Medical Policy

 

Subject: Nivolumab (Opdivo®)
Document #: DRUG.00075 Publish Date:    06/06/2018
Status: Revised Last Review Date:    05/03/2018

Description/Scope

This document addresses the use of nivolumab (Opdivo, Bristol-Myers Squibb Company, Princeton, NJ), a human programed death receptor-1 (PD-1) blocking antibody, for the treatment of unresectable metachronous metastases or unresectable advanced or metastatic colorectal cancer; recurrent, unresectable or metastatic squamous cell carcinoma of the head and neck; advanced hepatocellular carcinoma; relapsed or refractory Hodgkin lymphoma; resected advanced, unresectable or metastatic melanoma (cutaneous and uveal); metastatic or recurrent locoregional Merkel cell carcinoma; malignant pleural mesothelioma; metastatic non-small cell lung cancer; advanced or metastatic (clear cell) renal cell carcinoma (a form of kidney cancer); small cell lung cancer; and locally advanced or metastatic urothelial carcinoma. Nivolumab is also being studied for use in other malignancies (for example non-Hodgkin lymphoma) and solid tumors.

Note: Please see these documents for related topics:

Position Statement

Medically Necessary:

Colorectal Cancer:
The use of nivolumab is considered medically necessary for the treatment of individuals with colorectal cancer when all the following criteria are met:

  1. Being used as a single agent; and
  2. Individual meets one of the following criteria:
    1. Primary treatment as a single agent for unresectable metachronous metastases (defective mismatch repair/high microsatellite instability [dMMR/MSIH] only) and previous adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months; or
    2. Subsequent therapy as a single agent (if nivolumab or pembrolizumab not previously given) for unresectable advanced or metastatic disease (defective mismatch repair/high microsatellite instability [dMMR/MSIH] only) following previous treatment with oxaliplatin-irinotecan; and
  3. Has not received another PD-1 agent (for example, pembrolizumab); and
  4. Current Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; and
  5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Hepatocellular Carcinoma:
The use of nivolumab is considered medically necessary for the treatment of individuals with advanced hepatocellular carcinoma when the following criteria are met:

  1. Nivolumab is used as a single agent; and
  2. Demonstrated disease progression on or had intolerance to sorafenib; and
  3. Current ECOG performance status of 0-2; and
  4. Has not received treatment with another PD-1 agent (for example, pembrolizumab); and
  5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Hodgkin Lymphoma:
The use of nivolumab is considered medically necessary for the treatment of individuals with relapsed or refractory Hodgkin lymphoma except for those with lymphocyte-predominant Hodgkin lymphoma.

Malignant Pleural Mesothelioma:
The use of nivolumab as a single agent is considered medically necessary for the treatment of individuals with malignant pleural mesothelioma when the following criteria are met:

  1. Being used as subsequent therapy; or
  2. Individual is ineligible for platinum-based chemotherapy, defined as having one or more of the following risk factors for platinum-based chemotherapy toxicity:
    1. ECOG performance status equal to 2;
    2. Glomerular filtration rate less than 60 mL/min;
    3. Hearing loss (measured at audiometry) of 25 dB at two contiguous frequencies;
    4. Grade 2 or greater peripheral neuropathy; and
  3. Current ECOG performance status of 0-2; and
  4. Has not received treatment with another PD-1 agent (for example, pembrolizumab); and
  5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Melanoma (Cutaneous and Uveal):

  1. The use of nivolumab is considered medically necessary for the treatment of individuals with unresectable or metastatic melanoma when the following criteria are met:
    1. Nivolumab is used as a single agent, or in combination with ipilimumab, as first-line therapy for untreated melanoma; or
    2. Nivolumab is used as a single agent, or in combination with ipilimumab as second-line or subsequent therapy for documented disease progression while receiving or since completing most recent therapy, if PD-1 agent not previously used; and
    3. Current ECOG performance status of 0-2; and
    4. Has not received treatment with another PD-1 agent (for example, pembrolizumab); and
    5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.
  2. The use of nivolumab as a single agent is considered medically necessary for up to 12 months of adjuvant therapy for the treatment of individuals with resected advanced melanoma when the following criteria are met:
    1. The individual has resected stage IIIB, IIIC or stage IV disease; and
    2. Current ECOG performance status of 0-2; and
    3. Has not received treatment with another PD-1 agent (for example, pembrolizumab); and
    4. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Merkel Cell Carcinoma (MCC):
The use of nivolumab is considered medically necessary for the treatment of individuals with MCC when all the following criteria are met:

  1. Being used as a single agent; and
  2. Presence of metastatic or recurrent locoregional MCC determined to be not amenable to definitive surgery or radiation therapy; and
  3. Current ECOG performance status of 0-2; and
  4. Has not received treatment with another PD-1 agent (for example, pembrolizumab); and
  5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Non-Small Cell Lung Cancer (NSCLC):
The use of nivolumab is considered medically necessary for the treatment of individuals with metastatic NSCLC when all the following criteria are met:

  1. Being used as a single agent; and
  2. Demonstrated disease progression on or after platinum-containing chemotherapy; and
  3. Has not received treatment with another PD-1 agent (for example, pembrolizumab); and
  4. Current ECOG performance status of 0-2; and
  5. Not receiving therapy for an autoimmune disease, chronic condition or interstitial lung disease with a systemic immunosuppressant.

Renal Cell Carcinoma (RCC):

  1. The use of nivolumab is considered medically necessary for the treatment of individuals with advanced or metastatic RCC when all the following criteria are met:
    1. Being used as a single agent; and
    2. Histologic confirmation of RCC with clear-cell component; and
    3. Demonstrated progression after one or two prior anti-angiogenic regimens (for example, axitinib, bevacizumab, pazopanib, sorafenib, sunitinib, etc.) for treatment of advanced or metastatic disease; and
    4. Has not received treatment with another PD-1 agent (for example, pembrolizumab); and
    5. Current ECOG performance status 0-2; and
    6. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.
  2. The use of nivolumab is considered medically necessary for the treatment of individuals with intermediate- or poor-risk, advanced RCC when all the following criteria are met:
    1. Nivolumab is  used in combination with ipilimumab, as first-line therapy for previously untreated RCC; or
    2. Nivolumab is used in combination with ipilimumab if no checkpoint blockade (PD-1, PD-L1, or CTLA-4) antibody treatment has been previously administered; and
    3. Histologic confirmation of RCC with clear-cell component; and
    4. Current ECOG performance status 0-2; and
    5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Squamous Cell Carcinoma of the Head and Neck (SCCHN):
The use of nivolumab is considered medically necessary for the treatment of individuals with recurrent, unresectable or metastatic SCCHN when all the following criteria are met:

  1. Being used as a single agent; and
  2. Has demonstrated disease progression on or after platinum-containing chemotherapy; and
  3. Has not received treatment with another PD-1 agent (for example, pembrolizumab); and
  4. Current ECOG performance status of 0-2; and
  5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Small Cell Lung Cancer (SCLC):
The use of nivolumab is considered medically necessary for the treatment of individuals with small cell lung cancer when the following criteria are met:

  1. Nivolumab is used as a single agent, or in combination with ipilimumab, as subsequent therapy and individual meets one of the following:
    1. Demonstrated disease relapse within 6 months following complete or partial response or stable disease with initial treatment; or
    2. No response with initial treatment; or
    3. Primary progressive disease; and
  2. Has not received treatment with another PD-1 agent (for example, pembrolizumab); and
  3. Current ECOG performance status of 0-2; and
  4. Not receiving therapy for an autoimmune disease, chronic condition or interstitial lung disease with a systemic immunosuppressant.

Urothelial Carcinoma:
The use of nivolumab is considered medically necessary for the treatment of individuals with locally advanced or metastatic urothelial carcinoma when all the following criteria are met:

  1. Being used as a single agent; and
  2. Individual meets one of the following criteria:
    1. Has demonstrated disease progression on or after platinum-containing chemotherapy; or
    2. Has demonstrated disease progression within 12 months of receiving neoadjuvant or adjuvant treatment with platinum-containing chemotherapy; and
  3. Has not received treatment with another PD-1 agent (for example, pembrolizumab); and
  4. Current ECOG performance status of 0-2; and
  5. Not receiving therapy for an autoimmune disease or chronic condition requiring treatment with a systemic immunosuppressant.

Investigational and Not Medically Necessary:

The use of nivolumab is considered investigational and not medically necessary when the above criteria are not met, including but not limited to any of the following:

  1. Treatment used as first line therapy, except as described above;
  2. Presence of human immunodeficiency virus (HIV) infection, hepatitis B virus infection, or hepatitis C virus infection;
  3. The reason for treatment is other than for a diagnosis with accompanied criteria noted above.
Rationale

Melanoma (Cutaneous and Uveal):
Metastatic melanoma is an aggressive disease. The median survival for individuals with stage IV melanoma is 6–10 months, and less than 5% of individuals survive beyond 5 years (Khan, 2006). It has been estimated that approximately 50% of cutaneous melanomas carry the mutated BRAF gene which keeps the protein production constantly activated and driving cell growth (Davies, 2002). Most of these mutations occur at amino acid position 600, the most common of which results in the V600E amino acid substitution (Arkenau, 2011). Despite recent advances, melanoma treatment remains a challenge since there are few effective treatment options for individuals who relapse or do not respond to ipilimumab or BRAF inhibitors.

The National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology on Melanoma (2018) address the challenges with treatment for stage IV melanoma:

The therapeutic landscape for metastatic melanoma is rapidly changing with the recent development of novel agents, which has demonstrated better efficacy than traditional chemotherapy. The first generation of novel targeted and immunotherapy agents (ie, vemurafenib, dabrafenib, ipilimumab) demonstrated significantly improved response rates and outcomes compared with conventional therapies. Subsequently, a number of ongoing or recently completed phase II and phase III trials testing new immunotherapies, targeted therapies, and combination regimens have yielded noteworthy results. A second generation of effective agents and combination regimens are now available for treatment of advanced unresectable or metastatic melanoma.

On December 22, 2014 nivolumab was the second PD-1 antibody to achieve accelerated approval and breakthrough therapy status by the U.S. Food and Drug Administration (FDA), providing an option for individuals with late-stage cancer who have been through several other therapies and yet still have disease progression. The FDA approved nivolumab (as a single agent) for the treatment of unresectable or metastatic melanoma and disease progression in individuals following ipilimumab (Yervoy™ intravenous [IV]; Bristol-Myers Squibb, Princeton, NJ) and, if BRAF V600 mutation positive, a BRAF inhibitor. BRAF inhibitors are dabrafenib (Tafinlar® oral; GlaxoSmithKline, Research Triangle Park, NC) or vemurafenib (Zelboraf® oral; Genentech, San Francisco, CA). On September 30, 2015 the FDA granted accelerated approval for nivolumab in combination with ipilimumab for the treatment of individuals with unresectable or metastatic melanoma BRAF V600 wild-type. On January 23, 2016 the FDA expanded the use of nivolumab in combination with ipilimumab for the treatment of individuals with BRAF V600 wild-type and BRAF V600 mutation-positive unresectable or metastatic melanoma. The approval expands the original indication for combination therapy with nivolumab and ipilimumab regardless of BRAF mutation status based on results from the CheckMate-067 trial (Product Information Label, 2018).

The FDA accelerated approval of nivolumab was based on preliminary data from the CheckMate 037 trial. Continued approval of nivolumab is contingent on confirmatory trials underway. The single-arm, open-label, multicenter phase III trial randomized subjects 2:1 to nivolumab or chemotherapy (physician’s option of dacarbazine or carboplatin and paclitaxel). All subjects had disease progression following ipilimumab and a BRAF inhibitor, if the V600 mutation was positive. The preliminary data reported 120 subjects (median age 59.5 years) with unresectable or metastatic melanoma with disease progression within 24 weeks of their last dose of ipilimumab, and if BRAF V600 mutation positive, prior treatment with BRAF inhibitor. An overall response rate (ORR) was achieved in 32% of nivolumab subjects; of the 38 subjects with responses, 33 had duration from 2.6-10 months (13 subjects had response of 6 months or more). The trial excluded participants with prior treatment with another PD-1 agent, known autoimmune disease, an unstable chronic condition requiring corticosteroids or other immunosuppressive medication and active hepatitis B, hepatitis C or a history of HIV. The most common drug related adverse events reported were rash (21%), itching (19%), cough (17%), upper respiratory tract infections (11%), and peripheral edema (10%).

In 2015, Robert and colleagues reported on the results of the phase III CheckMate-066 trial of 418 participants (adults 18 years or older) with unresectable, untreated stage III or IV metastatic melanoma (per American Joint Committee of Cancer [AJCC] staging system) without a BRAF mutation. Participants were randomly assigned to receive nivolumab or dacarbazine. Additional inclusion criteria for the study included participants who had an ECOG score of 0 or 1 (on scale of 0 to 5). Major exclusion criteria included active brain or leptomeningeal metastases, uveal melanoma, and any active, known or suspected autoimmune disease. The 1-year overall survival (OS) was 72.9% with nivolumab versus 42.1% for chemotherapy group (hazard ratio [HR] = 0.42; p<0.001). The median progression-free survival (PFS) was 5.1 months versus 2.2 months, for nivolumab and dacarbazine, respectively. The safety profiles were similar between groups with treatment well tolerated in this population. There were no drug–related deaths reported. Grade 3 or 4 adverse events occurred in 11.7% of study participants treated with nivolumab and 17.6% of participants treated with dacarbazine. Common adverse events associated with use of nivolumab were fatigue, pruritus, and nausea. The authors concluded, “nivolumab was associated with a significant improvement in overall survival and progression-free survival, as compared with dacarbazine. Nivolumab was associated with a low risk of high-grade toxicity effects.”

The FDA expanded indication for combination use of nivolumab and ipilimumab as treatment of individuals with BRAF V600 wild-type unresectable or metastatic melanoma are based on findings from the Phase II Check-Mate-069 study. The double-blind trial with 142 treatment-naïve participants with stage III/IV melanoma were randomized in a 2:1 ratio to receive ipilimumab plus nivolumab (n=95) or ipilimumab monotherapy (n=47) until disease progression or death. The rate of confirmed objective response among participants with BRAF V600 wild-type tumors was 61% (44 of 72 participants) in the group that received combination therapy versus 11% (4 of 37 participants) in the ipilimumab monotherapy group (p<0.001). In summary the authors reported that:

The combination of ipilimumab plus nivolumab resulted in durable responses and substantially higher objective response rate, longer progression-free survival, and higher rates of complete response than ipilimumab monotherapy among patients with BRAF wild-type advanced melanoma and those with BRAF-mutant advanced melanoma. The incidence of grade 3 or 4 adverse events was higher with combination therapy, but adverse events were generally manageable when established safety guidelines were used. The risk-benefit profile of combined PD-1 and CTLA-4 blockade, as compared with monotherapy, will be further clarified by data from ongoing phase 3 double-blind trials.

Larkin and colleagues (2015) reported results from the CheckMate 067 trial (NCT01844505), a randomized, double-blind phase 3 study that assigned 945 treatment naïve participants with histologically confirmed stage III (unresectable) or IV metastatic melanoma to receive nivolumab alone (n=316), nivolumab plus ipilimumab (n=314), or ipilimumab alone (n=315). Additional inclusion criteria included adults age 18 years or older; ECOG score 0 or 1; BRAF V600 mutation status. Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria. Key exclusion criteria included presence of autoimmune disease, active brain metastases or ocular melanoma, condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications and prior treatment with another PD-1 agent. Co-primary endpoints were PFS and OS.

The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001) and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1-negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group.

In conclusion the authors found individuals with previously untreated advanced melanoma had longer PFS and higher rates of OS with nivolumab alone and with combination of nivolumab and ipilimumab than with ipilimumab alone.

The updated NCCN Drugs and Biologics Compendium™ and the NCCN clinical practice guideline (CPG) for melanoma (2018) include Category 2A recommendations for use of nivolumab as a single agent or combination with ipilimumab as first-line, second-line or subsequent therapy for treatment of metastatic or unresectable melanoma. The NCCN off-label recommendation is based on a phase III trial of nivolumab alone or combination nivolumab and ipilimumab versus ipilimumab alone in previously untreated participants with stage III or IV unresectable melanoma. The NCCN CPG for melanoma includes a Category 1 recommendation for the use of nivolumab in the treatment of adjuvant treatment for resected stage IIIB/C melanoma (preferred adjuvant immunotherapy regimen). “Nivolumab has shown a clinically significant improvement in relapse free survival (RFS) compared to high-dose ipilimumab, but its impact on overall survival (OS) has not yet been reported. Most panel members prefer adjuvant nivolumab over high-dose ipilimumab based on improved efficacy and less toxicity, even in the absence of reported OS data.”

Weber and colleagues (2017) reported results from the CheckMate 238 study (NCT02388906) a randomized, double-blind, phase 3 trial that randomly assigned 906 participants who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma and received adjuvant nivolumab or ipilimumab up to one year or until disease recurrence, or until disease recurrence, unacceptable toxic effects or withdrawal of consent. The authors reported:

A minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment.

In conclusion, individuals undergoing resection for stage IIIB, IIIC or IV melanoma, adjuvant therapy with nivolumab resulted in a longer recurrent-free survival and lower rate of grade 3 or 4 adverse events than adjuvant treatment with ipilimumab.

Recently, there has been increasing interest in the use of nivolumab for another form of metastatic uveal melanoma. In the recently updated NCCN Drugs and Biologics Compendium and the NCCN Clinical Practice Guideline for uveal melanoma (2018), the NCCN panel offers off-label recommendations (category 2A) for use of ipilimumab as a single agent or in combination with nivolumab for the treatment of unresectable disease. The NCCN panel recommendation for use of ipilimumab as a single agent is based on retrospective case series (Algazi, 2016) that evaluated nivolumab as a treatment option of uveal melanoma. The recommendation for combination therapy is based on unpublished data from a phase II multicenter, single arm, open-label study of nivolumab in combination with ipilimumab as first line in adults with metastatic uveal melanoma (NCT02626962).

The NCCN Drugs and Biologics Compendia and the NCCN Clinical Practice Guideline for central nervous system cancers (2018) offers a category 2A recommendation for nivolumab in combination with ipilimumab in the treatment of newly diagnosed or recurrent brain metastases secondary to melanoma and stable systemic disease or reasonable systemic treatment options.

NSCLC:
On March 4, 2015 the FDA expanded the indication for nivolumab to include treatment of individuals with metastatic squamous NSCLC with progression on or after platinum-based chemotherapy. On October 9, 2015 the FDA granted accelerated approval for nivolumab to treat individuals with advanced (metastatic) NSCLC whose disease progressed during or after platinum-based chemotherapy. (Product Information Label, 2018).

The FDA expanded use for metastatic squamous NSCLC was based on superior OS from the CheckMate-017 trial. This open-label, multicenter, multinational randomized trial allocated participants who had experienced disease progression while on or after receiving a platinum-based chemotherapy regimen to nivolumab (n=135) or docetaxel (n=137). Nivolumab demonstrated improvement in OS as compared with docetaxel, with median OS of 9.2 months (95% CI: 7.3, 13.3) for nivolumab population and 6 months (95% CI: 5.1, 7.3) for docetaxel (HR 0.59% CI: 0.44, 0.79, p=0.00025).

Rizvi and colleagues (2015) reported results from the CheckMate-063 study, a phase II single-arm, multicenter international study of participants with metastatic squamous NSCLC who had disease progression after platinum-based therapy and at least one systemic regimen. A total of 117 participants received IV nivolumab (3 mg/kg) treatment every 2 weeks until disease progression or complications related to drug toxicity. The major efficacy outcome was based on OS of participants with confirmed objective response, as assessed by an independent radiology review committee (IRC) using Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1).

Median time to response was 3.3 months (IQR 2.2-4.8). and median duration of response was not reached (95% CI 8.31-not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6.0 months, 95% CI 4.7-10.9). 20 (17% of 117 patients reported grade 3-4 treatment related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhea (three [3%]). There were two treatment associated deaths caused by pneumonia and ischemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease.

Few treatment options exist for advanced, refractory squamous non-small-cell lung cancer, with no clear standard of care. Our study shows clinically meaningful activity and a manageable safety profile of nivolumab for this patient population and supports assessment of nivolumab in phase 3 studies of first-line and second-line treatment.

In the non-small cell lung cancer CPG in oncology (2018), the NCCN panel offers a category 1 recommendation for use of nivolumab:

As subsequent therapy for patients with metastatic squamous cell carcinoma who have progressed on or after platinum-based chemotherapy based on data from a phase 3 randomized trial (CheckMate-017), the recent FDA approval, and results of a phase II trial. In an interim update, the NCCN Panel recommends nivolumab as subsequent therapy for patients with metastatic nonsquamous NSCLC who have progressed on or after platinum-based chemotherapy based on preliminary data from a phase III randomized trial (CheckMate-057). For patients receiving nivolumab, median overall survival was 12.2 months compared with 9.4 moths with docetaxel (HR 0.73, 95% CI, 0.59 to 0.89; P=.0015). Fewer grade 3 to 5 adverse events were reported for nivolumab (10%) when compared with docetaxel (54%) in the CheckMate-057 trial. Although many patients with metastatic nonsquamous NSCLC benefit from nivolumab, those whose tumors have PD-L1 staining of 1% to 10% or more have overall survival of 17.2 to 19.4 months compared with 8 to 9 months for docetaxel. Testing for PD-L1 is not required for prescribing nivolumab for NSCLC but may be useful information.

RCC:
On November 23, 2015 the FDA expanded the use of nivolumab for treatment of individuals with advanced (metastatic) renal cell carcinoma who have received prior anti-angiogenic therapy, based on results from the CheckMate-025 trial. Motzer and colleagues (2015) reported results from the CheckMate-025 trial, a randomized, open-label, phase 3 study that compared nivolumab with everolimus. A total of 821 participants with advanced (clear cell) RCC were randomized in a 1:1 ratio to receive nivolumab 3 mg per kilogram intravenously every 2 weeks or 10 mg of everolimus administered orally daily. The primary endpoint for the study was OS; the median OS for the nivolumab group was 25.0 months (95% CI, 21.8 to not estimable) versus19.6 months (95% CI, 17.6 to 23.1) for the everolimus group. “The hazard ratio for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority (P≤0.0148)”. Fewer grade 3 or 4 adverse events were reported in the nivolumab group with adverse events occurring in 19% of the nivolumab population compared to 37% of the everolimus population.

The NCCN Drugs and Biologics Compendium™ (2018) and the NCCN CPG for kidney cancer included a category 1 recommendation for off-label use of nivolumab as subsequent therapy as a single agent in treatment of individuals with clear cell histology after tyrosine kinase inhibitor therapy based on results from the CheckMate-025 trial reported by Motzer and colleagues (2015).

On April 16, 2018 the FDA granted expanded approval for nivolumab in combination with ipilimumab for the treatment of individuals with intermediate or poor-risk, previously untreated advanced RCC. The approval was based on results from the Check-Mate-214 trial (NCT002231749), a phase III pilot study that evaluated nivolumab in combination with ipilimumab (n=550; 425 had intermediate and poor-risk disease) or sunitinib (n=546, 422 had intermediate and poor-risk disease) for treatment of advanced RCC (Motzer, 2018). The authors reported findings:

At a median follow-up of 25.2 months in intermediate and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%.

In summary the authors concluded that the “overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma.”

In 2018, the NCCN panel updated the NCCN Drugs and Biologics Compendium and the NCCN Clinical Practice Guideline for kidney cancer to include category 1 recommendations nivolumab in combination with ipilimumab for the treatment of intermediate- and poor-prognosis risk groups with advanced clear cell RCC. The panel included a category 2A recommendation for use of nivolumab in combination with ipilimumab as a subsequent therapy for the treatment of advanced clear cell RCC. The recommendation for subsequent therapy is based on the Check-Mate 016 trial, a phase 1 study that evaluated efficacy in previously treated individuals. The reported ORR in previously treated individual was 45.5% (n=22) for the nivolumab (3mg/kg) and ipilimumab (1mg/kg) group and 38.5% (n=26) for the nivolumab (1mg/kg) in combination with ipilimumab (3mg/kg) group.

SCCHN:
On November 10, 2016, Bristol-Myers Squibb Company received FDA accelerated approval for use of nivolumab for the treatment of recurrent or metastatic SCCHN with disease progression on or after platinum-based therapy. The FDA approval was based on preliminary findings reported by Ferris and colleagues (2016) from the CheckMate-0141 trial, an open-label phase 3 trial comparing nivolumab to investigators choice chemotherapy. The NCCN Drugs and Biologics Compendium and the NCCN CPG in Oncology on head and neck cancer (2018) included a category 1 recommendation for off-label use of nivolumab in treatment of recurrent, unresectable or metastatic SCCHN, as a single agent with disease progression on or after platinum-containing chemotherapy. The recommendations are based on interim results from the CheckMate-141 trial that randomly assigned participants at a 2:1 ratio to receive intravenous nivolumab or a standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). Primary end point was overall survival, defined as the time from randomization to the date of death from any cause. Ferris and colleagues reported findings:

The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the standard-therapy group. Overall survival was significantly longer with nivolumab than with standard therapy, and nivolumab treated patients had a risk of death that was 30% lower than the risk among patients assigned to standard therapy (hazard ratio, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01). In conclusion, nivolumab prolonged survival, as compared with standard therapy, among patients with platinum-refractory squamous-cell carcinoma of the head and neck. Nivolumab was associated with fewer toxic effects of grade 3 or 4 than standard therapy (13.1% vs. 35.1%) and with maintenance of quality of life among patients with a treatment-refractory cancer that otherwise has serious adverse effects on quality of life as it leads to death.

Hodgkin Lymphoma, Classical:
On May 17, 2016 the FDA granted accelerated approval for nivolumab for the treatment of individuals with classic Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin.

The NCCN Drugs and Biologics Compendium and the NCCN CPG for Hodgkin disease (2017) included a 2A recommendation for off-label use of nivolumab as an additional therapy option when used as a single agent for individuals with relapsed or refractory cHL. The recommendation is based on uniform consensus and data from a phase I clinical trial abstract (NCT01592370). Ansell and colleagues (2015) reported preliminary findings of a study of 23 participants with relapsed or refractory Hodgkin lymphoma that were heavily pretreated, who received nivolumab every 2 weeks until they had a complete response (CR), tumor progression or excessive toxic effects from the medication. Twenty participants (87%) achieved an objective response, including a CR in 17% of participants and 70% with a partial response; the remaining 13% (n=3) had stable disease. At 24 weeks, the rate of progression-free survival was 86%; 11 subjects continued to participate in the study, 6 dropped out due to stem cell transplant, 4 due to disease progression and the remaining 2 due to drug toxicity. The authors concluded that “Nivolumab has substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin’s lymphoma.” Updated results were also reported in an abstract by Timmerman (2015). The author concluded that:

In Hodgkin lymphoma patients, the CR rate was 26% with a PR in 61% and stable disease in 13%. In Hodgkin lymphoma patients, the median duration of response was not reached (range, 2 to 91+ months) after a median follow-up of 86 weeks. Responses were ongoing in 50%. Median PFS for Hodgkin lymphoma patients was 92.1 weeks.

Urothelial Carcinoma:
In February 2017, the FDA granted accelerated approval for nivolumab in the treatment of individuals with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-based therapy or demonstrated disease progression within 12 months of receiving neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. The FDA approval was based on interim results from the CheckMate 275 trial (NCT02387996), a multicenter, single-arm, phase 2 study that evaluated effectiveness of nivolumab in 270 participants (18 years or older) with metastatic or surgically unresectable locally advanced urothelial carcinoma. The primary endpoint was an objective response (OR) in participants treated with nivolumab and PD-L1 expression (≥ 5% and ≥ 1%). Sharma and colleagues (2017) reported the following findings:

Confirmed objective response was achieved in 52 (19.6%, 95% CI 15.0-24.9) patients. Confirmed objective response was achieved in 23 (28.4%, 95% CI 18.9-39.5) of the 81 patients with PD-L1 expression of 5% or greater, 29 (23.8%, 95% CI 16.5-32.3) of the 122 patients with PD-L1 expression of 1% or greater, and 23 (16.1%, 95% CI 10.5-23.1) of the 143 patients with PD-L1 expression of less than 1%.

The authors identified no new safety concerns with use of nivolumab monotherapy. Treatment-related adverse events occurred in 174 (64%) of 270 participants. Fatigue was the most common treatment-related event of any grade, reported in 17% (n=45) of participants. 48 (18%) had grade 3 or 4 treatment-related events, most commonly diarrhea and fatigue. The authors concluded that “in view of the scarcity of treatment options and high unmet medical need in this patient population, these data support the use of nivolumab as a new treatment option if platinum-based chemotherapy is unsuccessful.”

Colorectal Cancer:
On July 31, 2017 the FDA expanded approval of nivolumab in the treatment of adults or adolescents (12 years or older) with MSI-H or dMMR metastatic colorectal cancer that has progressed following prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan (n=53). The FDA approval was based on unpublished data from the CheckMate 142 study which demonstrated an objective response rate in 28% (95% CI: 17-42; 15/53) among participant who received prior treatment (fluoropyrimidine, oxaliplatin, and irinotecan) (Product Label Information, 2018).

In March 2018, the NCCN Drugs and Biologics Compendium and the NCCN CPG in Oncology on colon cancer and rectal cancer lists off-label use of nivolumab for individuals with unresectable metachronous metastases or unresectable advanced or metastatic colorectal cancer. The recommendations were based on 2A category of evidence and uniform consensus. The panel recommends:

Use of pembrolizumab or nivolumab as treatment options in patients with metastatic MMR-deficient colorectal cancer in second- or third-line therapy. Patients progressing on either of these drugs should not be offered the other. Additional clinical trials are ongoing to confirm the benefit of these drugs in this setting.

Hepatocellular Carcinoma:
On September 22, 2017, Bristol-Myers Squibb Company received FDA accelerated approval for use of nivolumab for the treatment of individuals with advanced hepatocellular carcinoma who have been previously treated with sorafenib. The FDA approval was based data from the CheckMate 040 trial (NCT01658878), a phase 1/ 2 open-label pivotal study that evaluated tumor response rate and durability of nivolumab in participants with advanced hepatocellular carcinoma who progressed on or were intolerant to sorafenib. In the CheckMate -040 trial, nivolumab was evaluated in a subgroup of 154 participants, 14.3% (95% CI: 9.2-20.8; 22/154) of participants responded to treatment with nivolumab, 3 (1.9%) participants had a complete response and 12.3% of participants (n=19) had a partial response. Of the 22 participants that responded to treatment, the responses ranged from 3.2 to 38.2+ months; 91% of those participants had responses of six months or longer and 55% had responses of 12 months or longer (Product Label Information, 2018).

Merkel Cell Carcinoma:
In the NCCN Drugs and Biologics Compendium and the NCCN CPG in Oncology on Merkel cell carcinoma (2017), the panel included a category 2A recommendation for off-label use of nivolumab in the treatment of disseminated disease as clinical judgment dictates; the “preliminary data from non-randomized trials in patients with MCC demonstrate that rates of durable response are improved with PD-1/PD-L1 blockage compared with cytotoxic therapy.”

Malignant Pleural Mesothelioma:
Nivolumab (immunotherapy) is used as a subsequent systemic therapy for the treatment of malignant pleural mesothelioma (MPM), a highly aggressive cancer with poor prognosis and limited treatment options. Scherpereel and colleagues (2017) reported on preliminary results of the IFCT-1501 MAPS2 randomized phase II trial, an ongoing study evaluating second or third-line nivolumab versus nivolumab plus ipilimumab in MPM. There were more reported grade 3 & 4 toxicities in the combination arm (86.9%/ 16.4%) versus the nivolumab arm (77.8%/ 9.5%); there were 3 treatment related deaths reported in the combination arm (1 metabolic encephalopathy, 1 fulminant hepatitis, 1 acute renal failure). The authors concluded that immunotherapy may provide new options for individuals with MPM.

Small Cell Lung Cancer:
The NCCN Drug and Biologics Compendium and the NCCN SCLC Clinical Practice Guideline (2018) includes off-label recommendations (category 2A) for use of nivolumab and nivolumab plus ipilimumab as new treatment options for SCLC as subsequent therapy for treatment of primary progressive disease or use after disease relapse (6 months or less) after complete or partial response or stable disease with primary therapy. Antonia and colleagues (2016) reported interim results from the CheckMate 032 trial, a phase I/II multi-center, open-label trial that evaluated nivolumab with or without ipilimumab in participants with advanced or metastatic SCLC after disease progression with one or more platinum-containing regimen. Objective response rates were 10% (10/98) for nivolumab 3 mg/kg, 23% (14/61) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 19% (10/54) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. “The most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhea (none vs 3 [5%] vs 1 [2%]).” The overall frequency of grade 3 or 4 adverse events reported was about 20%, and less than 10% of participants enrolled in the study discontinued treatment as a result of treatment-related adverse events. The NCCN panel recommendations were based on the interim results from the SCLC cohort in the CheckMate 032 trial; currently there are ongoing phase III trials comparing nivolumab or nivolumab plus ipilimumab versus placebo as maintenance therapy after first-line therapy (CheckMate 451), and nivolumab versus single-agent chemotherapy as second-line therapy (CheckMate 331) in SCLC.

Other Indications:
Nivolumab is also currently being studied in ongoing clinical trials for other uses including, but not limited to other malignancies and solid tumors. The NCCN Drugs and Biologics Compendia and the NCCN Clinical Practice Guideline for anal cancer offered a category 2A recommendation for the use of nivolumab as subsequent treatment of metastatic squamous cell carcinoma of the anal canal. The NCCN Panel recommendation is based on results from an ongoing single-arm phase 2, multicenter study that assessed the safety and efficacy of nivolumab in refractory metastatic disease. Morris and colleagues (2017) reported preliminary findings, of the 37 enrolled participants 2 received a complete responses and 7 received partial response with overall response rate of 24% (95% CI, 15-33). Authors concluded that nivolumab provides a promising treatment for individuals with squamous cell carcinoma of the anal canal.  However, there is insufficient published evidence to support the use of nivolumab for such conditions.

Background/Overview

Colorectal cancer:
Colorectal cancer refers to malignancies originating from the large intestine (colon) or the rectum. The term colorectal cancer does not include anal cancer. According to the American Cancer Society, there will be an estimated 95,520 new cases of colon cancer and 39,910 new cases of rectal cancer diagnosed in 2017. It is expected that 50,260 persons will die from colon and rectal cancer combined in 2017.

Hepatocellular carcinoma:
Hepatocellular carcinoma is the most common form of liver cancer with about 40,710 new cases of liver and intrahepatic bile duct cancer diagnosed in 2017 and nearly 28,920 deaths from the disease annually in the U.S. Chronic infections with hepatitis B virus (HBV) or hepatitis C virus are the most common cause of liver cancer. (ACS, 2017).

Hodgkin Lymphoma, Classical:
Hodgkin lymphoma is a type of malignancy which starts in the lymphocytes, a type of white blood cell that fights infection. Hodgkin lymphoma most commonly affects people between the ages of 15 and 40 and people older than age 55. In Hodgkin lymphoma, cells in the lymphatic system grow abnormally and may spread beyond the lymphatic system. As the disease progresses, it compromises the body's ability to fight infection. Many initial signs and symptoms may be similar to those of influenza, such as fever, fatigue and night sweats. Eventually, tumors develop. Hodgkin lymphoma is distinguished by the presence of abnormal Reed-Sternberg cells with a majority of cases expressing CD15 and CD30 on immunohistochemistry testing of tissue. In developed countries, classical Hodgkin lymphoma accounts for approximately 95% of all Hodgkin disease (ACS, 2017).

Malignant Mesothelioma:
Malignant mesothelioma is a rare cancer where malignant cells are found in the lining of the chest or abdominal cavity, and occurs in approximately 2500 individuals in the U.S annually. Malignant pleural mesothelioma, the most common type, is difficult to treat because the majority of individuals have advanced disease at presentation. The NCCN CPG for malignant pleural mesothelioma (2018) reported the median overall survival for the disease to be approximately 1 year, with cure rare.

Melanoma (Cutaneous and Uveal):
Melanoma is a form of cancer that begins in melanocytes (cells that make the pigment melanin). In men, melanoma is often found on the trunk or the head and neck. In women, it often develops on the lower legs. Melanoma is rare in individuals with very dark skin. When it does develop in dark-skinned people, it tends to occur under the fingernails or toenails, or on the palms or soles. Occasionally, melanoma may arise in the lining of the brain (meninges), the digestive tract, lymph nodes, or other areas where melanocytes are found. People at high risk for developing melanoma include those with a personal or family history of the disease, fair complexions, and weakened immune systems.

The American Cancer Society (ACS) estimated that approximately 87,110 cases of melanoma (also referred to as malignant melanoma) will be diagnosed in the United States in 2017 (ACS, 2017). While melanoma accounts for only approximately 5% of skin cancer cases, it is estimated to be responsible for the vast majority of skin cancer deaths, with 9730 deaths projected in 2017. BRAF gene mutations are seen most commonly in melanoma, occurring in approximately 50% of cutaneous melanomas. Mutations of the BRAF gene have been associated with shorter progression-free intervals and overall decreased survival. When discovered early, melanoma can usually be cured with surgery. Once metastasis occurs, the prognosis is usually poor. In the metastatic stage of melanoma (stage IV), the average survival rate is about 6 months with a 1 year mortality rate of 75%. Treatment of metastatic melanoma may include lymphadenectomy, immunotherapy, radiation therapy, chemotherapy or participation in a clinical trial.

MCC:
MCC is an uncommon type of skin cancer, also known as neuroendocrine carcinoma, with up to 97% of cases primarily in the epidermis of the skin. According to the ACS (2017) there are approximately 1500 cases diagnosed in the United States each year, with more than 9 out of 10 individuals diagnosed at greater than 50 years of age. An overall 5-year survival rate for MCC was reported at nearly 60%.

NSCLC and SCLC:
Lung cancer is the leading cause of death from cancer worldwide, with advanced NSCLC representing the majority (85%) of these cases. According to the National Cancer Institute (NCI), in 2018, an estimated 222,500 new cases of lung cancer (NSCLC and SCLC) will be diagnosed in the United States, and of these, approximately 155,870 deaths (70%) will occur because of the disease. Over the past few decades there has been a decline in the overall incidence of mortality in SCLC in the United States. It has been estimated that only 15.7% of all individuals with lung cancer will survive 5 years or more following diagnosis (NCI, 2018).

RCC:
According to the NCI, in 2018 approximately 63,990 new cases of RCC will be diagnosed in the United States with an estimated 14,400 deaths resulting from the diagnosis. Clear-cell is among the most prevalent type of RCC. The majority of individuals with RCC are diagnosed when the tumor is still localized and amenable to surgical removal; approximately 73% of all individuals diagnosed with RCC survive 5 years past diagnosis (NCI, 2018).

SCCHN:
Head and neck cancers account for nearly 3 percent (approximately 62,000 cases) of all cancers in the United States, and an estimated 13,000 deaths, with nearly 90% from the squamous cell variety. Head and neck cancer usually begins in the squamous cells that line moist, mucosal surfaces inside the head and neck (for example, inside the mouth, nose and throat), and is commonly referred to as squamous cell carcinoma of the head and neck. Head and neck cancers can also begin in the salivary glands, but these are much less common (NCI, 2018).

Urothelial carcinoma:
Urothelial carcinoma is the most common type of bladder cancer and occurs in the urinary tract system, involving the bladder and related organs. The American Cancer Society estimates that in 2017 there will be approximately 76,030 new cases of bladder cancer (about 60,490 in men and 18,540 in women) and 16,870 deaths from bladder cancer (about 12,240 in men and 4630 in women) in the United States.

Nivolumab (Opdivo) 2018 FDA Product Information label includes the following warnings and precautions:
Warning: Immune-Mediated Adverse Reactions:

Administer corticosteroids based on the severity of the reaction.

Information for use in specific populations includes:

Pregnancy: Based on its mechanism of action and data from animal studies, Opdivo can cause fetal harm when administered to pregnant women.

Lactation: It is not known whether Opdivo is present in human milk. Because many drugs, including antibodies are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Opdivo, advise women to discontinue breastfeeding during treatment with Opdivo.

Females and males of reproductive potential: Based on its mechanism of action, Opdivo can cause fetal harm when administered to pregnant women.

Pediatric use: The safety and effectiveness of Opdivo have been established in pediatric patients age 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimide, oxaliplatin, and irinotecan.

Renal impairment: Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment.

Hepatic impairment: Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild hepatic impairment.

Definitions

BRAF: The oncogene which directs production of a protein in the regulating MAP kinase / ERKs signaling pathway, which affects cell division, differentiation, and secretion. BRAF is also known as v-raf murine sarcoma viral oncogene homolog B1, and its protein as serine/threonine-protein kinase B-Raf.

ECOG Performance Status: A scale used to determine the individual's level of functioning. This scale may also be referred to as the WHO (World Health Organization) or Zubrod score which is based on the following scale:

Line of therapy:

Melanoma: A type of cancer that begins in the melanocytes. Melanoma is also referred to as malignant melanoma and cutaneous melanoma.

Metastasis: A cancer that has spread from one part of the body to another; a metastatic tumor contains cells that are like those in the original (primary) tumor and have spread beyond the local lymph nodes; also referred to as stage IV cancer.

Monoclonal antibody: A protein developed in the laboratory that can locate and bind to specific substances in the body and on the surface of cancer cells.

Mutation: A permanent, transmissible change in genetic material.

Non-small cell lung cancer: A group of lung cancers that are named for the kinds of cells found in the cancer and how the cells look under a microscope. The three main types of non-small cell lung cancer are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Non-small cell lung cancer is the most common kind of lung cancer.

Unresectable: Unable to be removed with surgery.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS

 

J9299

Injection, nivolumab, 1 mg [Opdivo]

 

 

ICD-10 Diagnosis

 

 

C00.0-C14.8

Malignant neoplasm of lip, oral cavity and pharynx

 

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-C22.9

Malignant neoplasm of liver and intrahepatic bile ducts

 

C30.0-C33

Malignant neoplasm of nasal cavity, middle ear, accessory sinuses, larynx, trachea

 

C34.00-C34.92

Malignant neoplasm of bronchus and lung

 

C38.4

Malignant neoplasm of pleura

 

C43.0-C43.9

Malignant melanoma of skin

 

C4A.0-C4A.9

Merkel cell carcinoma

 

C45.0

Mesothelioma of pleura

 

C61

Malignant neoplasm of prostate [specified as urothelial carcinoma]

 

C64.1-C65.9

Malignant neoplasm of kidney, renal pelvis

 

C66.1-C66.9

Malignant neoplasm of ureter [specified as urothelial carcinoma]

 

C67.0-C67.9

Malignant neoplasm of bladder [specified as urothelial carcinoma]

 

C68.0

Malignant neoplasm of urethra [specified as urothelial carcinoma]

 

C69.30-C69.32

Malignant neoplasm of choroid

 

C69.40-C69.42

Malignant neoplasm of ciliary body

 

C76.0

Malignant neoplasm of head, face and neck

 

C78.00-C78.02

Secondary malignant neoplasm of lung

 

C79.31

Secondary malignant neoplasm of brain

 

C81.10-C81.99

Hodgkin lymphoma (classical)

 

Z85.038

Personal history of other malignant neoplasm of large intestine

 

Z85.118

Personal history of other malignant neoplasm of bronchus and lung

 

Z85.51

Personal history of malignant neoplasm of bladder

 

Z85.528

Personal history of other malignant neoplasm of kidney

 

Z85.53

Personal history of malignant neoplasm of renal pelvis

 

Z85.71

Personal history of Hodgkin lymphoma

 

Z85.820

Personal history of malignant melanoma of skin

 

Z85.821

Personal history of Merkel cell carcinoma

 

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Algazi AP, Tsai KK, Shoushtari AN, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 an PD-L1 antibodies. Cancer. 2016; 122(21):3344-3353.
  2. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015; 372(4):311-319.
  3. Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicenter, open-label, phase 1/2 trial. Lancet Oncol. 2016; 17:883-895.
  4. Arkenau HT, Kefford R, Long GV. Targeting BRAF for patients with melanoma. Br J Cancer. 2011; 104(3):392-398.
  5. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small cell lung cancer. N Eng J Med. 2015; 373(17):1627-1639.
  6. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015; 373(2):123-135.
  7. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002; 417(6892):949-954.
  8. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017; 389(10088):2492-2502.
  9. Ferris RL, Blumenschein G, Fayette J et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016 [Epub ahead of print].
  10. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010; 363(9):809-819.
  11. Hamanishi J, Mandai M, Ikeda T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2015; 33(34):4015-4022.
  12. Hellmann MD, Ott PA, Zugazagoitia J, et al. First report of a randomized expansion cohort from CheckMate 032. J Clin Oncol 2017; 35:Abstract 8503.
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  15. Morris VK, Salem ME, Nimeiri H, et al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017; 18(4):446-453.
  16. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015; 373(19):1803-1813.
  17. Motzer RJ, Tanner NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018; 378(14):1277-1290.
  18. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative oncology Group. Am J Clin Oncol. 1982; 5(6):649-655.
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  20. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Eng J Med. 2015; 372(21):2006-2017.
  21. Rizvi NA, Mazieres J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015; 16(3):257-265.
  22. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015; 372(4):320-330.
  23. Scherpereel A, Mazleres J, Greillier L, et al. Second- or third-line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Results of the IFCT-1501 MAPS2 randomized phase II trial. 2017; 35(18) [Epub Ahead of Print].
  24. Shahabi V, Whitney G, Hamid O, et al. Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab. Cancer Immunol Immunother. 2012; 61(5):733-737.
  25. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a muticentre, single-arm, phase 2 trial. Lancet Oncol. 2017; 18:312-322.
  26. Timmerman J, Armand P, Lesokhin AM, et al. Nivolumab in patients with relapsed or refractory lymphoid malignancies and classical Hodgkin lymphoma: Updated results of a phase 1 study (CA 209-039) [abstract]. Hematol Oncol. 2015; 33.
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  29. Weber JS, D’Angelo SP, Minor D, et al. nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate-037): a randomized, controlled, open-label, phase 3 trial. Lancet Oncol. 2015; 16(4):375-384.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Cancer Society. Cancer facts & figures 2017. Atlanta: American Cancer Society; 2017.
  2. Bristol-Myers Squibb. A study to compare BMS-936558 to the physician’s choice of either dacarbazine or carboplatin and paclitaxel in advanced melanoma patients that have progressed following anti-CTLA-4 therapy (CheckMate 037). NLM Identifier: NCT01721746. Last updated September 26, 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT01721746?term=Checkmate+037&rank=1. Accessed on March 26, 2018.
  3. Bristol-Myers Squibb. A study of nivolumab in participants with metastatic or unresectable bladder cancer. NLM Identifier: NCT02387996. Last updated February 25, 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT02387996. Accessed on March 26, 2018.
  4. Bristol-Myers Squibb. An immune-therapy study to evaluate the effectiveness, safety and tolerability of nivolumab or nivolumab in combination with other agents in patients with advanced liver cancer. (CheckMate 040). NLM Identifier: NLM Identifier: NCT01658878. Last updated February 23, 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT01658878. Accessed on March 26, 2018.
  5. Bristol-Myers Squibb. An investigational immune-therapy study of nivolumab, and nivolumab with other anti-cancer drugs, in colon cancer that has come back or has spread (CheckMate 142). NLM Identifier: NCT02060188. Last updated February 23, 2018. Available at: https://clinicaltrials.gov/ct2/show/NCT02060188. Accessed on March 26, 2018.
  6. Bristol-Myers Squibb. Phase 2, randomized, double blinded, study of nivolumab (BMS-936558) in combination with ipilimumab vs ipilimumab alone in subjects with previously untreated, unresectable or metastatic melanoma (CheckMate 069). NLM Identifier: NCT01927419. Last updated February 7, 2018. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01927419?term=checkmate+069&rank=1. Accessed on March 26, 2018.
  7. Bristol-Myers Squibb. Phase 3 study of nivolumab or nivolumab plus ipilimumab versus ipilimumab alone in previously untreated advanced melanoma (CheckMate 067). NLM Identifier: NCT01844505. Last updated March 16, 2018. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01844505. Accessed on March 26, 2018.
  8. Bristol-Myers Squibb. An investigational immune-therapy to determine the safety and effectiveness  of nivolumab and daratumumab, with or without pomalidomide and dexamethasone, in patients with  multiple myeloma. NLM Identifier: NCT01592370. Last updated September 6, 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT01592370. Accessed on March 26, 2018.
  9. Bristol-Myers Squibb. Study of BMS-936558 (nivolumab) compared to docetaxel in previously treated advanced or metastatic squamous cell non-small cell lung cancer (NSCLC) (CheckMate 017). NLM Identifier: NCT01642004. Last updated July 11, 2017. Available at: https://www.clinicaltrials.gov/ct2/show/NCT01642004?term=CheckMate-017&rank=1. Accessed on March 26, 2018.
  10. Bristol-Myers Squibb. Study of BMS-936558 vs. dacarbazine in untreated, unresectable or metastatic melanoma (CheckMate 066). NLM Identifier: NCT01721772. Last updated July 11, 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT01721772?term=Checkmate+066&rank=1. Accessed on March 26, 2018.
  11. Bristol-Myers Squibb. Study of nivolumab (BMS-936558) in subjects with advanced or metastatic squamous cell non-small cell lung cancer who have received at least two prior systemic regimens (CheckMate 063). NLM Identifier: NCT01721759. Last updated September 8, 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT01721759?term=Checkmate+063&rank=1. Accessed on March 26, 2018.
  12. National Cancer Institute. Common terminology criteria for adverse events. Version 4.03. June 2010. Available at: https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed on March 26, 2018.
  13. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium (electronic version). For additional information visit the NCCN website: http://www.nccn.org. Accessed on March 26, 2018.
  14. National Comprehensive Cancer Network® NCCN Clinical Practice Guidelines in Oncology. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on April 23, 2018.
    • Anal Carcinoma (V.1.2018). Revised February 6, 2018.
    • Bladder Cancer (V.3.2018). Revised March 14, 2018.
    • Central Nervous System Cancers. (V.1.2018). Revised March 20, 2018.
    • Colon Cancer (V.2.2018). Revised March 14, 2018.
    • Kidney Cancer (V.4.2018). Revised April 23, 2018.
    • Head and Neck Cancers (V.2.2018). Revised February 15, 2018.
    • Hepatobiliary Carcinoma (V.1.2018). Revised February 14, 2018.
    • Hodgkin lymphoma (V.1.2018). Revised December 20, 2017.
    • Malignant Pleural Mesothelioma (V.2.2018). Revised February 26, 2018.
    • Melanoma (cutaneous) (V.2.2018). Revised January 19, 2018.
    • Merkel Cell Carcinoma (V.1.2018). Revised September 18, 2017.
    • Non-Small Cell Lung Cancer (V.4.2018) Revised April 26, 2018.
    • Rectal Cancer (V.1.2018). Revised March 14, 2018.
    • Small Cell Lung Cancer (V.2.2018). Revised January 17, 2018.
    • Uveal Melanoma. (V.1.2018. Revised March 15, 2018.
  15. Nivolumab Monograph. Lexicomp® Online, American Hospital Formulary Services® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised August 10, 2017. Accessed on December 12, 2017.
  16. Nivolumab (systemic). In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated March 6, 2018. Available at: http://www.micromedexsolutions.com. Accessed on March 26, 2018.
  17. Opdivo® [Product Information], Princeton, NJ. Bristol-Myers Squibb; April 16, 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s058lbl.pdf. Accessed on April 16, 2018.
Websites for Additional Information
  1. American Cancer Society. Available at: http://www.cancer.org/docroot/home/index.asp. Accessed on April 5, 2018.
  2. American Cancer Society. Lung Cancer - Non-Small Cell. Available at: http://www.cancer.org/Cancer/LungCancer-Non-SmallCell/DetailedGuide/index. Accessed on April 4, 2018.
  3. American Cancer Society. Key statistics for melanoma skin cancer. Last reviewed February 1, 2016. Available at: http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-key-statistics. Accessed on April 4, 2018.
  4. American Joint Committee on Cancer (AJCC). Melanoma of the skin staging. 2009. Available at: https://cancerstaging.org/references-tools/quickreferences/Documents/MelanomaSmall.pdf. Accessed on April 4, 2018.
  5. Genetics Home Reference. BRAF. Reviewed December 2012. Available at: http://ghr.nlm.nih.gov/gene/BRAF. Accessed on April 4, 2018.
  6. National Cancer Institute. Available at: https://www.cancer.gov/types. Accessed on April 4, 2018.
    • Adult Hodgkin lymphoma (PDQ®). Last modified March 1, 2018.
    • Bladder Cancer Treatment (PDQ). Last modified March 9, 2018.
    • Colon Cancer Treatment (PDQ). Last modified February 16, 2018.
    • Malignant Mesothelioma Treatment (PDQ). Last modified February 6, 2018.
    • Melanoma Treatment (PDQ). Last modified March 22, 2018.
    • Metastatic squamous neck cancer with occult primary Treatment (PDQ). Last modified February 8, 2018.
    • Non-Small Cell Cancer Treatment (PDQ). Last modified March 31, 2018.
    • Rectal Cancer Treatment (PDQ). Last modified. February 16, 2018.
    • Renal Cell (Kidney) Carcinoma (PDQ). Last modified February 23, 2018.
    • Small Cell Lung Cancer (PDQ). Last modified February 9, 2018.
  7. National Cancer Institute. What you need to know about melanoma and other skin cancers. January 11, 2011. Available at: https://www.cancer.gov/publications/patient-education/skin.pdf. Accessed on April 4, 2018.
  8. National Library of Medicine. Medical Encyclopedia: Non-Small Cell Lung cancer. Updated August 1, 2015. Available at: https://medlineplus.gov/ency/article/007194.htm. Accessed on April 4, 2018.
Index

Advanced Hepatocellular Carcinoma
Advanced Renal Cell Carcinoma (RCC)
Hepatocellular Carcinoma
Hodgkin Lymphoma, Classic
Locally Advanced or Metastatic Urothelial Carcinoma
Malignant Pleural Mesothelioma
Metastatic Melanoma (Cutaneous and Uveal)
Metastatic or Recurrent Locoregional Merkel Cell Carcinoma
Nivolumab
Metastatic Squamous Non-Small Cell Lung Cancer (NSCLC)
Opdivo
Unresectable Melanoma

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.

Document History

Status

Date

Action

Revised

05/03/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

Revised

05/02/2018

Hematology/Oncology Subcommittee review. Clarified MN criteria for melanoma to include cutaneous and uveal melanoma. Added MN statement for nivolumab in combination with ipilimumab in treatment of individuals with intermediate- or poor risk, advanced RCC when criteria met. Updated Description, Rationale, References, Websites and Index sections.  Updated Coding section to add ICD-10-CM codes C69.30-C69.32, C69.40-C69.42, and C79.31.

Revised

01/25/2018

MPTAC review.

Revised

01/17/2018

Hematology/Oncology Subcommittee review. Clarified MN statement for nivolumab “as a single agent” in adjuvant therapy for the treatment of resected advanced melanoma when criteria met. Updated Rationale, References and Websites sections. Corrected range for Merkel cell in Coding section. 01/23/2018 Subsequent to the discussion on 01/17/2018 the Hematology/Oncology Subcommittee added MN statement for use of nivolumab with or without ipilimumab for the treatment of small cell lung cancer when criteria met. Updated Description and Rationale sections.

Revised

11/02/2017

MPTAC review. 11/16/2017 Subsequent to the discussion on 11/2/2017 the MPTAC review, the committee added MN statement for nivolumab as adjuvant therapy for the treatment of resected advanced melanoma when criteria met.

Revised

11/01/2017

Hematology/Oncology Subcommittee review. Reformatted MN statement. Added MN statement for hepatocellular carcinoma when criteria met. Added MN statement for malignant pleural mesothelioma when criteria met. Added MN statement for MCC when criteria met. The document header wording updated from “Current Effective Date” to “Publish Date”. Updated Coding, Description, Rationale, Background, Index, References and Websites sections. 11/13/2017 Subsequent to the 11/1/2017 Hematology/Oncology Subcommittee review, the Subcommittee added MN statement for nivolumab as adjuvant therapy for the treatment of resected advanced melanoma when criteria met.

Revised

05/04/2017

MPTAC review.

Revised

05/03/2017

Hematology/Oncology Subcommittee review. Reformatted Medically Necessary criteria. Added Medically Necessary criteria for colorectal cancer and urothelial carcinoma. Revised Investigational and Not Medically Necessary statement when the reason for the treatment is other than for diagnosis with accompanied criteria noted above. Updated Description, Rationale, Background, Coding, Index, References and Websites sections.

Revised

11/03/2016

MPTAC review.

Revised

11/02/2016

Hematology/Oncology Subcommittee review. Added MN criteria for squamous cell carcinoma of the head and neck. Revised I/NMN statement to address reason for treatment for diagnosis other than SCCHN. Updated Description, Rationale, Background, Coding, References, Websites, and Index sections.

Revised

05/05/2016

MPTAC review.

Revised

05/04/2016

Hematology/Oncology Subcommittee review. Clarified MN criteria for melanoma, NSCLC and RCC. Added MN criteria for Hodgkin lymphoma. Revised I/NMN statement to address reason for treatment for diagnosis other than Hodgkin lymphoma. Updated Description, Rationale, Background, References and Websites sections. Updated Coding section and removed C9453 deleted 12/31/2015.

Revised

11/05/2015

MPTAC review.

Revised

11/04/2015

Hematology/Oncology Subcommittee review. Revised medically necessary criteria for nivolumab in individuals with unresectable or metastatic melanoma and individuals with advanced NSCLC when criteria met. Added medically necessary statement for use of nivolumab in advanced clear cell RCC when criteria met. Updated investigational and not medically necessary indications. Updated Description, Rationale, Background, Index, References and Websites sections. Updated Coding section to include 01/01/2016 HCPCS changes; also removed ICD-9 codes.

Revised

08/06/2015

MPTAC review.

Revised

07/25/2015

Hematology/Oncology Subcommittee review. Added nivolumab and ipilimumab combined therapy for untreated melanoma as medically necessary with criteria. Updated rationale, references and websites.

 

07/01/2015

Updated Coding section with 07/01/2015 HCPCS changes.

New

05/07/2015

MPTAC review.

New

05/06/2015

Hematology/Oncology Subcommittee review. Initial document development.