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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-J2000-33

Original Effective Date: 04/15/15

Reviewed: 03/08/17

Revised: 04/15/17

Subject: Nivolumab (Opdivo®)

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:

Nivolumab (Opdivo) is a monoclonal antibody that enhances the antitumor response by binding to the programmed death receptor-1 (PD-1) and blocking its interaction with ligand 1 and 2 (PD-L1 and PD-L2). It has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic melanoma both as a single agent and in combination with ipilimumab. The FDA approved the use of nivolumab to treat patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. For patients with NSCLC and EGFR or ALK genomic tumor aberrations, nivolumab is recommended only after disease progression following targeted therapy for these aberrations. The FDA has also approved the use of nivolumab for advanced renal cell carcinoma in patients who have received prior anti-angiogenic therapy. In May 2016, nivolumab was approved for the treatment of Classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation bretuximab vedotin. The FDA approved the use of nivolumab in November 2016 for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck with disease progression on or after a platinum-based therapy. In February 2017, the FDA approved nivolumab for the treatment of locally advanced or metastatic urothelial carcinoma for patients who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Certain indications are approved under accelerated approval based on tumor response rate and durability of response (i.e., CHL, urothelial carcinoma, melanoma when use in combination with ipilimumab or for BRAF V600 mutation-positive disease as a single agent). Continued approval for these indications may be contingent upon verification and description of clinical benefit in the confirmatory trials.

The initial safety and efficacy of nivolumab were evaluated in a randomized, open-label phase 3 trial (CheckMate-37) of subjects with unresectable (Stage IIIc) or metastatic (Stage IV) melanoma and disease progression following ipilimumab and, if BRAF V600 mutation‒positive, a BRAF inhibitor. Subjects were randomized to receive nivolumab 3 mg/kg every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102), either dacarbazine or carboplatin plus paclitaxel. The primary endpoints were objective response rate (ORR) and overall survival. Efficacy was assessed in a single-arm, noncomparative, preplanned interim analysis in the first 120 patients who received nivolumab in Trial 1 and in whom the minimum duration of follow-up was six months.

At six months, the primary endpoint of ORR in the 120 patients who received nivolumab was 32% (4 complete and 34 partial responses) with 87% having a response duration of 2.6 to more than 10 months. The ORR included patients with and without BRAF V600 mutation-positive disease. Evidence of a clinical benefit outside of tumor response rate has not been established. The median duration of exposure was 5.3 months (range, 1 day to 13.8+ months), with a median of 8 doses (range, 1-31) in nivolumab-treated patients, and was 2 months (range, 1 day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24% of patients received nivolumab for more than 6 months and 3% of patients received nivolumab for more than 1 year.

Nivolumab was discontinued for adverse reactions in 9% of patients, while 26% of patients receiving nivolumab had a drug delay for an adverse reaction. The most common adverse reaction (reported in at least 20% of patients) was rash.

National Comprehensive Cancer Network (NCCN) Guidelines for Bladder cancer, Colon and Rectal Cancer, Head and Neck cancer, Hodgkin’s Lymphoma, Kidney Cancer, Melanoma, Non-Small Cell Lung Cancer, Small Cell Lung Cancer, all include recommendations for use of nivolumab.

POSITION STATEMENT:

I. Initiation of nivolumab (Opdivo) meets the definition of medical necessity for members diagnosed with ANY of the following conditions in Table 1 when ALL of the indication specific criteria are met:

Table 1

Indication

Specific Criteria

Bladder cancer (also includes cancer of the urethra, upper genitourinary tract, and prostate)

When ALL of the following are met:

1. Member is diagnosed with locally advanced or metastatic urothelial carcinoma

2. Member’s meets ONE of the following:

a. Disease progressed on or after platinum-based therapy (e.g., cisplatin or carboplatin)

b. Disease progressed within 12 months of neoadjuvant or adjuvant treatment with platinum-based therapy

3. Nivolumab will be used as a single agent

4. Dose does not exceed 240 mg every 2 weeks

Classical Hodgkin’s Lymphoma (CHL)

When ALL of the following are met:

1. ONE of the following:

a. For relapsed or refractory disease in members 18 years of age or older

b. For palliative therapy in members greater than 60 years of age

2. Nivolumab will be used as monotherapy

3. Dose does not exceed 3 mg/kg every 2 weeks

Colon or Rectal cancer

When ALL of the following are met:

1. Member has metastatic or unresectable advanced disease

2. Tumor is classified as microsatellite instability-high [MSI-H] or mismatch repair deficient [dMMR]

3. The member has not previously received nivolumab or pembrolizumab therapy

4. When used for ONE of the following

a. As subsequent therapy following disease progression with oxaliplatin-, irinotecan- or fluoropyrimidine-based therapy

b. As initial therapy in members who are not candidates for more intensive therapy

c. Following adjuvant FOLFOX or CapeOX if received within the previous year

5. Nivolumab will be used as a single agent

6. Dose does not exceed maximum FDA-approved dosing (either 3 mg/kg or 240 mg every 2 weeks)

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::

a. Used as subsequent therapy for member’s with predominant clear cell histology

b. Used as treatment for member’s with non-clear histology

3. Nivolumab will be used as monotherapy

4. Dose does not exceed 240 mg every 2 weeks

Melanoma

When ALL of the following are met:

1. Member’s disease is unresectable or metastatic

2. Nivolumab will be used as a single agent or in combination with ipilimumab

3. Member meets one of the following:

a. Nivolumab is used as first-line therapy

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

c. Nivolumab is used as reinduction therapy and ALL of the following:

i. Members disease relapsed or progressed greater than 3 months after initial clinical response or stable disease with previous nivolumab treatment

ii. Member does not have any remaining toxicity from previous nivolumab treatment

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

4. Dose does not exceed the following:

a. 240 mg every 2 weeks when used as a single-agent

b. 1 mg/kg every 3 weeks for four doses when used in combination with ipilimumab, followed by 240 mg every 2 weeks as a single-agent

Non-small Cell Lung Cancer (NSCLC)

When ALL of the following are met:

1. Member is diagnosed with adenocarcinoma, squamous cell, or large cell NSCLC

2. Member’s disease is metastatic

3. Member’s disease progressed on or after initial chemotherapy

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

5. The member has not previously received a checkpoint inhibitor (e.g., nivolumab, pembrolizumab, or atezolizumab)

6. Nivolumab will be used as monotherapy

7. Dose does not exceed 240 mg every 2 weeks

Small Cell Lung Cancer (SCLC)

When ALL of the following are met:

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. Nivolumab will be used as a single agent or in combination with ipilimumab

4. Dose does not exceed the following:

a. 3 mg/kg every 2 weeks when used as a single agent

b. 1 mg/kg every 3 weeks for four doses when used in combination with ipilimumab, followed by 3 mg/kg every 2 weeks as a single-agent

Squamous cell carcinoma of the Head and Neck (SCCHN)

When ALL of the following are met:

1. Member’s disease is recurrent, unresectable, or metastatic

2. Member’s disease progressed on or after platinum-based therapy (e.g., cisplatin or carboplatin)

3. Member’s ECOG performance status is 0-3

4. Nivolumab will be used as a single agent

5. Dose does not exceed 3 mg/kg every 2 weeks

Approval duration: 6 months

II. Nivolumab (Opdivo) meets the definition of medical necessity 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 dosing:

1. Treatment of hepatocellular carcinoma

2. Treatment of esophageal cancer

3. Treatment of gastric and gastro-esophageal junction cancer

Duration of approval: 6 months

III. Continuation of nivolumab (Opdivo) meets the definition of medical necessity for the indications in Table 1 and orphan indications for members meeting the following criteria:

1. 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

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

3. Nivolumab will be continued as a single-agent

4. Dose does not exceed the following based on indication:

a. Melanoma, NSCLC, Kidney, and Bladder cancer: 240 mg every 2 weeks

b. CHL, SCLC, SCCHN: 3 mg/kg every 2 weeks

c. Colon or rectal cancer, Hepatocellular, gastric and gastro-esophageal junction cancer and esophageal cancer: does not exceed maximum FDA-approved dosing

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

Dose Adjustments

Drug Availability

PRECAUTIONS:

Boxed Warning

None

Contraindications

None

Precautions/Warnings

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding

J9299

Injection, nivolumab, 1 mg

ICD-10 Diagnoses Codes That Support Medical Necessity

C00.0 – C08.9

Malignant neoplasm of lip, base of tongue, of other and unspecified parts of tongue, gum, floor of mouth, palate, of other and unspecified parts of mouth, parotid and salivary gland.

C09.0 – C10.9

Malignant neoplasm of tonsil and oropharynx

C11.0 – C11.9

Malignant neoplasm of nasopharynx

C12.0 – C14.8

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

C15.3 – C15.9

Malignant neoplasm of esophagus

C16.0 – C16.9

Malignant neoplasm of stomach

C17.0 – C17.9

Malignant neoplasm of small intestine

C18.0 – C18.9

Malignant neoplasm of colon

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

C22.2

Hepatoblastoma

C22.7

Other specified carcinomas of liver

C22.8

Malignant neoplasm of liver, primary, unspecified as to type

C22.9

Malignant neoplasm of liver, not specified as primary or secondary

C30.0

Malignant neoplasm of nasal cavity

C31.0 – C31.9

Malignant neoplasm of accessory sinuses

C32.0 – C32.9

Malignant neoplasm of larynx

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

Malignant melanoma of lip

C43.10

Malignant melanoma of unspecified eyelid, including canthus

C43.11

Malignant melanoma of right eyelid, including canthus

C43.12

Malignant melanoma of left eyelid, including canthus

C43.20

Malignant melanoma of unspecified ear and external auricular canal

C43.21

Malignant melanoma of right ear and external auricular canal

C43.22

Malignant melanoma of left ear and external auricular canal

C43.30

Malignant melanoma of unspecified part of face

C43.31

Malignant melanoma of nose

C43.39

Malignant melanoma of other parts of face

C43.4

Malignant melanoma of scalp and neck

C43.51

Malignant melanoma of anal skin

C43.52

Malignant melanoma of skin of breast

C43.59

Malignant melanoma of other part of trunk

C43.60

Malignant melanoma of unspecified upper limb, including shoulder

C43.61

Malignant melanoma of right upper limb, including shoulder

C43.62

Malignant melanoma of left upper limb, including shoulder

C43.70

Malignant melanoma of unspecified lower limb, including hip

C43.71

Malignant melanoma of right lower limb, including hip

C43.72

Malignant melanoma of left lower limb, including hip

C43.8

Malignant melanoma of overlapping sites of skin

C43.9

Malignant melanoma of skin, unspecified

C44.00

Malignant neoplasm of skin of lip

C44.02

Squamous cell carcinoma of skin of lip

C44.09

Other specified malignant neoplasm of skin of lip

C61

Malignant neoplasm of prostate (urothelial carcinoma)

C64.1 – C64.9

Malignant neoplasm of unspecified kidney, except renal pelvis

C65.1 – C65.9

Malignant neoplasm of unspecified renal pelvis

C66.1 – C66.9

Malignant neoplasm of ureter

C67.0 – C67.9

Malignant neoplasm of bladder

C68.0 – C68.9

Malignant neoplasm of other and unspecified urinary organs

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

C76.0

Malignant neoplasm of head, face and neck

C77.0

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

C78.00 – C78.89

Secondary malignant neoplasm of respiratory and digestive organs

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

C81.10 – C81.99

Hodgkin Lymphoma

D37.01

Neoplasm of uncertain behavior of lip

D37.02

Neoplasm of uncertain behavior of tongue

D37.04

Neoplasm of uncertain behavior of the minor salivary glands

D37.05

Neoplasm of uncertain behavior of pharynx

D37.09

Neoplasm of uncertain behavior of other specified sites of the oral cavity

D38.0

Neoplasm of uncertain behavior of larynx

D38.5

Neoplasm of uncertain behavior of other respiratory organs

D38.6

Neoplasm of uncertain behavior of respiratory organ, 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 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:

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:

Dabrafenib (Tafinlar®) Capsules
Ipilimumab (Yervoy®) Injection

Pembrolizumab (Keytruda®) Injection

Trametinib (Mekinist™) Tablets

OTHER:

None

REFERENCES:

  1. AHFS Drug Information. Bethesda (MD): American Society of Health-System Pharmacists, Inc; 2017 [cited 2017-02-14]. In: STAT!Ref Online Electronic Medical Library [Internet]. Available from: http://online.statref.com/.
  2. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2017 [cited 2017-02-14]. Available from: http://www.clinicalpharmacology.com/.
  3. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine; 2000 Feb 29 - [cited 2016-02-12]. Available from: http://clinicaltrials.gov/.
  4. DRUGDEX® System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 2017-02-14]. Available from: http://www.thomsonhc.com/.
  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. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Version 2.2017. Bladder cancer. Available at http://www.nccn.org/professionals/physician_gls/PDF/bladder.pdf. Accessed 2/15/17.
  7. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Version 1.2017. Colon cancer. Available at http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf. Accessed 12/21/16.
  8. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Version 1.2017. Head and Neck Cancer. Available at http://www.nccn.org/professionals/physician_gls/PDF/head-and-neck.pdf. Accessed 2/21/17.
  9. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Version 3.2016. Hodgkin Lymphoma. Available at http://www.nccn.org/professionals/physician_gls/PDF/hodgkins.pdf. Accessed 8/9/16.
  10. National Comprehensive Cancer Network®. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Kidney Cancer, v.2.2017 [cited 2017-02-21]. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
  11. National Comprehensive Cancer Network®. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Melanoma, v.1.2017 [cited 2017-02-21]. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
  12. National Comprehensive Cancer Network®. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Non-Small Cell Lung Cancer, v.4.2017 [cited 2017-2-21]. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp
  13. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Version 2.2017. Rectal cancer. Available at http://www.nccn.org/professionals/physician_gls/PDF/rectal.pdf. Accessed 2/21/17.
  14. National Comprehensive Cancer Network®. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Small Cell Lung Cancer, v.2.2017 [cited 2016-10-4]. Available from: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
  15. NCCN Drugs & Biologics Compendium [Internet]. Fort Washington (PA): National Comprehensive Cancer Network;2017 [cited 2017-02-14]. Available from: http://www.nccn.org/professionals/drug_compendium/content/contents.asp/.
  16. Opdivo (nivolumab) injection [package insert]. Bristol-Myers Squibb Company. Princeton, NJ. February 2017.
  17. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2017 [cited 2017-02-14]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.
  18. Postow MA, Chesney J, Pavlick AC et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. New Engl J Med. 2015; 372: 2006-17.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 03/08/17.

GUIDELINE UPDATE INFORMATION:

04/15/15

New Medical Coverage Guideline.

06/15/15

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

07/1/15

Revision of guideline; consisting of coding update.

08/15/15

Revision of guideline; consisting of position statement, coding.

11/15/15

Revision of guideline; consisting of updating position statement, description, dosing/administration, warnings, and references.

12/15/15

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

01/01/16

Annual HCPCS coding update: added code J9299 and deleted codes C9453 and J9999.

01/15/16

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

04/15/16

Review and revision to guidelines; updating position statement, references.

6/15/16

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

7/15/16

ICD-10 coding update.

8/15/16

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

9/15/16

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

10/15/16

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

11/15/16

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

02/15/17

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

04/15/17

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

Date Printed: August 20, 2017: 01:54 AM