Enfortumab Vedotin-ejfv (Padcev)

Number: 0967

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses enfortumab vedotin-ejfv (Padcev) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of enfortumab vedotin-ejfv (Padcev) is required of all Aetna participating providers and members in applicable plan designs. For precertification of Padcev, call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

1. Criteria for Initial Approval

   Aetna considers enfortumab vedotin-ejfv (Padcev) medically necessary for any of the following indications when criteria are met:

   Urothelial Carcinoma

   1. For treatment of urothelial carcinoma as a single agent when used as subsequent therapy following platinum-containing chemotherapy and prior treatment with a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor or when used as subsequent therapy for members who are ineligible for cisplatin-containing chemotherapy for any of the following subtypes:

      1. Urothelial carcinoma of the bladder in any of the following settings:

         1. Stage II disease if tumor is present following reassessment of tumor status 2-3 months after primary treatment with concurrent bladder preserving chemoradiotherapy and maximal transurethral resection of bladder tumor (TURBT); or
         2. Locally advanced or metastatic disease; or
         3. Metastatic or local recurrence post-cystectomy; or
         4. Muscle invasive local recurrence or persistent disease in a preserved bladder; or
      2. Primary carcinoma of the urethra with locally advanced, recurrent or metastatic disease;
      3. Urothelial carcinoma of the upper genitourinary tract or urothelial carcinoma of the prostate with locally advanced or metastatic disease; or

   2. For treatment of urothelial carcinoma in combination with pembrolizumab for members who are ineligible for cisplatin-containing chemotherapy for any of the following subtypes:

      1. Urothelial carcinoma of the bladder in any of the following settings:

         1. Stage II disease if tumor is present following reassessment of tumor status 2-3 months after primary treatment with concurrent bladder preserving chemoradiotherapy and maximal transurethral resection of bladder tumor (TURBT); or
         2. Locally advanced or metastatic disease; or
         3. Metastatic or local recurrence post-cystectomy; or
         4. Muscle invasive local recurrence or persistent disease in a preserved bladder; or
      2. Primary carcinoma of the urethra with locally advanced, recurrent or metastatic disease; or
      3. Urothelial carcinoma of the upper genitourinary tract or urothelial carcinoma of the prostate with locally advanced or metastatic disease.

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of enfortumab vedotin-ejfv (Padcev) therapy medically necessary in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Padcev for injection is supplied as 20 mg and 30 mg of enfortumab vedotin-ejfv as a lyophilized powder in a single-dose vial for reconstitution. Padcev is for intravenous infusion only and is not to be administered as an intravenous push or bolus. Padcev is not to be mixed with, or administered as an infusion with, other medicinal products. 

The recommended dose of Padcev is 1.25 mg/kg (up to a maximum dose of 125 mg) given as an intravenous infusion over 30 minutes on days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.

When given in combination with pembrolizumab, the recommended dose of Padcev is 1.25 mg/kg (up to a maximum of 125 mg for patients greater than or equal to 100 kg) given as an intravenous infusion over 30 minutes on days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity. Refer to the pembrolizumab prescribing information for the recommended dosing information of pembrolizumab.

Source: Astellas Pharma, 2023

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
52204	Cystourethroscopy, with biopsy(s)
52214	Cystourethroscopy, with fulguration (including cryosurgery or laser surgery) of trigone, bladder neck, prostatic fossa, urethra, or periurethral glands
52224	Cystourethroscopy, with fulguration (including cryosurgery or laser surgery) or treatment of MINOR (less than 0.5 cm) lesion(s) with or without biopsy
52234	Cystourethroscopy, with fulguration (including cryosurgery or laser surgery) and/or resection of; SMALL bladder tumor(s) (0.5 up to 2.0 cm)
52235	Cystourethroscopy, with fulguration (including cryosurgery or laser surgery) and/or resection of; MEDIUM bladder tumor(s) (2.0 to 5.0 cm)
52240	Cystourethroscopy, with fulguration (including cryosurgery or laser surgery) and/or resection of; LARGE bladder tumor(s)
77399 - 77417	Radiation Treatment Delivery
77427-77499	Radiation Treatment Management
96413 – 96416	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
J9177	Injection, enfortumab vedotin-ejfv, 0.25 mg
Other HCPCS codes related to the CPB:
G6003 - G6014	Radiation treatment delivery
G6015 - G6016	IMRT treatment delivery
J9022	Injection, atezolizumab, 10 mg
J9023	Injection, avelumab, 10 mg
J9045	Injection, carboplatin, 50 mg
J9060	Injection, cisplatin, powder or solution, 10 mg
J9173	Injection, durvalumab, 10 mg
J9263	Injection, oxaliplatin, 0.5 mg
J9271	Injection, pembrolizumab, 1 mg
J9299	Injection, nivolumab, 1 mg
ICD-10 codes covered if selection criteria are met:
C64.1 - C64.9	Malignant neoplasm of kidney
C65.1 - C65.9	Malignant neoplasm of renal pelvis
C66.1 - C66.9	Malignant neoplasm of right ureter
C67.0 - C67.9	Malignant neoplasm of bladder
C68.0 - C68.9	Malignant neoplasm of urethra, paraurethral glands, overlapping sites of urinary organs, and urinary system NOS

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Padcev (enfortumab vedotin-ejfv), as a single agent, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, and a platinum-containing chemotherapy or are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.
• Padcev, in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who are not eligible for cisplatin-containing chemotherapy. 

Compendial Uses

• Urothelial carcinoma
  
  
  • Bladder cancer
  • Primary carcinoma of the urethra
  • Upper genitourinary (GU) tract tumors
  • Urothelial carcinoma of the prostate

Enfortumab vedotin-ejfv is available as Padcev (Astellas Pharma US, Inc). Enfortumab vedotin-ejfv is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody. The small molecule, MMAE, is a microtubule-disrupting agent, attached to the antibody via a protease-cleavable linker. Nonclinical data suggest that the anticancer activity of enfortumab vedotin-ejfv is due to the binding of the ADC to Nectin-4-expressing cells, followed by internalization of the ADC-Nectin-4 complex, and the release of MMAE via proteolytic cleavage. Release of MMAE disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic cell death (Astellas Pharma, 2023).

Padcev carries a black box warning for serious skin reactions. Padcev can cause severe and fatal cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) in which, if suspected, healthcare professional should immediately withhold Padcev and consider referral for specialized care. Padcev should be permanently discontinued in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions. Other warnings and precautions include risk of hyperglycemia in which diabetic ketoacidosis may occur in patients with and without preexisting diabetes mellitus, pneumonitis which could be life-threatening or fatal, peripheral neuropathy, ocular disorders including vision changes, infusion site extravasation, and embryo-fetal toxicity. The most common adverse reactions, including laboratory abnormalities, (20% or more) included rash, aspartate aminotransferase increased, glucose increased, creatinine increased, fatigue, peripheral neuropathy, lymphocytes decreased, alopecia, decreased appetite, hemoglobin decreased, diarrhea, sodium decreased, nausea, pruritus, phosphate decreased, dysgeusia, alanine aminotransferase increased, anemia, albumin decreased, neutrophils decreased, urate increased, lipase increased, platelets decreased, weight decreased and dry skin (Astellas Pharma, 2023).

Urothelial Cancer

Urothelial cancer, formerly called transitional cell, accounts for more than 90% of all bladder cancers. Other types of urothelial cancers can occur in the renal pelvis, ureter, or urethra. The gold standard for the initial diagnosis of bladder cancer is cystoscopy. When cystoscopy is combined with urine cytology, it allows for detecting lesions that might be missed at cystoscopy or lesions of the upper urinary tract (i.e., ureter, renal pelvis). Transurethral resection of bladder tumor (TURBT) combined with pelvic examination under anesthesia is the initial step in the staging evaluation. Imaging of the upper urinary tract by computed tomography (CT) or magnetic resonance imaging (MRI) with intravenous contrast, or retrograde ureter pyelography performed at the time of TURBT is indicated to rule out a second primary lesion, even for patients with an established diagnosis of urothelial carcinoma of the bladder (Lemer, 2019). Platinum-containing chemotherapy, PD-1 and PD-L1 inhibitors are standard treatments for patients with bladder cancer.

On December 18, 2019, the FDA granted accelerated approval to Padcev (enfortumab vedotin-ejfv) for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received platinum-containing chemotherapy and have also received immunotherapy with a programmed death receptor-1 (PD-1), such as pembrolizumab (Keytruda), nivolumab (Opdivo), or cemiplimab (Libtayo), or with a programmed death-ligand 1 (PD-L1) inhibitor, such as atezolizumab (Tecentriq), avelumab (Bavencio), or durvalumab (Imfinzi) (Prescribing Information, 2019). Padcev is an antibody-drug conjugate (ADC) that targets Nectin-4, which is highly expressed in urothelial cancers. This indication is approved under accelerated approval based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Padcev was approved based on the results of the EV-201 (NCT03219333) clinical trial, a global, phase II, single-arm study of enfortumab vedotin 1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle) in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and anti–PD-1/L1 therapy (Rosenberg 2019). Platinum treatment was defined as platinum-containing chemotherapy in the neoadjuvant and/or adjuvant setting with recurrent or progressive disease within 12 months of completion, or platinum in the locally advanced or metastatic setting. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review. Key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability. Patients were excluded if they had active CNS metastases, ongoing sensory or motor neuropathy ≥ Grade 2, or uncontrolled diabetes defined as hemoglobin A1C (HbA1c) ≥ 8 % or HbA1c ≥ 7 % with associated diabetes symptoms. There were no limits for prior lines of therapy, including taxanes.

Enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma. Patients received enfortumab vedotin 1.25 mg/kg intravenously over approximately 30 minutes on days 1, 8, and 15 of each 28-day cycle. Weight-based dosing was calculated using the patient’s actual body weight, with a maximum dose of 125 mg. Dose modifications were permitted to manage treatment-related hematologic and nonhematologic toxicities and are outlined in the protocol. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or investigator decision. Median follow-up was 10.2 months (range, 0.5 to 16.5 months). Efficacy of enfortumab vedotin was assessed by appropriate imaging (computed tomography or magnetic resonance imaging) every 8 weeks (± 1 week), then every 12 weeks (± 1 week) after 1 year. Time points for response assessments were calculated from cycle 1, day 1. Complete or partial responses, as defined by RECIST version 1.1,19 were confirmed with repeat scans 4 to 5 weeks after initial response and assessed by blinded independent central review (BICR) and investigator. Safety assessments included physical and eye examinations, routine chemistry, and hematologic laboratory tests. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. Per protocol, certain adverse events observed in the EV-201 study were prespecified for assessment and analysis as composite terms and were observed until resolved, returned to baseline, or became chronic and adequately characterized. These events are summarized here in composite terms of peripheral neuropathy, rash, infusion-related reactions, and hyperglycemia.

Confirmed objective response rate was 44 % (95 % CI: 35.1 % to 53.2 %), including 12 % complete responses. Similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti-PD-1/L1 therapy. Median duration of response was 7.6 months (range of 0.95 to 11.30+ months).  The most common treatment-related adverse events were fatigue (50 %), any peripheral neuropathy (50 %), alopecia (49 %), any rash (48 %), decreased appetite (44 %), and dysgeusia (40 %). No single treatment-related adverse events grade 3 or greater occurred in 10 % or more of patients. The authors concluded that enfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti-PD-1/L1 therapies.

EV-301 is an ongoing phase-III clinical trial that compares enfortumab vedotin monotherapy with single-agent chemotherapy in patients with prior platinum and anti-PD-1/L1 therapy to establish the survival benefit of enfortumab vedotin in this patient population (EV-301; ClinicalTrials.gov identifier: NCT03474107). The EV-201 study is also actively enrolling a second cohort (Cohort 2) of patients who have received prior anti–PD-1/L1 therapy and are cisplatin ineligible without prior platinum treatment to determine if a similar benefit will be observed. In addition, enfortumab vedotin is being evaluated in a broader population of patients with urothelial carcinoma, including in the first-line setting where it is being studied in combination with anti–PD-1 and/or platinum-based therapies (EV-103; ClinicalTrials.gov identifier: NCT03288545). In this study, enfortumab vedotin is administered on days 1 and 8 of a 21-day cycle to coincide with the administration of the other agents. Nectin-4 is also expressed in other tumor types, and enfortumab vedotin may be explored in other solid tumors.

In July 2021, the FDA granted regular approval for Padcev for patients with locally advanced or metastatic urothelial cancer, and expanded the indication to include those who are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy. The regular approval was based on the overall survival results from the confirmatory EV-301 trial. At the time of pre-specified interim analysis, patients who received Padcev (n = 301) lived a median of 3.9 months longer than those who received chemotherapy (n = 307). Median overall survival was 12.9 versus 9.0 months, respectively (p = 0.001). The expanded indication is based on results of the Cohort 2 of the EV-201 trial (a single-arm, multi-cohort, multi-center, pivotal phase 2 clinical trial) which evaluated Padcev in patients (n = 89) with locally advanced or metastatic urothelial cancer who had been previously treated with a PD-1/L1 inhibitor, had not received a platinum-containing chemotherapy, and were ineligible for cisplatin. Padcev was given intravenously at a dose of 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. The primary endpoint was confirmed objective response rate per RECIST version 1.1 assessed by blinded independent central review. Efficacy and safety were analysed in all patients who received at least 1 dose of enfortumab vedotin. After a median follow-up of 16 months, 51 percent of patients who received Padcev had an objective response [95 % CI: 39.8 to 61.3], with a median duration of response of 13.8 months [95 % CI: 6.4 to not reached]. EV-201 is an ongoing study and the primary analysis is complete (Astellas Pharma, 2021; Yu et al, 2021).

On April 3, 2023, the U.S. Food and Drug Administration (FDA) granted accelerated approval to enfortumab vedotin-ejfv (Padcev) with pembrolizumab (Keytruda) for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. This FDA approval was based on efficacy results from the EV-103/KEYNOTE-869 study (FDA, 2023).

In the EV-103/KEYNOTE-869 study, an open-label, multi-cohort (dose escalation cohort, Cohort A, Cohort K) study, investigators evaluated the efficacy of Padcev in combination with pembrolizumab in  in patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-containing chemotherapy and received no prior systemic therapy for locally advanced or metastatic disease. A total of 121 patients received Padcev plus pembrolizumab. Patients in the dose escalation cohort (n=5), Cohort A (n=40), Cohort K (n=76) received Padcev 1.25 mg/kg as an IV infusion over 30 minutes on Days 1 and 8 of a 21-day cycle followed by pembrolizumab 200 mg as an IV infusion on Day 1 of a 21-day cycle approximately 30 minutes after Padcev. Treatment continued until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR). The confirmed ORR in 121 patients was 68% (95% CI: 59, 76), including 12% with complete responses. The median DoR for the dose escalation cohort + Cohort A was 22 months (range: 1+ to 46+) and for Cohort K was not reached (range: 1 to 24+) (Astellas Pharma, 2023; FDA, 2023).

Other Solid Tumors (e.g., Kidney Cancer, Sebaceous and Sweat Gland Carcinoma)

Parikh and Powles (2021) stated that immune checkpoint inhibitors have an established role in the treatment of newly diagnosed metastatic kidney cancer.  Treatment regimens combining nivolumab plus ipilimumab, pembrolizumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib have demonstrated superior overall survival (OS) compared with sunitinib in randomized studies; response rates varied from 42 % to 71.1 % with these combinations.  Atezolizumab and pembrolizumab have been approved for the treatment of cisplatin-ineligible patients with metastatic bladder cancer.  These and other checkpoint inhibitors have been examined in metastatic bladder cancer and are routinely used after progression on platinum-based chemotherapy.  Durable responses have been reported in bladder and kidney cancer.  Although some patients may experience immune-related adverse events (AEs) requiring treatment discontinuation, a portion of these patients will continue to experience a response off-therapy.  At the time of progression, patients with metastatic kidney cancer may be treated with anti-angiogenesis agents, and there are data suggesting that they may also be treated with a re-challenge of immunotherapy.  In patients with metastatic bladder cancer who have progression following immune checkpoint inhibition, there are considerable data supporting the use of enfortumab vedotin.  Ongoing studies are investigating novel combinations of immune checkpoint inhibitors with other agents; therefore, the treatment landscape of metastatic bladder and kidney cancer is expected to continue to evolve rapidly.

Ito et al (2022) noted that sebaceous carcinoma and sweat gland carcinoma (malignant tumors with apocrine and eccrine differentiation) are rare malignant adnexal tumors that differentiate toward sebaceous glands and eccrine and apocrine glands, respectively.  Because of the rarity of these malignancies, standard treatments for advanced disease have yet to be established.  The outcomes of patients with systemic metastasis remain poor, highlighting the need for novel treatment strategies.  Nectin-4 and its antibody-drug conjugate, enfortumab vedotin, have attracted attention as potential treatments for solid tumors.  These researchers examined the potential use of Nectin-4-targeted therapy for patients with sebaceous carcinoma and sweat gland carcinoma.  They immunohistochemically investigated Nectin-4 expression in 14 sebaceous carcinoma samples and 18 sweat gland carcinoma samples; and examined if Nectin-4-targeted therapy could be applied to these cancers.  These researchers found strong and frequent expression of Nectin-4 in both cancers.  All tumors exhibited positive staining at least in a part of the lesion, and the mean H-score, a semi-quantitative score ranging from 0 to 300, was 259.4 for sebaceous carcinoma and 253.1 for sweat gland carcinoma.  The authors concluded that these findings suggested that both sebaceous carcinoma and sweat gland carcinoma could be potentially treated with Nectin-4-targeted antibody-drug conjugates, such as enfortumab vedotin.

Bouleftour et al (2022) stated that Nectin-4 is over-expressed in multiple human malignancies.  Such aberrant expression is correlated with cancer progression and poor prognostic.  Nectin-4 has emerged as a potential biomarker and promising targeted therapy.  These investigators examined the available evidence on the Nectin-4 relevance in pre-clinical tumor models and summarized its clinical relevance regarding cancer.  They carried out a systematic review of published articles by searching in PubMed (Medline) from the database inception to May 2021, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.  Pre-clinical models unanimously demonstrated membrane and cytoplasmic location of the Nectin-4.  In addition, Nectin-4 was over-expressed whatever the location of the solid tumors.  Interestingly, a heterogeneity of Nectin-4 expression has been highlighted in bladder urothelial carcinoma.  High serum Nectin-4 level was correlated with treatment efficiency and disease progression.  Finally, generated anti-drug-conjugated targeting Nectin-4 induced cell death in multiple tumor cell lines.  The authors concluded that Nectin-4 emerges as a promising target for anti-cancer drugs development because of its central role in tumorigenesis, and lymphangiogenesis.  They stated that enfortumab vedotin targeting Nectin-4 demonstrated encouraging results and should be extended to other types of solid tumors.

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References