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Date Printed: October 23, 2017: 02:07 AM

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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-J2000-38

Original Effective Date: 06/15/15

Reviewed: 11/09/16

Revised: 12/15/16

Subject: Lenvatinib (Lenvima)

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 63,000 new thyroid carcinoma cases are predicted to be diagnosed in the United States in 2015. The main histologic types of thyroid carcinoma include: differentiated (including papillary, follicular, Hürthle), medullary, and anaplastic (aggressive undifferentiated tumor). Treatment options include surgery, whenever possible, followed by radioiodine (131I) and thyroxine therapy.

Lenvatinib (Lenvima), an oral receptor tyrosine kinase (RTK) inhibitor against vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), was approved by the U.S. Food and Drug Administration (FDA) in February 2015 for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). Lenvatinib was designated as an orphan drug for this same indication. The FDA approved lenvatinib for the treatment of renal cell cancer (RCC) in combination with everolimus for patients with advanced RCC following one prior anti-angiogenic therapy in May 2016.

The safety and efficacy of lenvatinib were evaluated in subjects with progressive thyroid cancer that was refractory to iodine-131 in a randomized, double-blind, Phase III study (SELECT). Subjects were randomized to receive lenvatinib 24 mg/day in 28 day cycles (n=261) or placebo (n=131). The primary endpoint was progression free survival, defined as the time from randomization until the earliest date of radiological disease progression or death from any cause.

The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death, 0.21; 99% confidence interval, 0.14 to 0.31; P<0.001). A progression-free survival benefit associated with lenvatinib was observed in all prespecified subgroups. The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial responses) and 1.5% in the placebo group (P<0.001). The median overall survival was not reached in either group.

Treatment-related adverse effects of any grade, which occurred in more than 40% of patients in the lenvatinib group, were hypertension (67.8%), diarrhea (59.4%), fatigue or asthenia (59.0%), decreased appetite (50.2%), decreased weight (46.4%), and nausea (41.0%). Discontinuations of the study drug because of adverse effects occurred in 37 patients who received lenvatinib (14.2%) and 3 patients who received placebo (2.3%). In the lenvatinib group, 6 of 20 deaths that occurred during the treatment period were considered to be drug-related.

National Comprehensive Cancer Network (NCCN) Guidelines for Thyroid Carcinoma recommend lenvatinib for the treatment of progressive and/or symptomatic iodine-refractory differentiated thyroid carcinomas (including papillary, follicular, Hürthle) in patients with unresectable, recurrent or persistent, locoregional disease or distant metastatic disease. NCCN Guidelines for Kidney Cancer recommend lenvatinib in combination with everolimus as subsequent therapy for relapse or for surgically unresectable stage IV disease with predominant clear cell histology that has progressed following first line therapy.

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.

I. Initiation of lenvatinib (Lenvima) meets the definition of medical necessity when ALL of the following criteria are met:

1. Differentiated thyroid cancer (i.e., papillary carcinoma, follicular carcinoma, Hürthle cell carcinoma)

a. Member’s disease is progressive and/or symptomatic

b. Member’s has ONE of the following:

i. Unresectable locoregional disease that is recurrent or persistent

ii. Distant metastatic disease

c. Member’s disease is resistant to radioiodine treatment

d. Lenvatinib is used as a single agent

e. Dose does not exceed 24 mg daily – dosage will be achieved using the fewest number of capsules per day

2. Kidney Cancer

a. Member has relapsed or surgically unresectable stage IV disease

b. Lenvatinib is used in combination with everolimus (Afinitor)

c. ONE of the following:

i. When used subsequent therapy for disease with predominant clear cell histology

ii. When used as treatment for disease with non-clear cell histology

d. The dose will not exceed 18 mg daily

Approval duration: 6 months

II. Lenvatinib (Lenvima) meets the definition of medical necessity when used for the following designated Orphan Drug indication (http://www.fda.gov/orphan/designat/list.htm) when the dose does not exceed the maximum FDA-approved dosing:

1. Medullary or anaplastic thyroid cancer

Approval duration: 6 months

III. Continuation of lenvatinib (Lenvima) meets the definition of medical necessity for the treatment of thyroid cancer or kidney cancer for members meeting the following criteria:

1. The member has been previously approved by Florida Blue or another healthplan in the past 2 years, OR the member has previously met all indication-specific criteria for coverage

2. Member’s disease has not progressed during treatment with lenvatinib

3. Dose does not exceed indication specific dosing and dosage will be achieved using the fewest number of capsules per day:

a. Thyroid cancer: 24 mg daily

b. Kidney cancer: 18 mg daily

Approval duration: 6 months

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

FDA-approved

Differentiated Thyroid Cancer: 24 mg orally, once daily

Kidney Cancer: 18 mg lenvatinib in combination with everolimus 5 mg, orally, once daily

Dose Adjustments

Differentiated Thyroid Cancer:

o Severe renal impairment: 14 mg once daily

o Severe hepatic impairment: 14 mg once daily

o Dose adjustment for adverse reactions: see prescribing information

Kidney Cancer:

o Severe renal impairment: 10 mg once daily

o Severe hepatic impairment: 10 mg once daily

o Dose adjustment for adverse reactions: see prescribing information

Drug Availability

• Capsules: 4 mg and 10 mg

PRECAUTIONS:

Boxed Warning

• None

Contraindications

• None

Precautions/Warnings

Hypertension - Control blood pressure prior to treatment. Withhold for Grade 3 hypertension despite optimal hypertensive therapy. Discontinue for life-threatening hypertension

Cardiac Failure - Monitor for clinical symptoms or signs of cardiac decompensation. Withhold for Grade 3 cardiac dysfunction. Discontinue for Grade 4 cardiac dysfunction

Arterial Thromboembolic Events - Discontinue following an arterial thromboembolic event

Hepatotoxicity - Monitor liver function tests before initiation of and periodically throughout treatment. Withhold for Grade 3 or greater liver impairment. Discontinue for hepatic failure

Proteinuria - Monitor for proteinuria before initiation of, and periodically throughout, treatment. Withhold for ≥2 grams of proteinuria for 24 hours. Discontinue for nephrotic syndrome

• Diarrhea – May be severe and recurrent. Use standard anti-diarrheal therapy. Withhold for Grade 3 and discontinue for grade 4 diarrhea

• Renal Failure and Impairment - Withhold for Grade 3 or 4 renal failure/impairment

• Gastrointestinal Perforation and Fistula Formation - Discontinue in patients who develop gastrointestinal perforation or life- threatening fistula

QT Interval Prolongation - Monitor and correct electrolyte abnormalities in all patients. Withhold for the development of Grade 3 or greater QT interval prolongation

• Hypocalcemia - Monitor blood calcium levels at least monthly and replace calcium as necessary

• Reversible Posterior Leukoencephalopathy Syndrome (RPLS) - Withhold for RPLS until fully resolved

• Hemorrhagic Events - Withhold for Grade 3 hemorrhage. Discontinue for Grade 4 hemorrhage.

Impairment of Thyroid Stimulating Hormone Suppression - Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC

Embryofetal Toxicity - Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding

C9399

Unclassified drugs or biologicals

J8999

Prescription drug, oral, chemotherapeutic, Not Otherwise Specified

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

C64.1

Malignant neoplasm of right kidney, except renal pelvis

C64.2

Malignant neoplasm of left kidney, except renal pelvis

C64.9

Malignant neoplasm of unspecified kidney, except renal pelvis

C65.1

Malignant neoplasm of right renal pelvis

C65.2

Malignant neoplasm of left renal pelvis

C65.9

Malignant neoplasm of unspecified renal pelvis

C73

Malignant neoplasm of thyroid gland

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:

No guideline specific definitions apply.

RELATED GUIDELINES:

Cabozantinib (Cometriq™) Capsules, 09-J1000-88
Imatinib Mesylate (Gleevec®) Tablets, 09-J1000-46

Pazopanib (Votrient™) Tablets, 09-J1000-49

Sorafenib (Nexavar®) Tablets, 09-J1000-50

Sunitinib Maleate (Sutent) Capsules 09-J1000-51

Vandetanib (Caprelsa®) Tablets, 09-J1000-38

OTHER:

Table 1: Common Terminology Criteria for Adverse Events v4.0 (CTCAE)

Grade

Description

1

Mild; asymptomatic or mild symptoms; clinical diagnostic observations only; intervention not indicated

2

Moderate; minimal, local or noninvasive intervention indicated; limited age-appropriate instrumental activities of daily living

3

Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living

4

Life-threatening consequences; urgent intervention indicated

5

Death related to adverse event

REFERENCES:

  1. AHFS Drug Information. Bethesda (MD): American Society of Health-System Pharmacists, Inc; 2016 [cited 2016-10-20]. In: STAT!Ref Online Electronic Medical Library [Internet]. Available from: http://online.statref.com/.
  2. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2016 [cited 2016-10-20]. Available from: http://www.clinicalpharmacology.com/.
  3. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine; 2000 Feb 29 - [cited 2015-04-24]. Available from: http://clinicaltrials.gov/.
  4. DRUGDEX® System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 2016-10-20]. Available from: http://www.thomsonhc.com/.
  5. Eisai, Inc. Lenvima (lenvatinib) capsule. 2016 [cited 2016-10-20]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f4bedd21-efde-44c6-9d9c-b48b78d7ed1e /.
  6. National Cancer Institute. Common Terminology Criteria for Adverse Events. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Accessed 4/24/16.
  7. National Comprehensive Cancer Network®. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Thyroid Carcinoma, v. 1.2016 [cited 2016-10-20]. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
  8. National Comprehensive Cancer Network®. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Kidney Cancer, v. 1.2017 [cited 2016-10-20]. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
  9. NCCN Drugs & Biologics Compendium [Internet]. Fort Washington (PA): National Comprehensive Cancer Network; 2016 [cited 2016-10-20]. Available from: http://www.nccn.org/professionals/drug_compendium/content/contents.asp/.
  10. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2016[cited 2016-10-20]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 11/09/16.

GUIDELINE UPDATE INFORMATION:

06/15/15

New Medical Coverage Guideline.

11/01/15

Revision: ICD-9 Codes deleted.

06/15/16

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

07/15/16

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

12/15/16

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

Date Printed: October 23, 2017: 02:07 AM