What is the potential role for nogapendekin alfa inbakicept-pmln in the treatment of Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC)?
- Bladder cancer is the 10th most common cancer worldwide with an estimated 82,000 new diagnoses and 17,000 deaths in 2023.1
- At initial diagnosis, most patients (80%) present with NMIBC2
- Intravesical instillation of BCG after transurethral resection of the bladder tumor (TURBT) is standard of care for intermediate and high-risk NMIBC patients, but up to 40% of patients will fail BCG therapy and approximately 50% will relapse after an initial response.3
- Nogapendekin alfa inbakicept is a first-in-class interleukin (IL)-15 receptor agonist and gained approval in combination with BCG for adults with BCG-unresponsive NMIBC.3
- BCG is a live attenuated form of Mycobacterium bovis; it is the most used agent for intravesical therapy due to its superiority in randomized clinical trials.4
- BCG causes immunomodulation and activation of various cytokines (interleukin [IL]-1, IL-2, IL-6, IL-8, IL-12), increased expression of interferon gamma (IFNg), and CD4 T cells and macrophages that target tumor cells.4
- Combination of BCG and nogapendekin alfa inbakicept-pmln causes a synergistic antitumor effect by further increasing interleukin activity against cancer cells.4
- Efficacy was evaluated in QUILT-3.032, a single-arm, multicenter trial of 77 patients with BCG-unresponsive, high-risk NMIBC with carcinoma in situ (CIS) with or without Ta/T1 papillary disease following transurethral resection.5,6
- Patients received nogapendekin alfa inbakicept-pmln induction via intravesical instillation with BCG followed by maintenance therapy for up to 37 months.5,6
- Tumor status was assessed with cystoscopy and urine cytology every 3 months for up to 2 years and biopsy (random or cystoscopy-directed) was required within the first 6 months after treatment initiation. 5,6
- The major efficacy outcomes were complete response (CR) and duration of complete response (DOR). 5,6
- CR was 62% (95% CI:51, 73). Fifty-eight percent of patients with CR had a DOR ≥ 12 months and 40% had a DOR ≥ 24 months. 5,6
- The most common adverse reactions (≥15%), including laboratory test abnormalities, were increased creatinine, dysuria, hematuria, urinary frequency, micturition urgency, urinary tract infection, increased potassium, musculoskeletal pain, chills, and pyrexia. 5,6
- Dosage interruptions due to adverse reactions occurred in 34% of patients receiving Nogapendekin alfa inbakicept-pmln with BCG. Adverse reactions (≥5%) that resulted in interruption of Nogapendekin alfa inbakicept-pmln with BCG were urinary tract infection (10%), dysuria (8%), hematuria (6%), and bladder irritation (6%).5,6
- Compared to other therapies for BCG-unresponsive NMIBC, nogapendekin alfa inbakicept-pmln appears to have a slightly better CR rate at 3 months (62%) compared to pembrolizumab (41%) and nadofaragene firadenovec (51%), and a manageable safety profile.7,8
- Choice of which therapy is best should be based on clinical status of disease (i.e. high-risk CIS versus Ta/T1 disease), patient characteristics (i.e. avoidance of cystectomy [nogapendekin alfa inbakicept-pmln has 90% probability of cystectomy at 24 months]), and side effect profile (i.e. nogapendekin alfa inbakicept-pmln displays more immune related side effects [fever, chills, etc.] due to its mechanism of action [IL-15 superagonist], and nadofaragene firadenovec displays more bladder-related symptoms (i.e. bladder inflammation, hematuria, etc.).6,7
- Nogapendekin alfa inbakicept-pmln has been added to the National Comprehensive Cancer Network (NCCN) Guidelines for bladder cancer under the section labeled, “Non-Muscle Invasive or Tis, Primary Evaluation/Surgical Treatment (BL-1).”
What role can the pharmacist play in the management of patients on nogapendekin alfa inbakicept-pmln?
- Pharmacists can ensure appropriate dosing and duration:
- For Induction: 400 mcg administered intravesically with BCG once a week for 6 weeks. A second induction course may be administered if complete response is not achieved at month 3.9
- For Maintenance: 400 mcg administered intravesically with BCG once a week for 3 weeks at months 4, 7, 10, 13 and 19. For patients with an ongoing complete response at month 25 and later, additional maintenance instillations with BCG may be administered once a week for 3 weeks at months 25, 31, and 37.9
- Pharmacists can help identify and manage toxicities:
- Due to the limited systemic exposure of nogapendekin alfa inbakicept-pmln, there are no known drug-drug interactions.9
- The most common (≥15%) adverse reactions, including laboratory test abnormalities, are increased creatinine, dysuria, hematuria, urinary frequency, micturition urgency, urinary tract infection, increased potassium, musculoskeletal pain, chills and pyrexia.9
- Serious adverse events: hematuria (3.4%), urinary tract infection (2.3%), and musculoskeletal pain (2.3%)9
- A fatal adverse event of cardiac arrest occurred in 1.1% of patients.9
- Pharmacists can counsel patients:
- Patient Counseling: Educate the patient to stay hydrated and that irritable bladder symptoms (red tinged urine, urinary frequency, microurination, etc.) may occur 24 hours following treatment. If symptoms persist after 24 hours, contact their healthcare provider. The patient should sit to urinate for 6 hours after treatment to prevent splashing.9
- Patient assistance program: ImmunityBio Patient Assistance Program
Clinical Pearls
- Instill intravesically only after dilution. Total time from vial puncture to the completion of the intravesical instillation should not exceed 2 hours.9
- Nogapendekin alfa inbakicept-pmln is available as a 400 mcg/0.4 mL, clear to slightly opalescent and colorless to slightly yellow solution in a single-dose vial for intravesical instillation after dilution.9
- Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake.9
- Delaying cystectomy can lead to the development of metastatic bladder cancer, which can be lethal. Risk increases the longer cystectomy is delayed. Reconsider cystectomy if patients with CIS do not have a complete response to treatment after a second induction course of nogapendekin alfa inbakicept (with BCG).9
- The admixture of nogapendekin alfa inbakicept-pmln in combination with BCG is instilled into the bladder via a catheter. After instillation is complete, the catheter is removed. The nogapendekin alfa inbakicept-pmln in combination with BCG admixture is retained in the bladder for 2 hours and then voided. Patients unable to retain the suspension for 2 hours should be allowed to void sooner, if necessary. Do not repeat the dose if the patient voids before 2 hours.9
- Systemic exposure of nogapendekin alfa inbakicept-pmln was less than 100 pg/mL following the approved recommended dosage in all patients. This was below the lower limit of quantitation in all patients.9
- Obtain purified protein derivative (PPD) test PRIOR to nogapendekin alfa inbakicept with Bacillus Calmette-Guérin (BCG) (intravesical) treatment initiation.9
- Verify pregnancy status prior to treatment initiation. Patients who could become pregnant should use effective contraception during therapy and for 1 week after the last dose of nogapendekin alfa inbakicept-pmln.9
References
1.Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17-48.
2.Pelucchi C, Bosetti C, Negri E, et al. Mechanisms of disease: The epidemiology of bladder cancer. Nat Clin Pract Urol. 2006 Jun;3(6):327-40.
3.Chou R, Selph S, Buckley DI, et al. Intravesical therapy for the treatment of nonmuscle invasive bladder cancer: a systematic review and meta-analysis. J Urol. 2017;197(5):1189-1199.
4.Bacillus Calmette-guerin (Tice BCG) [package insert]. Organon UAS Inc.; 2009
5.Center for Drug Evaluation and Research. FDA approves Nogapendekin Alfa inbakicept-PMLN for bladder cancer. U.S. Food and Drug Administration.
6.Chamie K, Chang SS, Kramolowsky EV, 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. Urol Pract. 2024;11(2):367-375.
7.Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107-117.
8.Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study [published correction appears in Lancet Oncol. 2021 Aug;22(8):e347]. Lancet Oncol. 2021;22(7):919-930.
9.Nogapendekin alfa inbakicept-pmln (Anktiva) [package insert]. ImmunityBio, Inc.; 2024
