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Date Printed: August 23, 2017: 06:07 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-J1000-34

Original Effective Date: 08/15/11

Reviewed: 09/14/16

Revised: 04/15/17

Subject: Ipilimumab (Yervoy™) Injection

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.

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

DESCRIPTION:

Ipilimumab (Yervoy™), a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), was approved by the US Food and Drug Administration (FDA) in March of 2011 for the treatment of metastatic melanoma. Approval was based on the results of a phase III study of subjects with unresectable metastatic disease that progressed during systemic therapy. Subjects were randomized to one of three arms: ipilimumab plus glycoprotein 100 peptide vaccine (gp100), ipilimumab monotherapy, or gp100 monotherapy. Overall survival was significantly prolonged in both arms treated with ipilimumab when compared to the gp100 alone arm (10 months vs. 6.4 months, p<0.05). Additionally, subjects achieved partial response or stable disease after ipilimumab re-induction. In a second phase III study, the efficacy and safety of ipilimumab was evaluated as first-line therapy for metastatic melanoma. Subjects were randomized to dacarbazine plus ipilimumab or dacarbazine plus placebo. Subjected treated with ipilimumab had a longer overall survival when compared with those treated with placebo (11.2 vs. 9.1 months); furthermore, treatment with ipilimumab significantly prolonged the 3-year overall survival when compared to placebo (20.8% vs. 12.2%, HR 0.72, p<0.01). In October 2015, the FDA approved the use of nivolumab in combination with ipilimumab for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The FDA most recently approved ipilimumab for adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.

Current National Comprehensive Cancer Network (NCCN) guidelines for the treatment of melanoma recommend ipilimumab for unresectable or metastatic melanoma when used as second-line or subsequent therapy as a single agent for disease progression if not previously used and member’s performance status is 0-2. The guidelines stipulate that re-induction with ipilimumab is an option for a select group of individuals who did not experience significant toxicity during prior ipilimumab therapy,relapsed following initial therapy or progressed after stable disease of at least three months, and have a performance status of 0-2. The NCCN guidelines recommend ipilimumab in combination with nivolumab as first-line therapy or second-line/subsequent therapy for disease progression if not previously used and member’s performance status is 0-2. When compared to the use of single agent ipilimumab or nivolumab, the guidelines note that the combined use significantly increases the risk for serious autoimmune toxicity warranting careful patient selection, education and monitoring. Additionally, combination ipilimumab/nivolumab has demonstrated an improvement in relapse-free survival in previously untreated unresectable stage III or IV melanoma compared to single agent use, although the impact on overall survival is not known. The NCCN melanoma guidelines recommend ipilimumab as adjuvant treatment of melanoma as a high-dose single agent for stage IIIA with metastases >1 mm or stage IIIB-C disease with nodal metastases following a complete lymph node dissection with or without wide excision, and for adjuvant treatment following complete lymph node dissection and/or complete resection of nodal recurrence. The guidelines highlight an improvement in recurrence-free survival and overall survival with adjuvant use. Approximately 53% of patients required drug discontinuation due to adverse events associated with adjuvant use of ipilimumab.

The NCCN guidelines for Central Nervous System cancers recommend ipilimumab as a single-agent for the treatment of recurrent brain metastases if active against the primary tumor (melanoma). The NCCN guidelines for Small Cell Lung Cancer support use of ipilimumab in combination with nivolumab as subsequent systemic therapy for patients with performance status of 0-2 who have primary progressive disease or who have relapsed within 6 months following complete or partial response or stable disease with initial treatment.

POSITION STATEMENT:

I. Initiation of treatment with ipilimumab (Yervoy™) meets the definition of medical necessity when used to treat EITHER of the following:

A. Unresectable or metastatic melanoma when ALL of the following are met:

1. Member has not received prior therapy with ipilimumab (for members who have received prior ipilimumab therapy as a single agent, refer to criteria for reinduction).

2. Member meets one of the following:

a. Ipilimumab is used in combination with nivolumab as first-line therapy

b. Ipilimumab is used as a single agent as second-line or subsequent therapy for disease progression if not previously used AND member’s ECOG performance status is 0-2

c. Ipilimumab is used in combination with nivolumab as second-line or subsequent therapy for disease progression if not previously used AND member’s ECOG performance status is 0-2

3. The dose does not exceed 3 mg/kg for a total of 4 doses

B. Adjuvant treatment of melanoma

1. Member has complete resection of melanoma with lymphadenectomy

2. Member has Stage III disease with regional nodes of greater than 1 mm and no in-transit metastasis

3. Ipilimumab is used as a single agent

4. The dose does not exceed 10 mg/kg every 3 weeks for a total of 4 doses

C. Recurrent brain metastases from metastatic melanoma when ALL of the following are met:

1. Ipilimumab is used as a single agent

2. Ipilimumab was active against the primary tumor (i.e., Melanoma)

3. The dose does not exceed 10 mg/kg for a total of 4 doses

D. Small cell lung cancer

1. ONE of the following:

a. Member’s disease relapsed within 6 months of initial chemotherapy

b. Member’s disease is progressive on initial chemotherapy

2. Member’s ECOG performance status is 0-2

3. Ipilimumab will be used in combination with nivolumab

4. The dose does not exceed 3 mg/kg for a total of 4 doses

Approval Duration: 4 months (16 weeks)

II. Reinduction of ipilimumab therapy for treatment of melanoma meets the definition of medical necessity when ALL of the following criteria are met:

A. Member has completed initial induction therapy (i.e., completed 4 cycles within a continuous 16 week period)

B. Member relapsed after initial clinical response or progressed after stable disease greater than three (3) months (i.e., at least 3 months have passed since week 12 of initial cycle)

C. Member did not have significant systemic toxicity with prior ipilimumab use as indicated by ANY of the following

1. Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day.

2. Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (7 or more over baseline), stool incontinence, need for intravenous hydration for more than 24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation

3. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper limit of normal or total bilirubin >3 times the upper limit of normal

4. Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations

5. Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis

6. Severe immune-mediated reactions involving any organ system (e.g., nephritis, pneumonitis, pancreatitis, non-infectious myocarditis)

7. Immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy or requires systemic treatment

D. Member’s ECOG performance status is 0-2

E. The dose does not exceed 3 mg/kg for a total of 4 doses.

Approval duration: 4 months (16 weeks)

III. Continuation of ipilimumab for adjuvant treatment of melanoma or for treatment of brain metastases due to melanoma meets the definition of medical necessity when the following criteria are met:

A. The member has demonstrated a beneficial response to therapy (e.g., brain mets are stable, no disease recurrence with adjuvant treatment)

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. Ipilimumab is used as a single agent

D. The dose does not exceed 10 mg/kg every 12 weeks.

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:

Unresectable or metastatic melanoma: 3 mg/kg administered intravenously (IV) over 90 minutes every three weeks for a total of 4 doses. In the event of toxicity, doses may be delayed, but all treatment must be administered within 16 weeks of the first dose.

Adjuvant treatment of patients with cutaneous melanoma with regional lymph node involvement of more than 1 mm who have undergone complete resection, including lymphadenectomy: 10 mg/kg administered intravenously (IV) over 90 minutes every three weeks for 4 doses followed by 10 mg/kg every 12 weeks for up to 3 years or until documented disease recurrence or unacceptable toxicity. In the event of toxicity, doses are omitted, not delayed.

Dose Adjustments/Discontinuation

Although dose adjustments are not required for persons with renal impairment or mild hepatic impairment, ipilimumab has not been evaluated in persons with moderate or severe hepatic impairment.

See prescribing information for recommended treatment modifications for immune-mediated adverse reactions.

Ipilimumab should be discontinued for any of the following:

• Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day.

• Failure to complete full treatment course within 16 weeks from administration of first dose (unresectable or metastatic melanoma treatment).

• Severe or life-threatening adverse reactions, including any of the following:

o Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (7 or more over baseline), stool incontinence, need for intravenous hydration for more than 24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation

o Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper limit of normal or total bilirubin >3 times the upper limit of normal

o Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations

o Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis

o Severe immune-mediated reactions involving any organ system (e.g., nephritis, pneumonitis, pancreatitis, non-infectious myocarditis)

o Immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy or requires systemic treatment

Drug Availability: ipilimumab is supplied as a 50 mg/10 mL or 200 mg/40 mL single-use vial.

PRECAUTIONS:

Boxed Warning

• Treatment with ipilimumab can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. Although the reactions may involve any organ system, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. These may occur initially during treatment or weeks to months following discontinuation.

• Permanently discontinue ipilimumab and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

• Assess members for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.

Warnings/Precautions

• Immune-mediated adverse reactions: Permanently discontinue for severe reactions. Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and member is receiving less than 7.5 mg prednisone or equivalent per day. Administer systemic high-dose corticosteroids for severe, persistent, or recurring immune-mediated reactions.

• Immune-mediated hepatitis: Evaluate liver function tests before each dose of ipilimumab

• Immune-mediated endocrinopathies: Monitor ACTH level, thyroid function tests and clinical chemistries prior to each dose. Evaluate at each visit for signs and symptoms of endocrinopathy. Institute hormone replacement therapy as needed.

Embryo-fetal toxicity: Can cause fetal harm. Advise of potential risk to a fetus and use of effective contraception.

BILLING/CODING INFORMATION:

HCPCS Coding:

J9228

Injection, ipilimumab, 1 mg

ICD-10 Diagnoses Codes That Support Medical Necessity:

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

C43.0 – C43.9

Malignant melanoma of skin

C69.90

Malignant neoplasm of unspecified site of unspecified eye

C69.91

Malignant neoplasm of unspecified site of right eye

C69.92

Malignant neoplasm of unspecified site of left eye

C78.00 - C78.02

Secondary malignant neoplasm of lung

C79.31

Secondary malignant neoplasm of brain

C79.51 - C79.52

Secondary malignant neoplasm of bone and bone marrow

C80.0

Disseminated malignant neoplasm, unspecified

C80.1

Malignant (primary) neoplasm, unspecified

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.

DEFINITIONS:

Table 1: Eastern Cooperative Oncology Group (ECOG) Performance Status

Grade

Description

0

Fully active, able to carry on all pre-disease performance without restriction

1

Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work

2

Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours

3

Capable of only limited self-care, confined to bed or chair more than 50% of waking hours

4

Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair

5

Dead

RELATED GUIDELINES:

Adoptive Immunotherapy, 01-96400-01

Autologous Bone Marrow and Stem Cell Transplantation, 02-38241-01

Brachytherapy-Oncologic Applications, 04-77260-20

Carboplatin (Paraplatin®) IV, 09-J0000-96

Dermatoscopy, 02-10000-17

Nivolumab (Opdivo), 09-J2000-33

Paclitaxel and Paclitaxel (protein-bound) IV, 09-J1000-05

Positron Emission Tomography (PET Scans) Oncologic Application, 04-78000-17

Proton Beam Therapy, 04-77260-18

Transpupillary Thermotherapy (TTT), 01-92000-20

Whole Body Photography for Early Detection of Malignant Melanoma, 01-96900-03

OTHER:

Table 2: 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 Aug 25]. In: STAT!Ref Online Electronic Medical Library [Internet]. Available from: http://online.statref.com/.
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.;2016. URL www.clinicalpharmacilogy-ip.com Accessed 8/25/16.
  3. Ingenix HCPCS Level II, Expert 2013.
  4. Ingenix ICD-9-CM for Physicians – Volumes 1 & 2, Expert 2013.
  5. Larkin J, Chiarion-Sileni V, Gonzalez R. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. New Engl J Med. 2015; 373: 23-34.
  6. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label phase 2 trial. Lancet Oncol 2012;13:459-65.
  7. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 8/25/16.
  8. 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.
  9. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Version 1.2016. Central Nervous System Cancers. Available at http://www.nccn.org/professionals/physician_gls/PDF/cns.pdf. Accessed 8/25/16.
  10. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Version 1.2017. Melanoma. Available at http://www.nccn.org/professionals/physician_gls/PDF/melanoma.pdf. Accessed 3/3/17.
  11. National Comprehensive Cancer Network®. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Small Cell Lung Cancer, v.1.2017 [cited 2016-8-25]. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp..
  12. National Comprehensive Cancer Network (NCCN). Drugs & Biologics Compendium [Internet]. Fort Washington (PA): National Comprehensive Cancer Network; 2017 [cited 2017 Mar 3]. Available from: http://www.nccn.org/professionals/drug_compendium/content/contents.asp/.
  13. Opdivo (nivolumab) injection [package insert]. Bristol-Myers Squibb Company. Princeton, NJ. September 2015.
  14. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2016 [cited 2016 Aug 25]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.
  15. Postow MA, Chesney J, Pavlick AC et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. New Engl J Med. 2015; 372: 2006-17.
  16. Yervoy (ipilimumab) [package insert]. Bristol-Myers Squibb. Princeton (NJ): September 2016.

COMMITTEE APPROVAL:

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

GUIDELINE UPDATE INFORMATION:

08/15/11

New Pharmacy Coverage Guideline.

01/01/12

Revision to guideline; consisting of updating coding.

02/15/12

Revision to guideline; consisting of modifying position statement and updating coding.

08/15/13

Review and revision to guideline consisting of reformatting and revising description section and position statement; reformatting dosage/administration and precautions section; updating position statement and references.

10/15/14

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

09/15/15

Revision to guideline; consisting of position statement, coding

11/15/15

Review and revision to guideline; consisting of revising position statement;, warnings/precautions section, definitions, coding and references.

12/15/15

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

07/15/16

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

09/15/16

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

10/15/16

Revision to guideline; consisting of updating position statement, description, dose adjustments, and references.

4/15/17

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

Date Printed: August 23, 2017: 06:07 AM