Bladder Cancer

An Urgent Need to Treat Bladder Cancer and Prevent Radical Cystectomy

Bladder cancer is the 10th most commonly-diagnosed cancer globally,¹ and in the U.S., the American Cancer Society estimates there will be 83,190 new cases and 16,840 deaths from bladder cancer in 2024.² At the time of diagnosis, about 80% of cases are non-muscle invasive bladder cancer (NMIBC), wherein the cancer is found only on the inner layer of the bladder wall.³

The standard therapy for NMIBC is intravesical instillation (delivery to the bladder via a catheter) of bacillus Calmette-Guerin (BCG).^4,5 BCG is a benign bacteria that induces an immune response in the bladder in proximity to the cancer cells, leading to clearance of the cancer in many patients. In ~30-40% of patients, however, BCG will fail, and in ~50% that initially respond, cancer will recur.⁶

Failure of BCG may lead to a lifetime of invasive examinations and possibly repeated treatments for recurrences. The recurrence of NMIBC typically diminishes a patient’s quality of life, poses a significant financial burden for most patients, and is associated with a greater mortality risk. For another ~50% of patients, controlling the disease will require them to undergo radical cystectomy – surgical removal of the bladder.⁷ Thus, there is an urgent unmet need to treat NMIBC and avoid radical cystectomy. Due this need, the U.S. Food and Drug Administration (FDA) has issued a guidance for the design of studies for the development of NMIBC treatments that includes the goal of avoiding this drastic surgery.

Bladder Cancer Clinical Trials

QUILT-3.032 Clinical Trial of Anktiva Plus BCG for BCG-Unresponsive NMIBC: Carcinoma in Situ (CIS)

In our Phase 2/3 open-label (patients and oncologists know what treatment the participant receives) multi-center trial QUILT-3.032,⁸ the ability of our interleukin-15 superagonist Anktiva (also known as N-803 and nogapendekin alfa inbakicept or NAI) to increase responses to BCG and extend the duration of those responses is being assessed in patients with high-risk BCG-unresponsive NMIBC. BCG-unresponsive patients are those who either never achieved a complete response (CR) with BCG alone, or in whom cancer returned after an initial response. The rationale for the addition of Anktiva to BCG is that in BCG-unresponsive patients, the immune response to BCG alone is not sufficient to clear the cancer and the immune-cell activating effects of Anktiva may overcome this limitation.

Based on early findings, Anktiva received both Breakthrough Therapy and Fast Track designations by the FDA for the treatment of BCG-unresponsive NMIBC carcinoma in situ (CIS) disease,⁹ as well as Fast Track designation for BCG-unresponsive NMIBC papillary disease¹⁰ and BCG-naïve NMIBC CIS disease.¹¹

In the study, patients who have first undergone transurethral resection of the bladder tumor (TURBT) to remove cancerous tissue receive BCG plus Anktiva weekly for six consecutive weeks during induction. The patients are then assessed for responses to the combination therapy at 3 and 6 months, and have an option to undergo induction again after the 3-month assessment if they have not achieved a CR. As maintenance therapy for those that achieve a CR, BCG plus Anktiva is given once a week for three weeks at every three months for up to 12 months and then at month 18.

There are three groups (cohorts) in the study. Cohort A comprises patients with CIS disease with or with Ta/T1 papillary disease and cohort B enrolls patients with high-grade papillary NMIBC. ‘Papillary’ means the cancer does not lie flat on the bladder wall and small projections are present; it is considered more advanced disease. Both Cohorts A and B receive Anktiva plus BCG. In cohort (C), patients with CIS with or without Ta/T1 disease received Anktiva alone. Cohort C is currently closed.

The most important assessment – the ‘primary endpoint’ – for cohort A is the rate of CR at either the 3- or 6-month response assessment. Secondary endpoints are duration of responses, the cystectomy avoidance rate, progression-free survival, disease-specific survival, and overall survival. For cohort B, the primary endpoint is disease-free survival at 12 months after the initiation of treatment. Assessment of safety, including treatment-emergent adverse events (TEAEs) and serious AEs (SAEs), is important for all cohorts.

At the January 15, 2022 data cutoff, 48 of 77 (62%; 95% confidence interval, CI – 51, 73) cohort A participants had achieved a CR. The DoRs ranged from 0 to more than 47 months, with 28 (58%) of responders having a DoR of ≥ 12 months and 19 (40%) a DoR of ≥ 24 months. Of the 77 participants, 24 (31%) received a second induction course.

SAEs occurred in 16% of patients receiving Anktiva with BCG, with hematuria (blood in the urine) being the only SAE occurring in ≥2% of patients. Permanent discontinuation of Anktiva with BCG due to adverse reactions occurred in 7% of patients, including musculoskeletal pain in 2.3%.

Quality of Life (QoL) as recorded by the participants themselves remained stable on the study, and at month 6, cohort A patients with a CR reported higher physical function scores than those without a CR.¹² The safety, efficacy, and QoL reported for the study of Anktiva and BCG in BCG-unresponsive CIS +/- Ta/T1 disease suggests a favorable risk: benefit ratio for the novel combination.

In May 2022, we announced the submission of a Biological License Authorization (BLA) to the U.S. FDA for Anktiva in combination with BCG for the treatment of patients with BCG-unresponsive bladder CIS with or without Ta or T1 disease and on April 22, 2024, the FDA issued approval for use of this novel therapeutic combination for this indication.

QUILT-3.032 Clinical Trial of Anktiva Plus BCG for BCG-Unresponsive NMIBC: Papillary disease

As mentioned above, participants in QUILT-3.032 cohort B also receive BCG plus Anktiva by the same regimen as cohort A. At the January 15, 2022 data cutoff, the 12-month disease-free survival rate was 55% (95% CI: 42.0, 66.8), with median disease-free survival of 19.3 months (95% CI: 7.4, [upper bound not reached]). At the cutoff date 67 of 72 patients, 93.1%, had not progressed to radical cystectomy and the 24-month disease-free survival rate was 97.7%.¹³

The trial is ongoing, with a goal of enrollment of 100 patients in both cohorts A and B.

QUILT-2.005 Clinical Trial of N-803 Plus BCG for BCG-Naive NMIBC

We are also conducted a Phase 1b open-label trial to study Anktiva and BCG in NMIBC patients who did not previously receive BCG, referred as being ‘BCG-naïve’. As described for the QUILT 3.032 study, patients were treated once weekly for 6 weeks. Three doses of N-803 were tested: 100, 200, and 400 μg along with 50 mg BCG. The rationale for the study is that Anktiva when used in combination with BCG will increase the complete response rate and produce durable responses.

Phase 1b part is completed and all nine participants (100%) achieved a CR. A dose of 400 μg of N-803 was established for Phase 2b. The responses were long-lasting in all patients, with all participants remaining disease-free 6 years after treatment.¹⁴

We are currently enrolling patients in Phase 2b, which is blinded, randomized, two-cohort, open-label, multi-center trial of intravesical BCG plus Anktiva versus BCG alone, in BCG naïve patients with high-grade NMIBC CIS (Cohort A) and NMIBC papillary (Cohort B). Planned enrollment for Cohort A (CIS) and Cohort B (papillary) is 366 and 230 patients, respectively.

1. World Cancer Research Fund International: Bladder Cancer Statistics https://www.wcrf.org/cancer-trends/bladder-cancer-statistics/ .
2. American Cancer Society: Key Statistics for Bladder Cancer (2024) https://www.cancer.org/cancer/types/bladder-cancer/about/key-statistics.html
3. Aldousari et al. Update on the management of non-muscle invasive bladder cancer. Can Urol Assoc J. 2010 Feb; 4(1): 56–64 doi: 5489/cuaj.777
4. Holzbeierlain et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline 2016 (amended 2020, 2024). https://www.auanet.org/guidelines-and-quality/guidelines/bladder-cancer-non-muscle-invasive-guideline.
5. Grabe-Heyne et al. Intermediate and high-risk non-muscle invasive bladder cancer: an overview of epidemiology, burden, and unmet needs. Frontiers in Oncology 2023 13:1170124. Doi: 10.3389/fonc.2023.1170124.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10272547/
6. Kodera et al. The management of bacillus Calmette-Guerin (BCG) failure in high-risk non-muscle invasive bladder cancer: a review article. Cureus 2023 15(6): e40962. doi: 10.7759/cureus.40962. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10369196/
7. Li R, Tabayoyong WB, Guo CC et al. Prognostic Implication of the United States Food and Drug Administration-defined BCG-unresponsive Disease. European Urology 2019; 75: 8-10. 2019. https://www.sciencedirect.com/science/article/abs/pii/S0302283818307164
8. ‘QUILT-3.032: A Multicenter Clinical Trial of Intravesical Bacillus Calmette-Guerin (BCG) in Combination With ALT-803 (N-803) in Patients With BCG Unresponsive High Grade Non-Muscle Invasive Bladder Cancer’ https://clinicaltrials.gov/study/NCT03022825
9. ‘ImmunityBio Announces FDA Acceptance of Biologics License Application for N-803 in BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer Carcinoma In Situ’ July 28, 2022. 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/
10. ‘Anktiva (N-803) plus BCG Vaccine’ Precision Vaccinations. Updated May 1, 2024. https://www.precisionvaccinations.com/vaccines/anktiva-n-803-plus-bcg-vaccine .
11. ‘Altor BioScience Corporation Announces FDA Fast Track Designation For Lead Candidate ALT-803 In Patients With Non-Muscle Invasive Bladder Cancer’ Biospace May 2, 2017. https://www.biospace.com/article/releases/altor-bioscience-corporation-announces-fda-fast-track-designation-for-lead-candidate-alt-803-in-patients-with-non-muscle-invasive-bladder-cancer-/
12. Chamie et al. ‘Quality of Life in the Phase 2/3 Trial of N-803 Plus Bacillus Calmette-Guérin in Bacillus Calmette-Guérin‒Unresponsive Nonmuscle-Invasive Bladder Cancer.’ Urology Practice Jan 2024; 11:367:367 (https://www.auajournals.org/doi/10.1097/UPJ.0000000000000517
13. Chamie et al. IL-15 Superagonist NAI in BCG-Unresponsive Non-Muscle Invasive Bladder Cancer. New England Journal of Medicine Evidence Nov 2022 2 (1):1-11. (https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200167
14. Rosser CJ, Tikhonenkov S, Nix JW, Chan OTM, Ianculescu I, Reddy S, et al. Safety, Tolerability, and Long-Term Clinical Outcomes of an IL-15 analogue (N-803) Admixed with Bacillus Calmette-Guérin (BCG) for the Treatment of Bladder Cancer. Oncoimmunology. 2021;10(1912885):1-7. https://pubmed.ncbi.nlm.nih.gov/33996264/