Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Nadofaragene firadenovec-vncg (e.g., Adstiladrin)

Description:

Nadofaragene firadenovec-vncg is a non-replicating adenoviral vector-based gene therapy indicated for the treatment of adult individuals with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors. Intravesical instillation of Nadofaragene firadenovec-vncg results in cell transduction and transient local expression of the IFNα2b protein that is anticipated to have anti-tumor effects.

Regulatory Status

On December 16, 2022, the Food and Drug Administration approved Nadofaragene firadenovec-vncg for the treatment of adult individuals with high-risk Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle invasive bladder cancer (NMICB) with carcinoma in situ (CIS) with or without papillary tumors.

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

Prior Approval is required for nadofaragene firadenovec-vncg  (e.g., Adstiladrin).

The Step Therapy Medication Act is applicable to fully insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.

Effective May 2024

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

INITIAL APPROVAL STANDARD REVIEW for up to 6 months:

Nadofaragene firadenovec-vncg meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:

1. Individual is 18 years of age and older (FDA, 2022); AND

2. Individual has a diagnosis of high-risk non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors (FDA, 2022; NCCN 2A); AND

3. Will be used as a single-agent; AND

4. Individual is unresponsive to Bacillus Calmette-Guérin (BCG) therapy, defined as (Boorjian, 2019):

a. Having received at least 2 previous courses of BCG within a 12-month period defined as:

i. At least five of the six induction doses and two of the three maintenance treatments of BCG; OR

ii. At least two of the six instillations of a second induction course in which maintenance BCG is not given; OR

b. Recurrences of high-grade Ta or T1 non-muscle-invasive bladder cancer within 6 months of disease-free state after BCG; OR

c. Recurrence of carcinoma in situ within 12 months of disease-free state after BCG; OR

d. Persistent high-grade Ta or carcinoma in situ or progression to T1 disease after BCG; AND

5. Will be used in one of the following:

a. Initial management after BCG failure (NCCN 2A); OR

b. Cytology-positive, imaging, and cystoscopy-negative, bladder biopsy-positive recurrent or persistent disease (NCCN 2A); AND

6. Individual is ineligible for or have elected not to undergo cystectomy (NCCN Bladder Cancer Guidelines); AND

7. Individual is not imunosuppressed; AND

8. Individual has an *Eastern Cooperative Oncology Group (ECOG) status of 0-2 (Boorjian, 2019); AND

9. Must be dosed in accordance with the FDA label.

CONTINUED APPROVAL for up to 6 months:

1. Individual has not experienced any disease progression during nadofaragene firadenovec-vncg treatment (FDA); AND 

2. Individual has not experienced any unacceptable toxicities from the drug (FDA); AND

3. Individual will be using nadofaragene firadenovec-vncg as a single agent (Boorjian, 2019);AND 

4. Individual has an ECOG performance status of 0-2* (Boorjian, 2019); AND

5. Must be dosed in accordance with the FDA label.  

*ECOG Performance Status Scale

0 Fully active, able to carry on all pre-disease performance without restriction.
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work.
2 Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours.
3 Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours.
4 Completely disable; cannot carry on any selfcare; totally confine to bed or chair.
5 Dead

The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).

Dosing and Administration

Dosing per FDA Guidelines

The recommended dose for Nadofaragene firadenovec-vncg is 75 mL at a concentration of 300 billion viral particles (vp) /mL, instilled once every 3 months.

Allow Nadofaragene firadenovec-vncg to be left in the bladder for 1 hour following instillation.

Nadofaragene firadenovec-vncg is available in single-use vials as a suspension for intravesical instillation.

Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Nadofaragene firadenovec-vncg for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in improving health outcomes.

For members with contracts without primary coverage criteria, Nadofaragene firadenovec-vncg, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective May 24, 2023 to April 2024

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

INITIAL APPROVAL STANDARD REVIEW for up to 6 months:

Individual is 18 years of age and older (FDA); AND
Individual has a diagnosis of high-risk non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors (NCCN 2A); AND
Will be used as a single-agent; AND
Individual is unresponsive to Bacillus Calmette-Guérin (BCG) therapy, defined as (Boorjian, 2019):

a. Having received at least 2 previous courses of BCG within a 12-month period defined as:

i. At least five of the six induction doses and two of the three maintenance treatments of BCG; OR

ii. At least two of the six instillations of a second induction course in which maintenance BCG is not given; OR

b. Recurrences of high-grade Ta or T1 non-muscle-invasive bladder cancer within 6 months of disease-free state after BCG; OR

c. Recurrence of carcinoma in situ within 12 months of disease-free state after BCG; OR

d. Persistent high-grade Ta or carcinoma in situ or progression to T1 disease after BCG; AND

5. Will be used in one of the following:

a. Initial management after BCG failure (NCCN 2A); OR

b. Cytology-positive, imaging, and cystoscopy-negative, bladder biopsy-positive recurrent or persistent disease (NCCN 2A); AND

6. Individual is ineligible for or have elected not to undergo cystectomy (NCCN Bladder Cancer Guidelines); AND

7. Individual has an *Eastern Cooperative Oncology Group (ECOG) status of 0-2 (Boorjian, 2019); AND

8. Must be dosed in accordance with the FDA label.

CONTINUED APPROVAL for up to 6 months:

Individual has not experienced any disease progression during nadofaragene firadenovec-vncg treatment (FDA); AND 
Individual has not experienced any unacceptable toxicities from the drug (FDA); AND
Individual will be using nadofaragene firadenovec-vncg as a single agent (Boorjian, 2019);AND 
Individual has an ECOG performance status of 0-2* (Boorjian, 2019); AND
Must be dosed in accordance with the FDA label.

*ECOG Performance Status Scale

0 Fully active, able to carry on all pre-disease performance without restriction.
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work.
2 Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours.
3 Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours.
4 Completely disable; cannot carry on any selfcare; totally confine to bed or chair.
5 Dead

Dosing and Administration

Dosing per FDA Guidelines

The recommended dose for Nadofaragene firadenovec-vncg is 75 mL at a concentration of 300 billion viral particles (vp) /mL, instilled once every 3 months.

Allow Nadofaragene firadenovec-vncg to be left in the bladder for 1 hour following instillation.

Nadofaragene firadenovec-vncg is available in single-use vials as a suspension for intravesical instillation.

Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Nadofaragene firadenovec-vncg for any indication or circumstance not described above including immunosuppressed individuals, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in improving health outcomes.

For members with contracts without primary coverage criteria, Nadofaragene firadenovec-vncg, for any indication or circumstance not described above including immunosuppressed individuals, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer.

In a phase 3, multicenter, open-label, repeat-dose study done in 33 centers (hospitals and clinics) in the USA, patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less were recruited. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumor). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849.

Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumor) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths.

Intravesical nadofaragene firadenovec was efficacious, with a favorable benefit: risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. (Boorjian SA, Alemozaffar M, Konety BR, et.al., 2021)

Many patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd-IFNα/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study ( ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd-IFNα/Syn3 (randomly assigned 1:1 to 1 × 1011 viral particles (vp)/mL or 3 × 1011 vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd-IFNα/Syn3 (1 × 1011 vp/mL, n = 21; 3 × 1011 vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd-IFNα/Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%). Conclusion rAd-IFNα/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy. (Shore ND, Boorjian SA, Canter DJ, et.al., 2019)

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through May 2024. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

References:

Boorjian SA, Alemozaffar M, Konety BR, et.al.(2021) 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 Jan;22(1):107-117. doi: 10.1016/S1470-2045(20)30540-4. Epub 2020 Nov 27. PMID: 33253641; PMCID: PMC7988888.

Nadofaragene firadenovec-vncg [package insert]. Kupio, Finland: Ferring Pharmaceuticals; 2022

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Bladder Cancer (Version 2.2022). Available at http://www.nccn.org. ©National Comprehensive Cancer Network, 2022 Access May 10, 2023

Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP.(1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec;5(6):649-655. PMID: 7165009.

Shore ND, Boorjian SA, Canter DJ, et.al.(2017) Intravesical rAd-IFNa/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study. J Clin Oncol. 2017 Oct 20;35(30):3410-3416. doi: 10.1200/JCO.2017.72.3064. Epub 2017 Aug 23. Erratum in: J Clin Oncol. 2019 Aug 20;37(24):2187. PMID: 28834453; PMCID: PMC5648171.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2025 American Medical Association.