Enfortumab vedotin-ejfv (Padcev)

Number: 0967

Policy

Note: REQUIRES PRECERTIFICATION

Precertification of Padcev is required of all Aetna participating providers and members in applicable plan designs. For precertification of Padcev, call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (866) 267-3277.

Urothelial Carcinoma

1. Bladder Cancer - Aetna considers enfortumab vedotin-ejfv (Padcev) medically necessary for the treatment of bladder cancer 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 for any of the following:

   1. Locally advanced or metastatic disease; or
   2. Metastatic or local recurrence post-cystectomy; or
   3. Muscle invasive local recurrence or persistent disease in a preserved bladder.
      

2. Primary Carcinoma of the Urethra -  Aetna considers enfortumab vedotin-ejfv (Padcev) medically necessary for the treatment of locally advanced, recurrent, or metastatic primary carcinoma of the urethra 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. 

3. Upper Genitourinary Tract Tumors or Urothelial Carcinoma of the Prostate - Aetna considers enfortumab vedotin-ejfv (Padcev) medically necessary for the treatment of locally advanced or metastatic upper genitourinary tract tumors or urothelial carcinoma of the prostate 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

Aetna considers continued treatment with enfortumab vedotin-ejfv (Padcev) medically necessary in members requesting reauthorization for the treatment of locally advanced or metastatic urothelial cancer when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Aetna considers enfortumab vedotin-ejfv (Padcev) experimental and investigational for all other indications because its effectiveness for other indications has not been established.

Dosing Recommendations

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.

Avoid use in patients with moderate or severe hepatic impairment. For intravenous infusion only. Do not administer as an intravenous push or bolus. Do not mix with, or administer as an infusion with, other medicinal products.

Source: Astellas Pharma, 2019

Background

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

Padcev (enfortumab vedotin-ejfv) 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.

Compendial Uses

Urothelial carcinoma

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

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 U.S. Food and Drug Administration 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, 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 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.

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 "+" :
HCPCS codes covered if selection criteria are met:
J9177	Injection, enfortumab vedotin-ejfv, 0.25 mg
Other HCPCS codes related to the CPB:
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

The above policy is based on the following references: