Description:
Nivolumab (Opdivo) is a human programmed death receptor (PD-1)-blocking antibody. It enhances the antitumor response by binding to PD-1 receptors and blocking its interaction with PD-L1 and PD-L2.

Policy:
OPDIVO is a programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of: 

• • First-line treatment of advanced RCC (in combination with cabozantinib) in adults.

BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be medically necessary if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and not medically necessary.

Rationale:
The 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 two 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 percent (four complete and 34 partial responses), with 87 percent 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, one day to 13.8+ months), with a median of eight doses (range, one-31) in nivolumab-treated patients, and was two months (range, one day to 9.6+ months) in chemotherapy-treated patients. In this ongoing trial, 24 percent of patients received nivolumab for more than six months, and 3 percent of patients received nivolumab for more than one year.

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

Nivolumab’s efficacy to treat squamous NSCLC was established in a randomized trial of 272 participants, of whom 135 received nivolumab and 137 received docetaxel. The trial was designed to measure the amount of time participants lived after starting treatment (overall survival). On average, participants who received nivolumab lived 3.2 months longer than those participants who received docetaxel.

The safety and efficacy of nivolumab to treat squamous NSCLC was supported by a single-arm trial of 117 participants who had progressed after receiving a platinum-based therapy and at least one additional systemic regimen. The study was designed to measure objective response rate (ORR), or the percentage of participants who experienced partial shrinkage or complete disappearance of the tumor. Results showed 15 percent of participants experienced ORR, of whom 59 percent had response durations of six months or longer.

National Comprehensive Cancer Network (NCCN) Guidelines for Melanoma (Version 3.2015) recommend nivolumab for treatment of metastatic or unresectable melanoma in all patients as first-line therapy and as second-line or subsequent therapy in patients with a performance status of 0 – 2 who have failed treatment with a BRAF inhibibitor. 

References:

1. Opdivo^® Prescribing Information. BMS. Princeton, NJ. December 2014.
2. Opdivo^® Dossier. BMS. Princeton, NJ. December 2014.
3. AHFS Drug Information. Bethesda (MD): American Society of Health-System Pharmacists, Inc; 2015 [cited 2015-02-12]. In: STAT!Ref Online Electronic Medical Library [Internet]. Available from: http://online.statref.com/.
4. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2015 [cited 2015-02-12]. Available from: http://www.clinicalpharmacology.com/.
5. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine; 2000 Feb 29 - [cited 2015-02-12]. Available from: http://clinicaltrials.gov/.
6. DRUGDEX® System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 2015-02-12]. Available from: http://www.thomsonhc.com/.
7. E.R. Squibb & Sons, LLC. Opdivo (nivolumab) injection. 2014 [cited 2015-02-12]. In: DailyMed [Internet]. Bethesda (MD): National Library of Medicine. Available from: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f570b9c4-6846-4de2-abfa-4d0a4ae4e394/.
8. National Comprehensive Cancer Network®. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Melanoma, v. 2.2015 [cited 2015-02-12]. 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; 2015 [cited 2015-02-12]. 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; 2015 [cited 2015-02-12]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.

Coding Section:

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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