Oncology Insights: First-in-class bladder cancer therapy and the Bacillus Calmette-Guérin (BCG) shortage

Approximately 83,000 new bladder cancer cases are diagnosed in the U.S. in each year. Here’s a look at the recent advancements and treatment options for bladder cancer, as well as an update on the BCG shortage.

May 15, 2024

Oncology Insights

First-in-class bladder cancer therapy and the Bacillus Calmette-Guérin (BCG) shortage

On April 22, 2024, a new treatment for bladder cancer emerged when the United States (U.S.) Food and Drug Administration (FDA) approved Anktiva® (nogapendekin alfa inbakicept-pmln [NAI]) for the treatment of  adult patients with Bacillus Calmette-Guérin (BCG)–unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.1 Two agents, intravenous Keytruda® (pembrolizumab) a programmed cell death protein 1 (PD1) inhibitor and intravesical Adstiladrin® (nadofaragene firadenovec-vncg) a viral vector, are also FDA indicated and recommended by the National Cancer Center Network (NCCN)  in the same disease setting but do not require BCG co-administration.2,4,5

Approximately 83,000 new bladder cancer cases are diagnosed in the United States in each year. NMIBC represents about 80% of new bladder cancer cases.9 Intravesical BCG is the standard treatment for intermediate- and high-risk patients. Unfortunately, 30% to 40% of patients recur despite adequate BCG treatment.6 A cystectomy, surgical removal of the bladder, is considered the standard of care (SOC) when NMIBC does not respond to BCG.3 However, surgery is complex with high morbidity and significant impact on quality of life.9 Consequently, there is a need for additional bladder-preserving treatments with greater complete and durable responses for patients who desire a bladder-sparing approach or are too frail for major surgery.

Nogapendekin alfa inbakicept-pmln is a novel, first-in-class agent that stimulates the interleukin-15 (IL-15) receptor on CD4+/ CD8+ T cells and NK cells leading these immune cells to recognize and attack bladder cancer cells.9 The combined intravesical administration with BCG produces a synergistic effect that leads to greater bladder cancer cell death and a durable complete response.

The current and long-standing global BCG shortage which led to rationing since 2019, will impact nogapendekin alfa inbakicept-pmln utilization.7 To help resolve the shortage, ImmunityBio, nogapendekin alfa inbakicept-pmln’s manufacturer, has partnered with the Serum Institute of India in an exclusive deal to manufacture BCG globally.8 Production includes the standard and a recombinant BCG formulation. However, a timeline for regulatory approval and market introduction is not fully established.

Most adverse effects seen with intravesical agents are grades 1 or 2 and include instillation site discharge, fatigue, bladder spasm and urgency to urinate as the most common.6,11 Three patients treated with nogapendekin alfa inbakicept-pmln experienced a grade 3 immune-related adverse event. For pembrolizumab, grade 3-4 adverse events occurred in thirteen patients and included arthralgia and hyponatremia.10

Head-to-head clinical trials of these three NMIBC therapy options have not been conducted. This table provides details pertaining to clinical trial outcomes, administration and cost.

Therapy Options 6, 10-12

Keytruda (Pembrolizumab) Adstiladrin (nadofaragene firadenovec-vncg) Anktiva  (nogapendekin alfa inbakicept-pmln) + BCG
Study KEYNOTE-057, phase 2, open label; 5-year follow-up; n=148 CS-003, phase 3 open label; 5-year follow-up; n=157 QUILT-3.032; phase 2/3, open label, n= 171; 36-month cutoff

 

Results Cohort Aa (n=96)

CR at 3mo (40.6%)

 

 

Overall CR (53.3%, n=55)

 

 

Cohort A a: Overall CR (71%, 58 of 82);

CR at 3-, 6-, and 12- mo

(55%, 56%, 45%)

Cohort B b : DFS rate at 12mo (55.4%); mDFS (19.3 mo)

Cohort C a, c: CR at 3mo (20%) and 6mo (10%)

Secondary Endpoint Cohort A:

DOR for responders 16.2mo (n=39)

 

OS all participants (27.1%)

mOS not reached

 

Time from first dose to cystectomy (9 mo)

Duration of CR at 24 mo (36.4%)

 

mHGRFS (12.2mo)

 

Cystectomy free survival- 64.6%

Cohort A: mDOR for responders was 26.6 mo

Cystectomy avoidance rate (93%)

PFS at 24 mo (87.4%)

OS (94.3%)

DSS (100%)

Administration Every 3 weeks x 24 mo, intravenous Every 3 mo; 4 doses; intravesical Weekly; max treatment duration (37 mo); intravesical
Annual cost (WAC) $192,700 $240,000 $437,440  (Anktiva ($429,600) + BCG ($7,840))
  • Secondary Endpoint 
Cohort A:  

DOR for responders 16.2mo (n=39) 

 

OS all participants (27.1%) 

mOS not reached 

 

Time from first dose to cystectomy (9 mo) 

Duration of CR at 24 mo (36.4%) 

 

mHGRFS (12.2mo) 

 

Cystectomy free survival- 64.6% 

Cohort A: mDOR for responders was 26.6 mo 

Cystectomy avoidance rate (93%) 

PFS at 24 mo (87.4%) 

OS (94.3%) 

DSS (100%) 

  • Administration 
Every 3 weeks x 24 mo, intravenous  Every 3 mo; 4 doses; intravesical  Weekly; max treatment duration (37 mo); intravesical 
Annual cost (WAC)  $192,700  $240,000  $437,440  (Anktiva ($429,600) + BCG ($7,840)) 

CR – complete response; DFS – disease free survival; DOR – duration of response; DSS – disease specific survival; HGRFS – high grade recurrence free survival; mo – months; OS – overall survival; WAC – wholesale acquisition cost 

a. Cohort A & C- carcinoma in situ (CIS) ± papillary tumors 

b. Cohort B- papillary without CIS 

c. Cohort C received NAI alone; enrollment discontinued due to futility about six months into the study  

Initial clinical outcomes with nogapendekin alfa inbakicept-pmln combined with BCG are promising. However, the global BCG shortage will limit uptake. In some cases, the length of therapy and cost for this first in class drug may far exceed that of the previously FDA approved and NCCN recommended therapies. As utilization of this novel agent is evaluated, consideration for administration in combination with BCG and in patients identified as most likely to benefit should be considered.  

References
  1. FDA approves nogapendekin alfa inbakicept-pmln for BCG-unresponsive non-muscle invasive bladder cancer. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nogapendekin-alfa-inbakicept-pmln-bcg-unresponsive-non-muscle-invasive-bladder-cancer. Accessed May 9, 2024
  2. US Food and Drug Administration. FDA Approves First Gene Therapy for the Treatment of High-Risk, Non-Muscle-Invasive Bladder Cancer. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-high-risk-non-muscle-invasive-bladder-cancer. Accessed on May 9, 2024.
  3. Flaig TW, Spiess PE, Abern M, et al. National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology. Bladder Cancer. V 4.2024 – May 9, 2024. Available at: https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed May 9, 2024.
  4. Adstiladrin [package inset]. Kuopio, Kastrup, Denmark; Ferring; September 2023.
  5. Keytruda [package inset]. Rahway, NJ; Merck; March 2024.
  6. Chamie K, Chang SS, Kramolowsky E, et al. IL-15 Superagonist NAI in BCG-Unresponsive Non-Muscle-Invasive Bladder Cancer. NEJM Evid. 2023 Jan;2(1):EVIDoa2200167. doi: 10.1056/EVIDoa2200167. Available at https://evidence.nejm.org/doi/full/10.1056/EVIDoa2200167 . Accessed May 9, 2024
  7. Facing global shortage, Merck commits to meeting patient demand. Available at https://www.merck.com/stories/facing-a-global-shortage-merck-commits-to-meeting-patient-demand/ . Accessed May 9, 2024.
  8. ImmunityBio, Serum Institute of India Agree on an Exclusive Arrangement for Global Supply of Bacillus Calmette-Guerin (BCG) Across All Cancer Types. Available at https://immunitybio.com/immunitybio-serum-institute-of-india-agree-on-an-exclusive-arrangement-for-global-supply-of-bacillus-calmette-guerin-bcg-across-all-cancer-types/. Accessed May 9, 2024.
  9. Cancer Stat Facts: Bladder Cancer. Available at https://seer.cancer.gov/statfacts/html/urinb.html. Accessed May 9, 2024.
  10. Long-term follow-up supports pembrolizumab monotherapy in BCG-unresponsive NMIBC. Available at https://www.urologytimes.com/view/long-term-follow-up-supports-pembrolizumab-monotherapy-in-bcg-unresponsive-nmibc. Accessed May 13, 2024.
  11. Efficacy of intravesical nadofaragene firadenovec for patients with carcinoma in situ (CIS), BCG-unresponsive non-muscle invasive bladder cancer (NMIBC): Longer-term follow-up from the Phase III trial; Abstract MP16-01. Available at https://www.auajournals.org/doi/abs/10.1097/JU.0000000000002001.01. Accessed May 13, 2024.
  12. IPD Analytics. Oncology: Bladder Cancer. Access May 23, 2024.

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