Pharmacy Practice in Focus: Oncology
Emerging therapeutic options represent a new age for treatment of high-risk non–muscle invasive bladder cancer.
In 2026, over 84,000 patients will be diagnosed with bladder cancer.1 Of those newly diagnosed, approximately 75% will present with non–muscle invasive bladder cancer (NMIBC), with disease primarily limited to the urothelial lining of the bladder. Although NMIBC is associated with an approximate 73% 5-year survival rate, over 50% of patients will have recurrence, and 30% will experience progression to metastatic disease.2,3 BCG instillations have been the standard of care for NMIBC for decades. However, with BCG failure rates at 40% and a historically long BCG shortage, alternative treatments or radical cystectomy must be considered.3,4
Almost all patients with NMIBC will undergo transurethral resection of a bladder tumor (TURBT) to stage and determine tumor risk. Risk stratification of NMIBC directs treatment type, intensity, and duration. After initial TURBT, a single dose of intravesical chemotherapy (gemcitabine or mitomycin) is administered within 24 hours of surgery. This can reduce the 5-year recurrence rate by approximately 35%. The American Urological Association and National Comprehensive Cancer Network (NCCN) classify patients with NMIBC into low-, intermediate-, and high-risk groups (Table 1).4
The first-line treatment for high-risk NMIBC is typically managed with TURBT followed by bladder instillations of BCG for up to 3 years.4 Due to the ongoing national shortage of BCG, modifications to dosing and duration of therapy or even use of alternative agents, such as docetaxel, gemcitabine, or mitomycin, have been utilized.4
In the past few years, several new localized treatments have received FDA approval for select patients with high-risk NMIBC (Table 2). Nadofaragene firadenovec-vncg (Adstiladrin; Ferring Pharmaceuticals) was FDA approved in 2022 based on the CS-003 single-arm trial (NCT02773849) in patients with high-grade BCG-unresponsive NMIBC. All patients received a dose of nadofaragene firadenovec-vncg 3 x 1011 viral particles/mL in 75-mL instillations every 3 months. The primary end point was complete response (CR) in the CIS (carcinoma in situ) cohort at any time within 12 months after the first dose.5
Nadofaragene firadenovec-vncg is an adenovirus vector–based gene therapy that delivers a copy of the gene encoding human interferon alfa-2b, which then stimulates antitumor immune responses and apoptosis. In the CIS cohort of 103 patients, 53.4% had a CR (95% CI, 43.3%-63.3%), with all CRs at month 3, and 24.3% remained recurrence free at 12 months (95% CI, 16.4%-33.7%). Of the patients, 70% had adverse events (AEs), with the most common being discharge around the catheter during instillation, fatigue, bladder spasms, and micturition urgency.5 In 2024, updated efficacy results showed that 13 patients with CRs remained recurrence free. No new safety signals were reported in this update.6
Nogapendekin alfa inbakicept-pmln (NAI; Anktiva; ImmunityBio, Inc) is an IL-15 superagonist that acts as a stimulator for natural killer and other immune cells. It is used in combination with BCG to synergistically enhance the immune system response to BCG. NAI was FDA approved in 2024 following the results of cohort A in the QUILT-3.032 trial (NCT03022825), an open-label, single-arm, 3-cohort, multicenter trial that included patients with BCG-unresponsive high-grade NMIBC. Cohort A included patients with CIS with or without papillary disease; patients received NAI 400 μg plus BCG 50 mg intravesical instillations. Seventy-one percent of patients achieved the primary end point of CR (95% CI, 59.6%-80.3%) at 3 or 6 months. The most common treatment-emergent adverse events (TEAEs) in the combination arm (cohorts A and B) were dysuria, pollakiuria, and hematuria. Grade 3 or greater events included hematuria (2%) and urinary tract infection (2%).7
The gemcitabine intravesical system (Inlexzo; Johnson & Johnson) was approved in 2024 based on cohort 2 of SunRISe-1, a single-arm, multicenter, phase 2b trial (NCT04640623) in patients with BCG-unresponsive, high-risk NMIBC who were ineligible for or declined radical cystectomy. The gemcitabine system is inserted via a catheter into the bladder and delivers 225 mg of gemcitabine over 3 weeks. The primary end point was the CR rate. The CR rate was 82.4% (95% CI, 72.6%-89.8%), with 70 of 85 patients achieving a CR during the study. The median duration of response was 25.8 months (95% CI, 8.3-not estimable), and 52.9% of responders (37 patients) maintained their response for at least 12 months. The system was generally well tolerated, with the most common TEAEs (> 15%) including urinary frequency, urinary tract infection, dysuria, micturition urgency, decreased hemoglobin, increased lipase levels, urinary tract pain, decreased lymphocytes, hematuria, increased creatinine, increased potassium, increased aspartate aminotransferase levels, decreased sodium, bladder irritation, and increased alanine aminotransferase levels.8,9
ABOUT THE AUTHORS
Rose DiMarco, PharmD, BCPS, BCOP, is the assistant director of pharmacy—oncology and infusion at Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University Hospital in Philadelphia, Pennsylvania.
Alison Hart, PharmD, BCOP, is the director of Oncology Pharmacy and Investigational Drug Services at the Sidney Kimmel Cancer Center in Philadelphia, Pennsylvania.
TICE BCG or BCG is an attenuated, live culture preparation of the BCG strain of Mycobacterium bovis. Its mechanism of action when given intravesically is thought to trigger a local immune response that destroys tumor cells. It is the gold standard treatment for intermediate and high-risk NMIBC, reducing both recurrence and progression rates.10,11 Unfortunately, since 2012, there has been a global BCG shortage, resulting in operational and clinical challenges. The NCCN guidelines have published principles to guide the allocation of limited BCG supplies during shortages.4
Sasanlimab (Pfizer), a subcutaneous PD-1 inhibitor, was studied in a global, phase 3, randomized, open-label trial (CREST; NCT04165317) in combination with BCG vs BCG alone in patients with BCG-naive, high-risk NMIBC. The primary end point, investigator-assessed event-free survival at 36 months, was 82.1% with the combination vs 74.8% with BCG alone (HR, 0.68; 95% CI, 0.49-0.94; 1-sided P = .0095). A total of 91.7% of patients on combination therapy achieved a complete response, compared with 67.7% on BCG alone.
Grade 3 or greater treatment-related AEs occurred in 29.1% of patients in the sasanlimab plus BCG arm compared with 6.3% in the BCG monotherapy arm. A total of 15.7% of patients who received the combination experienced a grade 3 or greater immune-related AE, with immune-related hepatitis occurring in 3.4% of patients. It is expected that sasanlimab will have a Prescription Drug User Fee Act date in the second quarter of 2026, which will likely add another layer of complexity (and cost) to the treatment of high-risk NMIBC amid the ongoing BCG shortage.12
Despite several recent FDA approvals, more data are needed to fully elucidate the treatment of NMIBC. BCG remains the standard of care for most patients with NMIBC, but the optimum treatment strategy (dose, frequency, duration, plus/minus combination therapy) has not been determined. Novel agents such as nadofaragene firadenovec-vncg and nogapendekin alfa inbakicept-pmln are both indicated for patients after BCG treatment failure, which may present a barrier in settings where BCG supply is constrained. The high cost of therapy and extensive compounding considerations, especially with novel treatments, may also limit access. Future directions in the treatment of NMIBC should include BCG-sparing options, cost mitigation, improved access, and the inclusion of patient-reported outcomes in clinical trials and real-world data.
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