PHARMACY FRIENDS

and Cohort A — treated patients with enfortumab vedotin-ejfv plus pembrolizumab, while Cohort K patients were randomized to either the combination or to enfortumab vedotin-ejfv alone.7 Participants were patients who had not received prior systemic therapy for locally advanced or metastatic disease and were ineligible for cisplatin-containing chemotherapy.7

Of 121 patients who received enfortumab vedotin-ejfv plus pembrolizumab, 68% had a confirmed objective response, including 12% that had complete responses.7 Median duration of response for the dose escalation cohort and Cohort A was 22 months and for Cohort K was not reached.7 Adverse reactions associated with treatment occurring in more than 20% of patients, including laboratory abnormalities, included increased glucose, aspartate aminotransferase, creatinine, alanine aminotransferase, lipase, and calcium; decreased hemoglobin, lymphocytes, sodium, albumin, phosphate, weight, appetite, potassium, neutrophils; peripheral neuropathy; fatigue; rash; diarrhea; pruritus; nausea; dysgeusia; urinary tract infection; constipation; peripheral edema; dry eye; dizziness; arthralgia; and dry skin.6

Enfortumab vedotin-ejfv was previously approved by the FDA in 2021 for adult patients with locally advanced or metastatic UC who had previously received a PD-1 or PD-L1 inhibitor and platinum containing chemotherapy or who are ineligible for cisplatin-containing chemotherapy and had previously received one or more prior lines of therapy.8

Nadofaragene firadenovec-vncg (ADSTILADRIN®)

In December 2022, the FDA approved nadofaragene firadenovecvncg (ADSTILADRIN®) for the treatment of adult patients with high-risk BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.9 Nadofaragene firadenovec-vncg is a non-replicating adenoviral vector-based gene therapy.9

Safety and effectiveness of the gene therapy was demonstrated in a multicenter clinical study that included 157 patients with high-risk BCG-unresponsive NMIBC; 98 of those patients had BCG-unresponsive CIS with or without papillary tumors and could be evaluated for response.10 Nadofaragene firadenovec-vncg was administered into the bladder via a urinary catheter once every three months for up to 12 months or until unacceptable toxicity or recurrent high-grade NMIBC.10

Of the patients using nadofaragene firadenovec, 51% achieved a complete response, defined as the disappearance of all signs of cancer as seen on cystoscopy, biopsied tissue, and urine.10 Median duration of response was 9.7 months, and 46% of responding patients remained in complete response for at least one year.10 Adverse reactions associated with treatment included bladder discharge, fatigue, bladder spasm, urinary urgency, hematuria, chills, fever, and painful urination.9 The drug is expected to launch later in 2023.

ICER Review

A 2022 Institute of Clinical and Economic Review (ICER) report assessed the cost-effectiveness of nadofaragene firadenovec and pembrolizumab in BCG-unresponsive NMIBC.11 The report concluded that, using a placeholder price, nadofaragene firadenovec was cost-effective in the non-CIS population, but not in the CIS population.11 ICER noted the health-benefit price benchmark for nadofaragene firadenovec is $158,600 to $262,000 per year. 11 Further, pembrolizumab, at the current list price, was not cost-effective in the CIS population.11 Ultimately, ICER noted that the cost per quality-adjusted life-year gained and threshold price estimates can be used in pricing and reimbursement negotiations.11

Management Strategies

Over the years, multiple immune checkpoint inhibitors (ICIs) have received approval as single agents or following chemotherapy in early and late-stage UC.12 Without definitive cost-effectiveness data, payers are concerned about the added spend for this therapy class.12 As ICIs tend to have high costs, payers may seek pricing discounts or other management strategies.12 Although UC accounts for only 4% of new cancer cases in the U.S. and the number of metastatic UC (mUC) cases is even smaller, higher cost treatments tend to be a concern for payers.12 The population of cisplatin-ineligible mUC patients only account for about half of the mUC cases and may require different treatment and management for improved outcomes; due to the small size of this subset of the UC population, these patients may not be a high priority in terms of payer management.12 However, as the long-term outcomes of ICIs and treatments for mUC continue to be examined, payers may continue to consider and evaluate appropriate access and management of this category.

A 2020 study of Medicare claims assessed the lifetime economic burden of UC.12 Results showed that stage III UC had the highest cost per patient, driven by intensive care with multi-modal management, including cystectomy and multi-drug chemotherapy.13 Stage IV UC had the lowest cost per patient, which could be due to the less intense therapy.13 However, across all stages, hospitalizations contributed the greatest spend to the lifetime cost.13 Access to and utilization of treatments that may decrease hospitalizations — in frequency and duration — may play a role in lowering costs.13

With the introduction of the first gene therapy for bladder cancer and its associated high costs, management tools will prove critical in ensuring appropriate access and managing costs. Particularly, criteria around the specific patient population and indications will be key. In a 2022 survey of commercial payers, commercial payers with 79% of beneficiaries said they expected to manage nadofaragene firadenovec to label soon after launch.14 Factors noted by respondents were the gene therapy’s “potential to be better than standard of care” and the high unmet need in the population with the approved indication.14 Management strategies of interest to payers for this therapy were step therapy requirements or quantity limits.14 Prior authorization and other utilization management strategies may be appropriate measures for payers to ensure patients with appropriate diagnoses who are ineligible for other care regimens are able to access proper treatment.

References

1. “Bladder Cancer: Statistics,” Cancer.Net, Mar. 2023, https://www. cancer.net/cancer-types/bladder-cancer/statistics.

2. Markman, Maurie. “Bladder cancer types.” Cancer Treatment Centers of America, May 18, 2022, https://www.cancercenter.com/cancertypes/bladder-cancer/types.

3. “Key Statistics for Bladder Cancer,” American Cancer Society, 13 Jan. 2023, https://www.cancer.org/cancer/types/bladder-cancer/about/ key-statistics.html.

4. “Bladder Cancer: Types of Treatment.” American Society of Clinical Oncology, Dec. 2021, https://www.cancer.net/cancer-types/bladdercancer/types-treatment#gene-therapy.

5. “FDA approves first targeted therapy for metastatic bladder cancer.” U.S. Food & Drug Administration, 12 Apr. 2019, https://fda.gov/newsevents/press-announcements/fda-approves-first-targeted-therapymetastatic-bladder-cancer.

6. “FDA D.I.S.C.O. Burst Edition: FDA approval of Padcev (enfortumab vedotin-ejfv) with Keytruda (pembrolizumab) for locally advanced or metastatic urothelial carcinoma,” U.S. Food & Drug Administration, 3 May 2023, https://www.fda.gov/drugs/resources-informationapproved-drugs/fda-disco-burst-edition-fda-approval-padcevenfortumab-vedotin-ejfv-keytruda-pembrolizumab-locally.

7. Holmes, Christopher J., et al. “Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer,” Journal of Clinical Oncology, 1 Jan. 2023, https://ascopubs. org/doi/10.1200/JCO.22.01643.

8. “FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer.” U.S. Food & Drug Administration, 9 Jul. 2021, https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-grants-regular-approval-enfortumabvedotin-ejfv-locally-advanced-or-metastatic-urothelial-cancer.

9. “FDA Approves First Gene Therapy for the Treatment of HighRisk, Non-Muscle Invasive Bladder Cancer,” U.S. Food & Drug Administration, 16 Dec. 2022, https://www.fda.gov/news-events/ press-announcements/fda-approves-first-gene-therapy-treatmenthigh-risk-non-muscle-invasive-bladder-cancer.

10. Boorjian, Stephen A., et al. “Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.” The Lancet Oncology, Jan. 2021, https://pubmed.ncbi.nlm.nih. gov/33253641/.

11. Joshi, Mrinmayee, et al. “Cost-Effectiveness of Nadofaragene Firadenovec and Pembrolizumab in Bacillus Calmette-Guérin Immunotherapy Unresponsive Non-Muscle Invasive Bladder Cancer.” ISPOR, 15 Dec. 2022, https://www.valueinhealthjournal. com/article/S1098-3015(22)04779-9/fulltext.

12. Walia, AS, et al. “Cost-Effectiveness of Immune Checkpoint Inhibitors in Urothelial Carcinoma-A Review.” Cancers, 24 Dec. 2021, https://pubmed.ncbi.nlm.nih.gov/35008237/.

13. Aly, A, et al. “The Real-World Lifetime Economic Burden of Urothelial Carcinoma by Stage at Diagnosis.” Journal of Clinical Pathways, May 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433100/ pdf/nihms-1607319.pdf.

14. “Oncologists Express Interest in New Bladder Cancer Gene Therapy Adstiladrin.” AISHealth, 16 Feb. 2023, https://www.mmitnetwork. com/aishealth/spotlight-on-market-access/oncologists-expressinterest-in-new-bladder-cancer-gene-therapy-adstiladrin/.