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This medical policy (medical coverage guideline) is Copyright 2017, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2017 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association. The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

09-J2000-06

Original Effective Date: 12/15/13

Reviewed: 08/10/16

Revised:09/15/16

Subject: Afatinib (Gilotrif™) Tablets

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Dosage/ Administration Position Statement Billing/Coding Reimbursement Program Exceptions Definitions
           
Related Guidelines Other References Updates  
           

DESCRIPTION:

Approximately 200,000 new cases of lung cancer are predicted to be diagnosed in the United States in 2013 and non-small cell lung cancer (NSCLC) will comprise approximately 85% of these cases. Despite the multiple subtypes of NSCLC, first-line treatment for advanced disease has historically included platinum-based doublet chemotherapy – it is only recently with the discovery of molecular targets and targeted therapy that new treatment options have started to emerge. One molecular target, epidermal growth factor (EGFR), is detectable in 80% of NSCLC cases. Two common mutations in EGFR, Del19 (deletion mutation in exon 19) and L858R (substitution of arginine for leucine at codon position 858) in exon 21, are considered activating mutations that promote malignant cell growth, proliferation, and migration. There are few treatment options for advanced, EGFR-mutation positive NSCLC and only erlotinib and afatinib are available in the United States.

Afatinib (Gilotrif™) was approved by the U.S. Food and Drug Administration (FDA) on July 12, 2013 for the first-line treatment of metastatic NSCLC in individuals whose tumors have an EGFR mutation of either an exon 19 deletion or an exon 21 substitution as detected by an FDA-approved test. Prior to FDA approval, afatinib was designated as an orphan drug for this same indication. Afatinib binds to the kinase domains of EGFR, HER2, and HER4 and irreversibly inhibits tyrosine kinase auto-phosphorylation, resulting in downregulation of ErbB signaling and inhibition of tumor cell proliferation.

The safety and efficacy of afatinib were evaluated in subjects with previously untreated EGFR-mutation positive, metastatic NSCLC (n=345) in a randomized, open-label, controlled Phase III study. Subjects were randomized to receive afatinib 40 mg once daily until disease progression (n=230) or up to six cycles of pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 every 21 days (n=115); randomization was stratified according to EGFR mutation status and race (Asian vs non-Asian). The primary endpoint was progression-free survival (PFS) by central independent review, with secondary endpoints of overall survival and objective response rate (complete response and partial response).

Afatinib was administered for a median of 11 months with a mean overall compliance of 98% per patient. A dose reduction to less than 40 mg/day was required for 120 patients (52%). At the time of data cutoff for the primary analysis, median follow-up time was 16.4 months. Median PFS was 11.1 months for subjects receiving afatinib compared with 6.9 months for those receiving pemetrexed plus cisplatin (Difference: 4.2 months; HR: 0.58; 95%CI: 0.43 to 0.78; p=0.001). At the time of data cutoff, 98 subjects (28%) had died and preliminary overall survival did not differ between groups. Overall objective response rate was 50.4% in the afatinib group and 19.1% in the pemetrexed plus cisplatin group (p<0.001). The most common drug-related adverse events for afatinib-treated subjects were diarrhea (95%), rash (62%), and paronychia (57%), while nausea (66%), decreased appetite (53%), and vomiting (42%) were most common for subjects treated with pemetrexed plus cisplatin. A total of 8% of subjects receiving afatinib discontinued treatment due to adverse events compared to 12% of subjects receiving pemetrexed plus cisplatin.

National Comprehensive Cancer Network (NCCN) Guidelines for Non-Small Cell Lung Cancer (Version 4.2016) recommend afatinib for advanced, EGFR-mutation positive NSCLC.

POSITION STATEMENT:

Comparative Effectiveness

The Food and Drug Administration has deemed the drug(s) or biological product(s) in this coverage policy to be appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Therefore, coverage (i.e., administration) in a provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility is not considered medically necessary.

Initiation of afatinib (Gilotrif) meets the definition of medical necessity when ALL of the following criteria are met:

1. Member is diagnosed with metastatic or recurrent non-small cell lung cancer (NSCLC)

2. Member has a documented epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutation as detected by an FDA-approved test – laboratory documentation must be provided

3. Member meets ONE of the following:

a. Member is using afatinib as monotherapy (without concomitant chemotherapy)

b. Member is using afatinib in combination with cetuximab for metastatic disease AND member’s disease has progressed on EGFR tyrosine kinase inhibitor therapy (e.g., afatinib, erlotinib, gefitinib)

4. Afatinib dose does not exceed 40 mg daily (dosage will be achieved using the fewest number of tablets per day) with the following exception:

a. Dose does not exceed 50 mg daily (dosage will be achieved using the fewest number of tablets per day) AND member is receiving a concomitant P-glycoprotein (P-gp) inducer (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort)

5. Member age is 18 years or older

Duration of approval: 1 year

Continuation of afatinib (Gilotrif) meets the definition of medical necessity when ALL of the following criteria are met:

1. Authorization/reauthorization has been previously approved by Florida Blue or another health plan in the past two years for NSCLC, OR the member currently meets all indication-specific initiation criteria.

2. Dose does not exceed 40 mg/day(dosage will be achieved using the fewest number of tablets per day) with the following exception:

a. Dose does not exceed 50 mg daily (dosage will be achieved using the fewest number of tablets per day) AND member is receiving a concomitant P-glycoprotein (P-gp) inducer (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort)

Approval duration: 1 year

Afatinib (Gilotrif) meets the definition of medical necessity when used for the following designated Orphan Drug indication when the dose does not exceed the maximum FDA-approved dose:

1. Treatment of malignant brain and central nervous system tumors

Duration of approval: 1 year

DOSAGE/ADMINISTRATION:

FDA-approved:

• 40 mg orally once daily

Dose Adjustments

• Withhold for any of the following drug-related adverse reactions:

• Grade 3 or higher

• Diarrhea of Grade 2 persisting for 2 or more consecutive days while taking anti-diarrheal medication

• Cutaneous reactions of Grade 2 that is prolonged (lasting more than 7 days) or intolerable

• Renal dysfunction of Grade 2 or higher

NOTE: Resume treatment at a reduced dose (i.e., 10 mg/day less than dose at which adverse reaction occurred) when the adverse reaction fully resolves, returns to baseline, or improves to Grade 1.

Permanently discontinue for:

• Life-threatening bullous, blistering, or exfoliative skin lesions

• Confirmed interstitial lung disease

• Severe drug-induced hepatic impairment

• Persistent ulcerative keratitis

• Symptomatic left ventricular dysfunction

• Severe or intolerable adverse reaction occurring at a dose of 20 mg per day

P-gp Inhibitors

• Reduce afatinib daily dose by 10 mg if not tolerated; resume previous afatinib dose after discontinuation of P-gp inhibitor

P-gp Inducers

• Increase afatinib daily dose by 10 mg as tolerated; resume previous afatinib dose 2 to 3 days after discontinuation of P-gp inhibitor

Drug Availability

40 mg, 30 mg, and 20 mg tablets

PRECAUTIONS:

Boxed Warning

None

Contraindications

None

Precautions/Warnings

• Diarrhea

• Bullous and Exfoliative Skin Disorders

• Interstitial lung disease

• Hepatic toxicity

• Keratitis

• Embryofetal toxicity

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding:

J8999

Prescription drug, oral, chemotherapeutic, Not Otherwise Specified

C9399

Unclassified drugs or biologicals ( (Hospital Outpatient Use ONLY)

ICD-10 Diagnoses Codes That Support Medical Necessity: (Effective 10/01/15)

C00.0 – C00.9

Malignant neoplasm of lip

C01.0

Malignant neoplasm of base of tongue

C02.0

Malignant neoplasm of dorsal surface of tongue

C02.1

Malignant neoplasm of border of tongue

C02.2 – C02.4

Malignant neoplasm of ventral surface of tongue, anterior two-thirds of tongue, part unspecified, lingual tonsil

C02.8

Malignant neoplasm of overlapping sites of tongue

C02.9

Malignant neoplasm of tongue, unspecified

C03.0 – C03.9

Malignant neoplasm of upper gum, lower gum, gum unspecified

C04.0 – C04.9

Malignant neoplasm of floor of mouth

C05.0 – C05.9

Malignant neoplasm of palate

C06.0 – C06.9

Malignant neoplasm of other and unspecified parts of mouth

C09.0 – C09.9

Malignant neoplasm of tonsil

C10.0 – C10.9

Malignant neoplasm of oropharynx

C12

Malignant neoplasm of pyriform sinus

C13.0 – C13.9

Malignant neoplasm of hypopharynx

C14.0 – C14.8

Malignant neoplasm of other and ill-defined sites in the lip, oral cavity and pharynx

C18.0 – C18.9

Malignant neoplasm of colon

C19 – C21.8

Malignant neoplasm of rectosigmoid junction, rectum, anus and anal canal

C22.1

Intrahepatic bile duct carcinoma

C23 – C24.9

Malignant neoplasm of gallbladder and other and unspecified parts of biliary tract

C31.0 – C31.1

Malignant neoplasm of maxillary or ethmoidal sinus

C32.0 – C32.9

Malignant neoplasm of larynx

C33

Malignant neoplasm of trachea

C34.00– C34.92

Malignant neoplasm of of bronchus or lung

C44.00 – C44.09

Unspecified malignant neoplasm of skin of lip

C71.0

Malignant neoplasm of brain cerebrum, except lobes and ventricles

C71.1

Malignant neoplasm of brain frontal lobe

C71.2

Malignant neoplasm of brain temporal lobe

C71.3

Malignant neoplasm of brain parietal lobe

C71.4

Malignant neoplasm of brain occipital lobe

C71.5

Malignant neoplasm of brain cerebral ventricle

C71.6

Malignant neoplasm of brain cerebellum

C71.7

Malignant neoplasm of brain brain stem

C71.8

Malignant neoplasm of brain overlapping lesion of brain

C71.9

Malignant neoplasm of brain brain, unspecified

C76.0

Malignant neoplasm of head, face, and neck

C77.0

Secondary and unspecified malignant neoplasm of lymph nodes of head, face and neck

C78.89

Secondary malignant neoplasm of other digestive organs

D37.01 – D37.09

Neoplasm of uncertain behavior of lip, tongue, salivary glands and pharynx

D38.0

Neoplasm of uncertain behavior of larynx

D38.5 – D38.6

Neoplasm of uncertain behavior of other respiratory organs or unspecified respiratory organ

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Part D: BCBSF has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline.

Medicare Advantage: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline revised date.

DEFINITIONS:

None

RELATED GUIDELINES:

Erlotinib (Tarceva®) Tablets, 09-J1000-44

OTHER:

None

REFERENCES:

  1. AHFS Drug Information. Bethesda (MD): American Society of Health-System Pharmacists, Inc; 2016 [cited 2016 Jul 08]. In: STAT!Ref Online Electronic Medical Library [Internet]. Available from: http://online.statref.com/.
  2. Boehringer Ingelheim Pharmaceuticals, Inc. Gilotrif (afatinib) tablet, film coated. 2013 [cited 2016 Jul 08]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=fd638e5e-8032-e7ca-0179-95e96ab5d387/.
  3. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2016 [cited 2016 Jul 08]. Available from: http://www.clinicalpharmacology.com/.
  4. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine; 2000 Feb 29 - [cited 2016 Jul 08]. Available from: http://clinicaltrials.gov/.
  5. DRUGDEX® System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 2016 Jul 08]. Available from: http://www.thomsonhc.com/.
  6. Geater SL, Zhou C, Hu C-P, et al. LUX-Lung 6: Patient-reported outcomes (PROs) from a randomized open-label, phase III study in first-line advanced NSCLC patients (pts) harboring epidermal growth factor receptor (EGFR) mutations. (Abstract 8061). American Society of Clinical Oncology Annual Meeting 2013. Chicago, IL: ASCO; 2013.
  7. Katakami N, Atagi S, Goto K, Hida T, et al. LUX-Lung 4: A Phase II Trial of Afatinib in Patients With Advanced Non-Small-Cell Lung Cancer Who Progressed During Prior Treatment With Erlotinib, Gefitinib, or Both. J Clin Oncol. 2013 Sep 20;31(27):3335-3341.
  8. Miller VA, Hirsh V, Cadranel J, Chen YM, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol. 2012 May;13(5):528-38.
  9. NCCN Drugs & Biologics Compendium [Internet]. Fort Washington (PA): National Comprehensive Cancer Network; 2016 [cited 2016 Jul 08]. Available from: http://www.nccn.org/professionals/drug_compendium/content/contents.asp/.
  10. National Comprehensive Cancer Network®. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Non-small cell lung cancer, v. 4.2016 [cited 2016 Jul 23]. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
  11. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2016 [cited 2016 Jul 08]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.
  12. Sequist LV, Yang JC, Yamamoto N, O'Byrne K, et al. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol. 2013 Sep 20;31(27):3327-3334.
  13. Wu YL, Zhou C, Hu C-P, et al. LUX-Lung 6: A randomized, open-label, phase III study of afatinib (A) versus gemcitabine/cisplatin (GC) as first-line treatment for Asian patients (pts) with EGFR mutation-positive (EGFR M+) advanced adenocarcinoma of the lung (Abstract 8016). American Society of Clinical Oncology Annual Meeting 2013. Chicago, IL: ASCO; 2013.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Coverage Committee on 08/10/16.

GUIDELINE UPDATE INFORMATION:

12/15/13

New Medical Coverage Guideline.

12/15/14

Review and revision to guideline; consisting of description, position statement, references.

12/15/15

Review and revision to guideline, consisting of updating position statement, decription, references.

07/15/16

Revision to guidelines; consisting of position statement and ICD10 coding

09/15/16

Review and revision to guideline, consisting of updating position statement, coding, references.

Date Printed: June 23, 2017: 06:21 PM