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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-J1000-83

Original Effective Date: 01/15/13

Reviewed: 12/14/16

Revised: 01/15/17

Subject: Regorafenib (Stivarga®) 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:

Regorafenib (Stivarga) is an oral multikinase inhibitor. It works by inhibiting tyrosine kinases that promote angiogenesis and tumor growth such as vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet derived growth factor receptor (PDGFR)-alpha, PDGFR-beta, and TIE2 and oncogenic kinases c-KIT, REF, and BRAF.

Regorafenib was initially approved in 2012 for the treatment of metastatic colorectal cancer (mCRC) in persons who have previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF therapy; and an anti-EGFR therapy if RAS mutation-negative (wild type). The approval was expanded in 2013 to include treatment of locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) in persons who have previously received imatinib and sunitinib.

Approval of regorafenib for the treatment of mCRC was based on a single Phase III, multi-center, double-blind, placebo controlled, randomized trial. A total of 760 subjects with documented cancer of the colon or rectum were randomized 2:1 to regorafenib 160 mg orally once daily or placebo. The primary endpoint was overall survival (OS). In a pre-planned interim analysis, the median OS was 6.4 months and 5 months in the regorafenib and placebo arms, respectively. The trial was terminated for efficacy as the primary endpoint of OS was met.

The approval for treatment of GIST was also based on a single Phase III, multi-center, double-blind, placebo-controlled, randomized trial in which 199 subjects were randomized to regorafenib 160 mg daily or placebo. Progression-free survival (PFS), the primary endpoint, was statistically greater in the regorafenib arm when compared to placebo (4.8 months vs. 0.9 months, respectively; p<0.001).

The National Comprehensive Cancer Network (NCCN) guidelines for colon and rectal cancer support the use of regorafenib for unresectable advanced or metastatic disease not previously treated with the agent. NCCN recommends use after first disease progression following FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) with or without bevacizumab in patients with disease positive for the KRAS/NRAS mutation. NCCN also supports the use of regorafenib for second or subsequent disease progression following treatment with irinotecan- and oxaliplatin-based regimens as well as FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) with or without bevacizumab (in patients with mutant or wild type tumors). The NCCN guidelines also support use in patients whose disease has progressed through all available regimens. The NCCN guidelines for GIST recommend regorafenib for the treatment of progressive disease when the patient is no longer receiving benefit with imatinib or sunitinib.

POSITION STATEMENT:

I. Initiation of regorafenib (Stivarga®) meet the definition for medical necessity for the following indications when the dosage does not exceed 160 mg daily for 21 days of a 28 day cycle:

A. Colon or Rectal Cancer and ALL of the following are met:

1. Regorafenib will be used as a single agent.

2. Member has metastatic or unresectable advanced disease

3. Member has not previously received regorafenib

4. Member meets ONE of the following:

a. Regorafenib is used following disease progression with FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) +/- bevacizumab AND the member’s disease is positive for the KRAS/NRAS mutation

b. Regorafenib is used as third-line or subsequent (i.e., fourth line or greater) therapy for disease progression after previous treatment with THREE or more of the following agents (combination use or in separate regimens):

i. Anti-EGFR therapy* (e.g., panitumumab or cetuximab) if KRAS/NRAS gene is normal (i.e., without mutation, also known as wild type).

ii. Anti-VEGF therapy* (e.g., bevacizumab, ziv-aflibercept or ramucirumab).

iii. Fluoropyrimidine-containing chemotherapy (e.g., fluorouracil or capecitabine).

iv. Irinotecan-containing chemotherapy

v. Oxaliplatin-containing chemotherapy

vi. Trifluridine/tipiracil

B. Soft Tissue Sarcoma – Gastrointestinal Stromal Tumors (GIST) and BOTH of the following are met:

1. Disease is progressive

2. Member is no longer receiving benefit (i.e., tumor has progressed) from imatinib (Gleevec) or sunitinib (Sutent)

C. When used as a single agent for the following designated Orphan Drug indications (http://www.fda.gov/orphan/designat/list.htm) when the dose does not exceed the maximum FDA-approved dose:

1. Treatment of hepatocellular carcinoma

Duration of approval: 180 days (all indications)

II. Continuation of regorafenib (Stivarga®) meets the definition of medical necessity for the treatment of colon or rectal cancer, soft tissue sarcoma, or hepatocellular carcinoma when the following criteria are met:

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

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 160 mg daily for 21 days of a 28 day cycle

Approval duration: 1 year

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: regorafenib is indicated for treatment of the following conditions

• Metastatic colorectal cancer in persons who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild type, an anti-EGFR therapy

• Locally advanced, unresectable or metastatic gastrointestinal stromal tumor in persons who have been previously treated with imatinib and sunitinib malate.

The recommended dose is 160 mg regorafenib (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-day cycle. Regorafenib should be swallowed whole and administered with food at the same time each day (a low-fat meal, less than 30% fat)

Dose adjustments:

Interrupt for the following:

• Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia (PPE)] that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 HFSR

• Symptomatic Grade 2 hypertension

• Any CTCAE Grade 3 or 4 adverse reaction

Reduce the dose to 120 mg:

• For the first occurrence of Grade 2 HFSR of any duration

• After recovery of any Grade 3 or 4 adverse reaction

• For Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation; only resume if the potential benefit outweighs the risk of hepatotoxicity

Reduce the dose to 80 mg:

• For re-occurrence of Grade 2 HFSR at the 120 mg dose

• After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity)

Discontinue permanently for the following:

• Failure to tolerate 80 mg dose

• Any occurrence of AST/ ALT elevation more than 20 times the upper limit of normal (ULN)

• Any occurrence of AST/ ALT elevation more than 3 times the ULN with concurrent bilirubin more than 2 times ULN

• Re-occurrence of AST/ ALT elevation more than 5 times the ULN despite dose reduction to 120 mg

• For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks

Drug Availability: regorafenib is supplied as a 40 mg tablet.

PRECAUTIONS:

Contraindications

None

Boxed Warning

• Severe and sometimes fatal hepatotoxicity has been observed in clinical trials.

• Monitor hepatic function prior to and during treatment.

• Interrupt and then reduce or discontinue regorafenib for hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis, depending upon severity and persistence.

Warnings and Precautions

Hepatotoxicity: Monitor liver function tests and dose reduce or discontinue based on severity and duration.

• Hemorrhage: Permanently discontinue regorafenib for severe or life-threatening hemorrhage.

• Dermatological toxicity: Interrupt and then reduce or discontinue regorafenib depending on severity and persistence of dermatologic toxicity.

• Hypertension: Temporarily or permanently discontinue regorafenib for severe or uncontrolled hypertension.

• Cardiac ischemia and infarction: Withhold regorafenib for new or acute cardiac ischemia/infarction and resume only after resolution of acute ischemic events.

• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Discontinue regorafenib

• Gastrointestinal perforation or fistulae: Discontinue regorafenib

• Wound healing complications: Stop regorafenib before surgery. Discontinue in persons with wound dehiscence.

• Embryo-fetal toxicity: Can cause fetal harm. Advise women of potential risk to a 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)

C17.0

Malignant neoplasm of duodenum

C17.1

Malignant neoplasm of jejunum

C17.2

Malignant neoplasm of ileum

C17.8

Malignant neoplasm of overlapping sites of small intestine

C17.9

Malignant neoplasm of small intestine, unspecified

C18.0

Malignant neoplasm of cecum

C18.1

Malignant neoplasm of appendix

C18.2

Malignant neoplasm of ascending colon

C18.3

Malignant neoplasm of hepatic flexure

C18.4

Malignant neoplasm of transverse colon

C18.5

Malignant neoplasm of splenic flexure

C18.6

Malignant neoplasm of descending colon

C18.7

Malignant neoplasm of sigmoid colon

C18.8

Malignant neoplasm of overlapping sites of colon

C18.9

Malignant neoplasm of colon, unspecified

C19

Malignant neoplasm of rectosigmoid junction

C20

Malignant neoplasm of rectum

C21.8

Malignant neoplasm of overlapping sites of rectum, anus and anal canal

C22.0

Liver cell carcinoma

C49.4

Malignant neoplasm of connective and soft tissue of abdomen

C49.8

Malignant neoplasm of overlapping sites of connective and soft tissue

C49.9

Malignant neoplasm of connective and soft tissue, unspecified

C49.A0 – C49.A9

Gastrointestinal stromal tumor, unspecified

C78.00 – 78.02

Secondary malignant neoplasm of unspecified lung

C78.6

Secondary malignant neoplasm of retroperitoneum and peritoneum

C78.7

Secondary malignant neoplasm of liver and intrahepatic bile duct

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

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

DEFINITIONS:

VEGF - Vascular endothelial growth factor.

EGFR - Epidermal growth factor receptor.

RELATED GUIDELINES:

Bevacizumab (Avastin®) Injection, 09-J000-66
Capecitabine (Xeloda®) Tablets, 09-J1000-42

Human EGFR Inhibitors (cetuximab; panitumumab) IV, 09-J0000-94

Imatinib Mesylate (Gleevec®) Tablets, 09-J1000-46

Irinotecan HCl (Camptosar®) IV, 09-J0000-99

KRAS Mutation Analysis, 05-86000-28

Oxaliplatin (Eloxatin®) IV, 09-J1000-00
|
Ramucirumab (Cyramza™) Injection, 09-J2000-14

Sunitinib Malate (Sutent®) Capsules, 09-J1000-51

Ziv-aflibercept (Zaltrap®) IV, 09-J1000-80

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. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.;2016. URL www.clinicalpharmacilogy-ip.com Accessed 11/21/16.
  2. Ingenix HCPCS Level II, Expert 2013.
  3. Ingenix ICD-9-CM for Physicians-Volumes 1 & 2, Expert 2013
  4. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 11/21/16.
  5. 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 11/18/15.
  6. National Comprehensive Cancer Network. Cancer Guidelines. Cancer Guidelines and Drugs and Biologics Compendium. Accessed 11/28/16.
  7. National Comprehensive Cancer Network®. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Colon Cancer, v.1.2017 [cited 2016 Nov 28]. 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®). Rectal Cancer, v.1.2017 [cited 2016 Nov 28]. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
  9. National Comprehensive Cancer Network®. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Soft Tissue Sarcoma, v.2.2016 [cited 2016 Nov 28]. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
  10. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2016 [cited 2016 Nov 28]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.
  11. Regorafenib. In McEvoy GK, editor. AHFS drug information 2016 [monograph on the internet]. Bethesda (MD): American Society of Health-System Pharmacists; 2016 [cited 2016 Nov 21].
  12. Stivarga (regorafenib) [package insert]. Bayer HealthCare Pharmaceuticals Inc. Wayne (NJ): August 2016.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Coverage Committee on 12/14/16.

GUIDELINE UPDATE INFORMATION:

01/15/13

New Medical Coverage Guideline.

05/15/13

Revision to guideline; consisting of adding new indication of GIST to the position statement.

01/15/14

Review and revision to guideline; consisting of updating description, dosage/administration, and precautions sections and revising approval duration.

01/15/15

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

11/01/15

Revision: ICD-9 Codes deleted.

01/15/16

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

10/01/16

Update to ICD-10 codes.

01/15/17

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

Date Printed: June 23, 2017: 06:29 PM