Print

Date Printed: June 28, 2017: 11:45 PM

Private Property of Blue Cross and Blue Shield of Florida.
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-J1000-88

Original Effective Date: 03/15/13

Reviewed: 09/14/16

Revised: 02/15/17

Subject: Cabozantinib capsules and tablets (Cometriq®, Cabometyx®)

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:

Cabozantinib (Cometriq®) was approved by the U.S. Food and Drug Administration (FDA) on November 29, 2012 for the treatment of patients with progressive metastatic medullary thyroid cancer (MTC). Cabozantinib is a small molecule that inhibits the activity of multiple tyrosine kinases, including RET, MET, and VEGF receptor 2.

The approval was based on the demonstration of improved progression-free survival (PFS) observed in an international, multi-center, randomized (2:1), placebo-controlled trial enrolling 330 patients with metastatic MTC. Patients were required to have progressive disease within 14 months prior to entry. Patients were randomized to receive cabozantinib 140 mg (n = 219) or placebo (n = 111) orally once daily. Randomization was stratified by age and prior tyrosine kinase inhibitor (TKI) use. Patients were treated until disease progression or intolerable toxicity. At the time of disease progression, cross-over to cabozantinib was not permitted in patients receiving placebo. An independent radiology review committee (IRC), using the modified RECIST criteria, determined radiographic progression and tumor response. Of 330 patients, 67% were male, the median age was 55 years, 23% were 65 years or older, 54% had a baseline ECOG performance status of 0, and 92% had undergone thyroidectomy. Twenty-five percent (25%) received two or more prior systemic therapies and 21% had been previously treated with a TKI. A statistically significant PFS prolongation was demonstrated in the cabozantinib arm compared to the placebo arm [HR 0.28 (95% CI: 0.19, 0.40); p <0.0001]. The estimated median PFS was 11.2 and 4.0 months for the cabozantinib and placebo arms, respectively.

Cabozantinib (Cabometyx®) was FDA approved in April 2016 for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. In a randomized, open-label, multicenter trial in patients with advanced RCC and use of at least one prior anti-angiogenic therapy, treatment with cabozantinib significantly improved median PFS as compared with everolimus (7.4 months vs. 3.8 months; HR 0.58; p<0.0001). Significant improvements were also demonstrated in overall survival (21.4 months vs. 16.5 months; HR 0.66; p=0.0003) and confirmed objective response rate of partial responses (17% vs. 3%; p<0.0001).

National Comprehensive Cancer Network (NCCN) Guidelines for Thyroid cancer currently recommend cabozantinib for MTC. Of note, NCCN states that several factors should be considered prior to initiating therapy with a kinase inhibitor which includes the following: therapy may improve progression-free survival but is not curative, side effects may have a significant effect on quality of life, rates of disease progression are variable, and the pace of disease progression should be factored into treatment decisions. More specifically, patients with indolent disease who are asymptomatic may not be appropriate for kinase inhibitors due to side effects adversely affecting the patient’s quality of life whereas patients with rapidly progressing disease may experience benefit even in the presence of side effects. The NCCN guidelines additionally recommend cabozantinib for kidney cancer and non-small cell lung cancer.

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 cabozantinib meets the definition of medical necessity when used as a single agent in member’s meeting the following criteria:

A. Medullary thyroid carcinoma (MTC) when ALL of the following are met:

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

2. Member has ONE of the following:

i. Unresectable locoregional disease

ii. Distant metastatic disease

3. Dose does not exceed 140 mg per day* using the fewest number of capsules per day.

B. Non-Small Cell Lung Cancer (NSCLC) when BOTH of the following are met:

1. Member has tested positive for a RET fusion rearrangement

2. Dose does not exceed 60 mg per day using the fewest number of tablets per day.

C. Kidney cancer when ALL of the following are met

1. Member is diagnosed with relapsed or surgically unresectable stage IV disease

2. ONE of the following:

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

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

3. Dose does not exceed 60 mg per day** using the fewest number of tablets per day.

D. When used for treatment of the following designated Orphan Drug indications (http://www.fda.gov/orphan/designat/list.htm) and the dose does not exceed 140 mg per day using the fewest number of capsules:

1. Metastatic or locally advanced papillary thyroid cancer.

2. Follicular thyroid carcinoma.

3. Anaplastic thyroid carcinoma.

Approval duration: 180 days

II. Continuation of cabozantinib meets the definition of medical necessity when used as a single agent for thyroid carcinomas, NSCLC, or RCC and ALL of the following criteria are met:

A. The member’s disease has not progressed while receiving treatment with cabozantinib

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

C. The dose does not exceed the following:

a. Thyroid carcinomas: 140 mg per day* using the fewest number of capsules per day.

b. NSCLC: 60 mg per day using the fewest number of tablets per day.

c. Kidney cancer: 60 mg per day** using the fewest number of tablets per day.

Approval duration: 1 year

*NOTE: Avoid use with strong CYP3A4 inhibitors and inducers. If a CYP3A4 strong inducer (e.g. carbamazepine, phenobarbital, phenytoin, rifampin, rifabutin, rifapentine) cannot be avoided, the dose may need to be increased by 40 mg to a maximum of 180 mg per day for FDA-approved indications. A dose reduction should be considered if coadministration with a CYP3A4 inhibitor cannot be avoided.

**NOTE: Avoid use with strong CYP3A4 inhibitors and inducers. If a CYP3A4 strong inducer cannot be avoided, the dose may need to be increased by 20 mg to a maximum of 80 mg per day for FDA-approved indications. A dose reduction should be considered if coadministration with a CYP3A4 inhibitor cannot be avoided.

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.

Recommended Dose

FDA-approved:

Medullary thyroid cancer (MTC): The recommended daily dose of cabozantinib is 140 mg (one 80-mg and three 20-mg capsules).

Renal cell carcinoma (RCC): The recommended daily dose of cabozantinib is 60 mg (tablets).

Do not administer cabozantinib with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking. Continue treatment until disease progression or unacceptable toxicity occurs.

Swallow capsules or tablets whole. Do not open capsules and do not crush tablets. Do not substitute tablets and capsules.

Do not take a missed dose within 12 hours of the next dose.

Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during cabozantinib therapy.

Dose adjustment:

Hepatic Impairment

Indication:

MTC: Cabozantinib starting dose should be reduced to 80 mg once daily in patients with mild to moderate hepatic impairment. Use is not recommended for use in patients with severe hepatic impairment.

RCC: Cabozantinib starting dose should be reduced to 40 mg once daily in patients with mild or moderate hepatic impairment. Use is not recommended in patients with severe hepatic impairment.

CYP3A4 Inhibitors

Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving cabozantinib.

For patients who require treatment with a strong CYP3A4 inhibitor, see prescribing information for indication specific dose modification.

CYP3A4 Inducers

Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available.

Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum)) that are known to induce cytochrome P450 activity.

For patients who require treatment with a strong CYP3A4 inducer, see prescribing information for indication specific dose modification.

Adverse Reactions

For patients who experience adverse reactions, see prescribing information for indication specific dose modification or permanent discontinuation.

Surgery

Stop treatment at least 28 days prior to scheduled surgery, including dental surgery.

Drug Availability

PRECAUTIONS:

CONTRAINDICATIONS: None

PRECAUTIONS/WARNINGS:

Black Box Warning

Cabozantinib capsules (Cometriq)

Perforations and fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of cabozantinib-treated members. Discontinue cabozantinib for perforation or for fistula formation.

Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of cabozantinib-treated members. Monitor members for signs and symptoms of bleeding. Do not administer cabozantinib to members with severe hemorrhage.

Warnings and Precautions

Cabozantinib capsules (Cometriq):

Wound Complications: Wound complications have been reported with cabozantinib. Stop treatment with at least 28 days prior to scheduled surgery. Resume therapy after surgery based on clinical judgment of adequate wound healing. Withhold cabozantinib in members with dehiscence or wound healing complications requiring medical intervention.

Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) occurred in 1% of cabozantinib-treated members. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of cabozantinib and periodically during cabozantinib therapy. Advise members regarding good oral hygiene practices.

For invasive dental procedures, withhold cabozantinib treatment for at least 28 days prior to scheduled surgery, if possible.

Proteinuria: Monitor urine protein regularly during treatment. Discontinue cabozantinib in members who develop nephrotic syndrome.

Cabozantinib tablets (Cabometyx):

Hemorrhage: Do not administer if recent history of severe hemorrhage

GI Perforation and fistulas: Monitor for symptoms and discontinue if necessary.

Diarrhea: Interrupt therapy and utilize supportive antidiarrheal treatments for severe diarrhea.

Cabozantinib capsules and tablets (Cometriq, Cabometyx)

Thrombotic Events:

Discontinue cabozantinib in members who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Hypertension: Monitor blood pressure prior to initiation and regularly during cabozantinib treatment. Discontinue for hypertensive crisis or severe hypertension that cannot be controlled.

Palmar-Plantar Erythrodysesthesia Syndrome: Withhold cabozantinib in members who develop intolerable PPES or until improvement to Grade 1.

Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) member.

Perform an evaluation for RPLS in any member presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue cabozantinib in members who develop RPLS.

Embryo-fetal Toxicity: Cabozantinib can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryo lethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the member becomes pregnant while taking this drug, the member should be apprised of the potential hazard to the fetus.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding

C9399

Unclassified drugs or biologicals

J8999

Prescription drug, oral, chemotherapeutic, NOS

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

C33

Malignant neoplasm of trachea

C34.00 – C34.02

Malignant neoplasm of unspecified main bronchus

C34.10 – C34.12

Malignant neoplasm of upper lobe, unspecified bronchus or lung

C34.2

Malignant neoplasm of middle lobe, bronchus or lung

C34.30 – C34.32

Malignant neoplasm of lower lobe, unspecified bronchus or lung

C34.80 – C34.82

Malignant neoplasm of overlapping sites of unspecified bronchus and lung

C34.90 – C34.92

Malignant neoplasm of unspecified part of unspecified bronchus or lung

C64.1 – C64.9

Malignant neoplasm of unspecified kidney, except renal pelvis

C65.1 – 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 products: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline revised date.

DEFINITIONS:

Anaplastic thyroid carcinoma: is a form of thyroid cancer which has a very poor prognosis due to its aggressive behavior and resistance to cancer treatments. Anaplastic tumors have a high miotic rate and lymphovascular invasion. It rapidly invades surrounding tissues (such as the trachea). The presence of regional lymphadenopathy in older patients in whom needle aspiration biopsy reveals characteristic vesicular appearance of the nuclei would support a diagnosis of anaplastic carcinoma.

Follicular thyroid carcinoma: is the second most common type of thyroid cancer and accounts for 15% of thyroid cancer which occurs more commonly in women of over 50 years old.

Medullary thyroid cancer (MTC): is a form of thyroid cancer which originates from the parafollicular cells (C cells), which produce the hormone calcitonin. Medullary tumors are the third most common of all thyroid cancers.

Papillary thyroid cancer: is the most common type of thyroid cancer, representing 75% to 85% of all thyroid cancer cases. It occurs more frequently in women and presents in the 30-40 year age group. It is also the predominant cancer type in children with thyroid cancer, and in patients with thyroid cancer who have had previous radiation to the head and neck.

RELATED GUIDELINES:

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. Cabozantinib. In: McEvoy GK, editor. AHFS drug information 2016 [monograph on the Internet]. Bethesda (MD): American Society of Health-System Pharmacists; 2016 [cited 2016 Aug 25]. Available from http://online.statref.com subscription required to view.
  2. Clinical Pharmacology. Copyright© 2015 Elsevier. Accessed 8/25/16.
  3. Cabometyx (cabozantinib tablets) [package insert]. Exelixis, Inc. San Francisco, CA. May 2016.
  4. Cometriq™ (cabozantinib capsules) [package insert]. Exelixis, Inc. San Francisco, CA. May 2016.
  5. Facts & Comparisons® e Answers. ©2013 Wolters Kluwer Health. Accessed 01/22/13.
  6. FDA Orphan Drug Designations and Approvals. Available at: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/. Accessed 8/25/16.
  7. Ingenix HCPCS Level II, Expert 2012.
  8. Ingenix ICD-9-CM for Physicians-Volumes 1 & 2, Expert 2012.
  9. Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colorado: Thomson Healthcare. Updated periodically. Accessed 8/25/16.
  10. 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 9/24/15.
  11. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Version 1.2016. Thyroid Carcinoma. Available at http://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. Accessed 08/25/16.
  12. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Version 2.2017. Kidney Cancer. Available at http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed 1/6/17.
  13. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Version 3.2017. Non-Small Cell Lung Cancer. Available at http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed 1/6/17.
  14. National Comprehensive Cancer Network (NCCN). Drugs & Biologics Compendium [Internet]. Fort Washington (PA): National Comprehensive Cancer Network; 2017 [cited 2017 January 6]. Available from: http://www.nccn.org/professionals/drug_compendium/content/contents.asp/.
  15. Tuttle, RM. Novel therapeutic options for aggressive thyroid cancer: Integrating information from the recent clinical trials into clinical practice. Clinical Thyroidology [serial online]. 2009;21(1):3–7.
  16. Wells SA, Sylvia LA, Henning D et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015; 25: 567-610.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 09/14/16.

GUIDELINE UPDATE INFORMATION:

03/15/13

New Medical Coverage Guideline.

11/15/14

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

11/01/15

Revision: ICD-9 Codes deleted.

11/15/15

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

1/15/16

Revision to guideline; consisting of revising position statement, updating coding and references.

9/15/16

Revision to guideline; consisting of revising description, position statement, dosing, warnings/precautions and references.

10/15/16

Revision to guideline; consisting of revising position statement and references.

02/15/17

Revision to guideline; consisting of revising position statement and references.

Date Printed: June 28, 2017: 11:45 PM