Emerging Treatments for Bacillus Calmette-Guerin-Unresponsive Nonmuscle-Invasive Bladder Cancer

Educational Objectives

The goal of this program is to improve the management of Bacillus Calmette-Guerin (BCG) unresponsiveness in nonmuscle invasive bladder cancer (NMIBC). After hearing and assimilating this program, the clinicians will be able to:

1. Develop an appropriate treatment regimen with maintenance doses of BCG in patients with NIMBC.
2. Select appropriate treatments for BCG unresponsiveness in patients with NIMBC.

Summary

Mechanism of action: Bacillus Calmette-Guerin (BCG) vaccine works through the cellular and humoral immune response; BCG connects with fibronectin in urothelial cells and urothelial carcinoma; endocytosis occurs in dendritic cells and cancer cells that release antigens; interleukin (IL)-6 and IL-8 start the immune response, which attracts other immune cells (eg, CD4, CD8, granulocytes, natural killer cells, macrophages); more cytokines (ie, IL-1, IL-2, IL-15, interferon [IFN]-γ, tumor necrosis factor-α) are then secreted, increasing the immune response to the cancer antigen; most acceptable guidelines recommend giving induction and maintenance BCG (Lamm et al; 2000); adding maintenance was found to increase recurrence- and progression-free survival rates; a meta-analysis by Jiang et al comparing BCG, with or without maintenance, with mitomycin showed that BCG is only superior with maintenance

Response to treatment: adequate BCG is defined as 2 courses of BCG, ie, 5 of 6 induction doses and 2 of 3 maintenance doses or 2 induction courses in 6 mo; BCG unresponsiveness is defined as high-grade T1 disease developing after 1 induction; if there is response at 3 mo but high-grade disease persists at 6 mo, it is unresponsive; US Food and Drug Administration (FDA) trial guidelines for BCG-unresponsive patients accept single-arm trials; for carcinoma in situ (CIS), meaningful outcome is defined as an initial complete response (50% at 6 mo, durable response of 30% at 12 mo, and 25% at 18 mo); for papillary disease, recurrence-free survival (RFS) rate of 30% at 12 mo and 25% at 18 mo is needed

Treatment for BCG-unresponsive disease: valrubicin — received US FDA approval based on a trial of 90 patients with CIS who were unresponsive to BCG (Steinberg et al; 2000); 21% had a complete response at 6 mo, 8% had a durable response, and 56% underwent radical cystectomy; intravesical (IVE) therapy — combination of gemcitabine and docetaxel is effective; in a study by Steinberg et al (2020), RFS rates were 60% and 46%, and high-grade RFS rates were 65% and 52% at 1 yr and 2 yr, respectively; 43% required cystectomy; a phase 1 trial (DeCastro et al; 2020) of IVE cabazitaxel, gemcitabine, and cisplatin had promising results (1-yr RFS rate of 0.8; 2 yr estimated RFS rate of 0.64); no dose-limiting toxicity was seen; phase 2 is ongoing; a retrospective study by Tan WS et al (2019) saw promising results with mitomycin plus hyperthermia (at 43° over 1 hr), but phase 3 trial results were conflicting

Immunotherapy for BCG-unresponsiveness: may be IVE or systemic; CG0070 — an oncolytic virus that selectively attaches to cancer cells that have defective retinoblastoma pathway and lyses them; a phase 2 trial (Packiam et al; 2019) saw response rates of 44% in 6 mo and 23% at 18 mo, with CIS having worse outcomes; adverse events were well-tolerated; ALT-803 trial (Chamie et al; 2021) — based on IVE IL-15; N-803 enhances attachment of IL-15 to IL-2 receptor and increases the half-life of IL-15; complete response rate was 72% and probability of maintaining response at 12 mo was 59%

Other trials: nadofaragene firadenovec — a nonreplicating adenovirus that attaches to cancer cells, secretes IFN-α2, and increases transduction of the virus to cells; in a phase 3 trial, 53% of CIS patients had complete response at 3 mo and 24% had durable response at 12 mo; pembrolizumab — a PD-1 inhibitor approved by the US FDA; in a phase 2 trial, 39 of 96 patients had complete response at 3 mo and 46% at 12 mo; incidence of adverse events was low and no treatment-related deaths occurred; radical cystectomy is the gold standard for BCG unresponsiveness; early cystectomy (within 2 yr) has better outcomes; nonmuscle-invasive disease has better outcomes than muscle-invasive disease; patients not eligible for or refusing cystectomy can be treated with pembrolizumab (valrubicin is no longer considered effective); encourage patients to enroll in clinical trials for targeted therapies and immunotherapies

Readings

Chamie K, Chang S, Gonzalgo ML, et al. Phase II/III clinical results of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) patients. Journal of Clinical Oncology. 2021;39:6_suppl, 510-510; 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-Guerin unresponsive or recurrent/relapsing urothelial carcinoma of the bladder. J Urol. 2020; 204:247-253; Jiang SJ, Ye LY, Meng FH. Comparison of intravesical bacillus Calmette-Guerin and mitomycin C administration for non-muscle invasive bladder cancer: A meta-analysis and systematic review. Oncol Lett. 2016;11(4):2751-2756. doi:10.3892/ol.2016.4325; Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000;163(4):1124-1129; Lamm DL, Morales A. A BCG success story: From prevention of tuberculosis to optimal bladder cancer treatment. Vaccine. 2021;39(50):7308-7318. doi:10.1016/j.vaccine.2021.08.026; Packiam VT, Johnson SC, Steinberg GD. Non–muscle-invasive bladder cancer: Intravesical treatments beyond Bacille C almette-G uérin. Cancer. 2017; 123:390-400; Packiam VT, Barocas DA, Chamie K, et al. MP43-02 CG0070, an oncolytic adenovirus, for BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC): 18 month follow-up from a multicenter phase II trial. J Urol. 2019; e617-e617; Redelman-Sidi G, Glickman MS, Bochner BH. The mechanism of action of BCG therapy for bladder cancer — a current perspective. Nat Rev Urol. 2014; 11:153-162; Steinberg G, Bahnson R, Brosman S, et al. Efficacy and safety of valrubicin for the treatment of bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. J Urol. 2000; 163:761-767; 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; 203:902-909; Tan WS, Hendricksen K, Wilby D, et al. PD13-10 oncological outcomes Of BCG unresponsive non-muscle invasive bladder cancer patients treated with postoperative chemohypothermia: A multicentre European retrospective analysis. J Urol. 2019; 201:e229-30.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Salmasi was recorded at the 29th Annual Perspective in Urology: Point Counterpoint, held November 18-21, 2021, and presented by Grand Rounds in Urology. For information about upcoming CME activities from this presenter, please visit Grandroundsinurology.com. Audio Digest thanks the speakers and Grand Rounds in Urology for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0.50 CE contact hours.

Lecture ID:

UR451202

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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