Bridging the Gap Between Clinical Trial Evidence and Real-World Practice in NMIBC

Introduction

Bladder cancer is the sixth most common cancer in the United States with predictions of approximately 84,870 new cases and 17,420 deaths in 2025.^1,2 Bladder cancer also has a high overall cost, approximately $4 to $5 billion spent annually in treatment and healthcare-related costs.³ Treatment, prognosis and management of bladder cancer is divided into three subtypes depending on the depth of bladder wall invasion and whether metastases are present: non-muscle invasive bladder cancer (NMIBC); muscle invasive, non-metastatic bladder cancer; and metastatic bladder cancer.⁴ NMIBC constitutes 75% of cases at diagnosis, and it has a favorable prognosis of greater than 70% survival at 10 years.^4,5 Mainstay treatment for NMIBC includes resection of all visible disease, followed by intravesical chemotherapy.⁴ In higher-risk disease, cystectomy or intravesical Bacillus-Calmette Guerin (BCG) instillation are the primary treatments.⁴ Despite this, an estimated 31% to 78% of patients with NMIBC will experience a recurrence or new recurrence within 5 years.⁴ Additionally, with a median age at diagnosis of 73 years, factors that need to be accounted for when choosing next-line options include the patient’s performance status and comorbid medical conditions.^1,4 This poses significant challenges in managing patients with NMIBC who are unresponsive to first-line treatment options, particularly to patients with high-risk NMIBC who did not respond to BCG.

This article explores current treatment approaches for patients with BCG-unresponsive NMIBC, as well as their economic considerations.

Clinical Management of BCG-Unresponsive NMIBC

The depth of tumor invasion, tumor histology and grade are factors used to estimate the probability of recurrence and progression to muscle-invasive disease.⁴ Following the American Joint Committee on Cancer (AJCC) staging system, NMIBC is separated into three subtypes based on extent of disease following surgical resection: (1) non­invasive papillary tumors confined to the epithelial mucosa (stage Ta) (70%-75% incidence and 6% progression rate), (2) tumors invading the subepithelial connective tissue (Stage T1) (20%-25% incidence and 17% pro­gression rate) and (3) urothelial carcinoma in situ (stage CIS) (5%-10% incidence).^4,6

Papillary tumors tend to be friable and have a higher propensity for bleeding.⁴ They also tend to recur in the bladder at either the same stage as the initial tumor or at a more advanced stage.⁴

White light cystoscopy (WLC), an office-based procedure involving insertion of a camera via the urethra, is the current standard used to evaluate and stage bladder cancer. ^4,6 While WLC has a high sensitivity for detecting papillary lesions, its inability to differentiate non-papillary and flat lesions from inflammatory lesions, or detect small or multifocal lesions, may reduce the accuracy in tumor staging.⁴ Enhanced methods such as narrow-band imaging or blue light cystoscopy have offered improved sensitivity and specificity for identifying bladder tumors and may move toward being more frequently used modalities in the future.⁴ Following treatment for NMIBC, urine cytology and cystoscopy is recommended at three- to six-month intervals for the first two years and at longer intervals as appropriate thereafter.⁴

Bacillus-Calmette Guerin (BCG) is an intravesical therapy indicated for the treatment and prophylaxis of CIS of the bladder and for prophylaxis of stage Ta and/or T1 papillary tumors after transurethral resection.⁷ Meta-analyses have shown that adjuvant BCG followed by maintenance therapy is an appropriate standard-of-care first-line therapy following transurethral resection compared to combination therapy in intermediate- and high-risk patients.⁸ Additionally, BCG was the only therapy associated with a decreased risk of progression.⁶ Despite high initial response to BCG treatment, approximately half of patients will have recurrence within five years or will be considered BCG-unresponsive.⁹

The American Urological Association/Society of Urologic Oncology (AUA/SUO) guidelines recommend against additional BCG for patients who have documented recurrence of disease (high-grade NMIBC and/or CIS) within six months of two courses of induction BCG or after induction BCG plus maintenance.⁶ Following recurrence, literature supports radical cystectomy as next-line treatment for those who are fit for surgery and have persistent or recurrent high-risk urothelial cancer despite adequate BCG therapy.^6,10 The NCCN guidelines support this recommendation of cystectomy (preferred) while also introducing other options, including intravesical chemo­therapy, pembrolizumab, nadofaragene firadenovec, or nogapendekin alfa inbakicept + BCG for next-line treatment in patients who are BCG-unresponsive or BCG intolerant.⁴

The NCCN guidelines recommend cystectomy as the preferred next-line option in the BCG-unresponsive or BCG-intolerant setting; however, many patients prefer bladder-sparing interventions or are ineligible for surgery due to their comorbidities and/or poor performance status that increase the risk for complications.^4,5,11

Furthermore, radical cystectomy also poses substantial physical and emotional burden; a cross-sectional survey of individuals one to ten years after a bladder cancer diagnosis found that patients who had radical cystectomies (either alone or in combination with other modalities), also reported greater challenges related to body image, sexual intimacy, sexual enjoyment and male sexual problems.¹² In addition, more financial difficulties were found in younger patients undergoing radical cystectomy (mean global health score, 26 [95% CI, 19-33]) compared to those undergoing transurethral resection of a bladder tumor (global health score, 15 [95% CI, 9.1-22)].¹²

Alternative intravesical chemotherapy (i.e., gemcitabine/docetaxel) is another option for patients with persistent or recurrent high-grade NMIBC within 12 months of completion of adequate BCG therapy.⁵ In a retrospective multicenter analysis, 276 patients received at least six weekly doses of sequential gemcitabine and docetaxel.¹³ One-year recurrence free rate was 65% and two-year recurrence-free rate was 52%.¹³ Durability and long-term outcomes are presently unknown.

In addition to cystectomy or intravesical chemotherapy, the NCCN guidelines also recommend nadofaragene firadenovec (gene therapy) and pembrolizumab (immune checkpoint inhibitor) as next-line treatment options for BCG-unresponsive or BCG-intolerant NMIBC.⁴

Emerging Therapies for BCG-Unresponsive NMIBC: Clinical Evidence and Safety Profiles

Nadofaragene firadenovecis a nonreplicating adenoviral vector-­based gene therapy approved by the FDA for the treatment of high-risk BCG-unresponsive NMIBC with CIS, with or without papillary tumors.¹⁴ In the phase 3, open-label CS-003 trial (NCT02773849), patients with persistent CIS or high-grade Ta or T1 tumors following adequate BCG therapy received intravesical nadofaragene firadenovec (75 mL; 3 × 10¹¹ viral particles), and in the absence of high-grade recurrence, this was repeated at days 90, 180, and 270.¹⁵ Patients without high-grade recurrence at 12 months could continue receiving nadofaragene firadenovec every three months.¹⁵ At a median follow-up time of 19.7 months, 53.4% (55/103; 95% CI, 43.3-63.3) of patients in the CIS cohort, and 72.9% (35/48; 95% CI, 58.2-84.7) in the high-grade Ta or T1 cohort, had a complete response at three months.¹⁵ At 12 months, 24.3% (25/103; 95% CI, 16.4-33.7) of the CIS cohort, and 43.8% (21/48; 95% CI, 29.5-58.8) of the high-grade Ta or T1 cohort, remained high-grade recurrence free (HGRF).¹⁵ The most common treatment-related adverse events (≥10%) were grades 1-2 and included discharge around the catheter during instillation (25%), fatigue (20%), bladder spasm (16%: 15% grade 1-2, 1% grade 3), micturition urgency (15%: 14% grade 1-2, 1% grade 3-4), chills (12%), dysuria (11%), and pyrexia (10%).¹⁵

Long-term follow-up data showed that HGRF survival at five years was 4.8% (95% CI, 2.2-12.2) in the CIS cohort and 15% (95% CI, 6.1-27.8) in the high-grade Ta or T1 cohorts.¹⁶ The Kaplan-Meyer estimated probability of remaining HGRF for at least 57 months was 13% (95% CI, 6.9-21.5) in the CIS cohort and 33% (95% CI, 19.5-46.6) in the high-grade Ta or T1 cohort.¹⁶ Cystectomy-free survival at 60 months was 43% (95% CI, 35.2-53.7) in the CIS cohort and 59% (95% CI, 43.1-71.4) in the Ta/T1 cohort.¹⁶ Kaplan-Meyer estimated overall survival at 60 months was 80% (95% CI, 71.0-86.0).¹⁶

Pembrolizumabis an immune checkpoint inhibitor that binds to the PD-1 receptor found on T cells and blocks its interaction with PD-1 ligands (PD-L1 and PD-L2), signaling upregulation of PD-1–mediated T-cell proliferation and cytokine production.¹⁷ High PD-1 expression in BCG-relapsing tumors has been shown to be a predictive factor for subsequent recurrence after initial BCG therapy.¹⁸ In the open-label, single-arm, phase 2 trial KEYNOTE-057 (NCT02625961), two cohorts of BCG-unresponsive NMIBC patients who declined or were ineligible for radical cystectomy were studied: Cohort A (CIS ± papillary tumors) and Cohort B (high-grade Ta or any-grade T1 tumors without CIS).^19,20 Patients received pembrolizumab, 200 mg, intravenously every three weeks for up to 35 cycles or until recurrence, progression, unacceptable toxicity, or study withdrawal.²⁰

In Cohort A, 41% (39/96; 95% CI, 30.7-51.1) of patients achieved a complete response at three months, with a median duration of complete response of 16.2 months (95% CI, 6.7-36.2).¹⁹ At 12 months, 46% (18/39) of responders remained in complete response.¹⁹ Treatment-related adverse events occurred in 66% (67/101) of patients, of which 13% experienced grade 3-4 events.¹⁹ Common grade 1-2 events included diarrhea (11%), fatigue (11%) and pruritus (10%).¹⁹ Most common grade 3-4 events were arthralgia (2%) and hyponatremia (3%).¹⁹

In Cohort B, the 12-month disease-free survival was 43.5% (95% CI, 34.9-51.9) with a median disease-free survival of 7.7 months (95% CI, 5.5-13.6).²⁰ Treatment-­related adverse events occurred in 73% of patients; 14% of were grade 3-4 events, most commonly colitis (2%) and diarrhea (2%).²⁰ Ten (8%) patients required systemic corticosteroids for manage­ment of these adverse events, and no deaths were attributed to immune-mediated adverse events or infusion reactions.²⁰

Overall, both pembrolizumab and nadofaragene firadenovec demonstrate benefit as bladder-sparing options for patients with BCG­unresponsive NMIBC who are ineligible or decline radical cystectomy at the time of recurrence.⁴ Both studies, however, have several limitations. Both studies had a single-arm design; this prevents direct comparison with other agents/other treatment modalities to evaluate relative effectiveness.²¹ Differences in trial design between these studies further hinder cross-study comparisons and interpretation of relative treatment benefit.³

Economic Evaluation and Cost-Effectiveness Analysis of NMIBC Therapies

The absence of direct head-to-head trials among treatment options for BCG-unresponsive NMIBC presents significant challenges in eval­uating and comparing long-term cost-effectiveness.³ One study attempted to address this gap by modeling the incremental cost-effectiveness ratios (ICERs) of nadofaragene firadenovec, oportuzumab monatox and pembrolizumab against a hypothetical standardized comparator that had a 0% complete response at three months in both CIS ± Ta/T1 and high-grade Ta/T1 populations.³ In the CIS ± Ta/T1 group, base-case cost-effectiveness values in 2020 were $151,000 per quality-adjusted life year (QALY) gained for nadofaragene firadenovec, $382,000 per QALY gained for oportuzumab monatox, and $114,000 per QALY gained for pembrolizumab.³ For the high-grade Ta/T1 population, oportuzumab monatox base-case cost-effectiveness values were estimated at $93,000 per QALY gained for nadofaragene firadenovec, and $123,000 per QALY gained for oportuzumab monatox, with pembrolizumab not evaluated in this subgroup.³

Another tool used to evaluate cost-effectiveness is the health benefit price benchmark (HBPB), the suggested highest price a manu­facturer should charge based on the degree of overall health improvement the patient would receive from the treatment.²¹ The HBPB range for nadofaragene firadenovec ranges from $158,600 to $262,000 per year, while the HBPB range for oportuzumab monatox ranges from $92,800 to $162,100 per year.²¹ No HBPB was calculated for pembrolizumab due to its original indication not including NMIBC.³

Overall, these cost analysis tools are useful in linking appropriate drug pricing with clinical effectiveness, but they should be interpreted with caution. The use of a hypo­thetical comparator across multiple single-arm, nonrandomized studies limits the accuracy and generalizability of these models toward real-world settings. Thus, there is an urgent need for real-world evidence collection to support more informed value-based pricing strategies.

Clinical Implementation and Future Research Directions

To better support the integration of these therapies into the treatment pathway for patients with BCG-unresponsive NMIBC who are ineligible for or decline cystectomy, adding them to clinical guidelines and healthcare formularies is crucial. Recommendations to utilize these therapies should be specific to populations unresponsive to prior BCG treatment, and policies may consider documentation of previous trials of BCG as a prerequisite for approval to optimize the accessibility and applicability of these high-cost treatments.

Future studies should also prioritize the conduct of randomized trials and more applicable study designs to evaluate real-world effectiveness. Measurement of health-related quality of life, long-term clinical efficacy and real-world durability will increase our know­ledge of the long-term efficacy and ​feasibility of these therapies.

Additionally, patient advocacy organizations play a critical role in advancing treatment access and affordability. Their engagement helps promote transparency in pricing, urges timely access of care and encourages head-to-head comparative data to be investigated. Collaboration among stakeholders — clinicians, researchers, insurance companies and patients — helps to push the boundaries of current treatment landscapes and advance clinical research and treatment in an evidence-based manner.

Conclusion

Treatment of BCG-unresponsive NMIBC remains a complex challenge in a patient population that is typically older and may not be candidates for aggressive interventions, such as radical cystectomy, to prevent recurrence.^5,11 Emerging bladder-sparing options, including nadofaragene firadenovec and pembrolizumab, have shown early promise; however, more robust real-world evidence is still needed to confirm their long-term efficacy and safety. ^3,21 As the treatment landscape for NMIBC advances and we introduce new therapies, the integration of real-world, long-term clinical outcomes and economic data will be critical to guide both clinical practice and health policy decision-making.

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