with CIS with or without papillary tumors who are ineligible for or are unwilling to undergo cystectomy.¹⁰ In the single-arm, multicenter, phase 2 KEYNOTE-057 trial, the CR rate with pembrolizumab was 41% (95% CI, 31%-51%) and the median duration of response was 16.2 months.

“I think this is a particularly exciting area of urologic oncology and bladder cancer specifically because we have a number of different clinical trials that are coming in the BCG-unresponsive disease state from a variety of different therapeutic strategies,” Boorjian said. Some of the different emerging strategies include vaccines, interleukin-15 super agonists, immune checkpoint inhibition, small molecule inhibitors of IDO1, viral gene transfer, and oncolytic adenovirus.

Boorjian highlighted an ongoing phase 3 trial (NCT02773849) of a replication-deficient adenoviral vector, rAd-IFN-alpha (nadofaragene firadenovec), in patients with high-grade, BCG-unresponsive NMIBC for which he was an investigator. The adenoviral vector delivers the IFN gene directly to bladder cells and turns the bladder into a “bioreactor.”

The study has enrolled 157 patients and is looking at the CR rate at any time for patients with CIS (n = 103) as a primary end point. Fifty-five patients achieved a CR (53.4%) and 45.5% of patients with an initial CR maintained their CR at 1 year.

Boorjian commented, “we may have a real opportunity here to extrapolate lessons learned from clinical trials in the BCG-unresponsive population to earlier in NMIBC [disease settings].”

_References:

_{1. Lerner SP, Boorjian SA, Kamat AM, McKiernan JM, Ritch CR. what to do during bcg shortage for high-risk nmibc patients? Presented at: AUA Virtual Experience; June 27-28, 2020.}

_{2. Letter Re: BCG Shortage. Bladder Cancer Advocacy Network. February 19, 2019. Accessed June 29, 2020. https://bcan.org/wp-content/uploads/2019/05/BCAN-Letter-Re-BCG-Shortage-for-Web.pdf}

_{3. Oddens J, Brausi M, Sylvester R, et al. Final results of an eortc-gu cancers group randomized study of maintenance bacillus calmette-guérin in intermediate- and high-risk ta, t1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol. 2013;63(3):462-472. doi:10.1016/j.eururo.2012.10.039}

_{4. Schmidt S, Kunath F, Coles B, et al. Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer (Review). Cochrane Database of Systematic Reviews. 2020;1. doi:10.1002/14651858.CD011935.pub2}

_{5. Malmström PU, Sylvester RJ, Crawford DE, et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin c versus bacillus calmette-guérin for non-muscle-invasive bladder cancer. Eur Urol. 2009;56(2):247-256. doi:10.1016/j.eururo.2009.04.038Di}

_{6. Lorenzo G, Perdonà S, Damiano R, et al. Gemcitabine versus bacille calmette-guérin after initial bacille calmette-guérin failure in non-muscle-invasive bladder cancer: a multicenter prospective randomized trial. Cancer. 2010;116(8):1893-1900. doi:10.1002/cncr.24914}

_{7. Steinberg RL, Thomas LJ, Brooks N, et al. Multi-institution evaluation of sequential gemcitabine and docetaxel as rescue therapy for nonmuscle invasive bladder cancer. J Urol. 2020;203(5):902-909. doi:10.1097/JU.0000000000000688}

_{8. DeCastro GJ, Sui W, Pak JS, et al. A phase i trial of intravesical cabazitaxel, gemcitabine and cisplatin for the treatment of nonmuscle invasive bacillus calmette-guérin unresponsive or recurrent/relapsing urothelial carcinoma of the bladder. J Urol. Published online March 2, 2020. doi:10.1097/JU.0000000000000919}

_{9. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: aua/suo guideline. J Urol. 2016;196(4):1021-1029. doi:10.1016/j.juro.2016.06.049}

_{10. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. News release. FDA. January 8, 2020. Accessed June 29, 2020. https://bit.ly/2ZiTFoa}