Pending Policies - Prescription Drugs


Nivolumab (Opdivo)

Number:RX502.055

Effective Date:11-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

When the requested chemotherapeutic agent is being utilized in a regimen in combination with other chemotherapeutic agents, the entire regimen (including dose, frequency, and duration) must be consistent with recommendations in at least one authoritative source, including but not limited to FDA labeling and nationally recognized compendia or clinical guidelines such as National Comprehensive Cancer Network (NCCN) and CMS coverage policy. HCSC may require a provider to submit documentation from nationally recognized compendia, clinical guidelines, or active Phase III clinical trials supporting the requested regimen.

Nivolumab (Opdivo®) may be considered medically necessary for the following indications:

Melanoma:

o Single agent first-line therapy for unresectable or metastatic melanoma.

o Single agent second-line or subsequent therapy (see NOTE 1) for unresectable or metastatic melanoma disease progression, if anti-PD-1 monotherapy not previously used. The patient must meet the 0-2 ECOG performance scale (see NOTE 2).

o Single agent or in combination with Yervoy™ as first-line therapy (see NOTE 3) of unresectable or metastatic melanoma, when patient has the BRAF V600 wild-type (see NOTE 4).

o Single agent first-line followed by Opdivo® in combination with Yervoy™ as subsequent therapy (see NOTE 3) of unresectable or metastatic melanoma, when patient has the BRAF V600 wild-type (see NOTE 4) with disease progression (only if Opdivo® OR Keytruda® not previously used).

o Single agent or in combination with Yervoy™ as second-line or subsequent therapy (see NOTE 3) of unresectable or metastatic melanoma, when patient has the BRAF V600 mutation-positive with disease progression following treatment with a BRAF inhibitor (see NOTE 4) (such as vemurafenib [Zelboraf®] or dabrafenib [Tafinlar®]).

o Single agent after maximum clinical benefit from BRAF targeted therapy (see NOTE 4) of unresectable or metastatic melanoma. The patient must meet the 0-2 ECOG performance scale (see NOTE 2).

o Single agent as a re-induction therapy for patients with unresectable or metastatic melanoma who experience disease control and have no residual toxicity, but subsequently experience disease progression/relapse >3 months after treatment discontinuation. The patient must meet the 0-2 ECOG performance scale (see NOTE 2).

o In combination with Yervoy™ for treatment (see NOTE 3) of brain metastases if active against primary melanoma tumor for recurrent disease.

o Single agent as adjuvant treatment for patients with melanoma with lymph node involvement or metastatic disease who have undergone complete resection.

Small-Cell Lung Cancer (SCLC):

o Subsequent systemic therapy as a single agent OR in combination with Yervoy™ (see NOTE 3) when metastatic SCLC with relapsed disease within 6 months following a complete/partial response/stable disease with initial treatment or primary progressive disease. The patient must meet the 0-2 ECOG performance scale (see NOTE 2).

 Non-Small-Cell Lung Cancer (NSCLC):

o Single agent second-line subsequent therapy for metastatic (squamous and non-squamous [see NOTE 5]) NSCLC and progression on or after platinum-based chemotherapy and if Keytruda® OR Tecentriq™ not previously given, when the patient meets the 0-2 ECOG performance scale (see NOTE 2).

Malignant Pleural Mesothelioma (MPM):

o Single agent subsequent systemic therapy for MPM. The patient must meet the 0-2 ECOG performance scale (see NOTE 2).

o Subsequent systemic therapy, in combination only with Yervoy™ for MPM (see NOTE 3).

Renal Cell Carcinoma (RCC):

o Single agent therapy for advanced Stage IV, relapsed, or metastatic RCC clear-cell histology who have received prior antiangiogenic therapy.

o Single agent therapy for advanced Stage IV, relapsed, or metastatic RCC non-clear-cell histology.

o First-line systemic therapy, in combination only with Yervoy™ (see NOTE 3) for relapsed or surgically unresectable stage IV (advanced) RCC.

o Subsequent systemic therapy, in combination only with Yervoy™ (see NOTE 3) for relapsed or surgically unresectable stage IV (advanced) RCC.

Hodgkin Lymphoma (HL):

o Additional single agent treatment for refractory/relapsed classical HL when the patient has been treated previously with brentuximab vedotin (Adcetris™) or following high-dose chemotherapy followed by autologous hematopoietic stem-cell transplant and post-transplantation therapy with brentuximab vedotin (Adcetris™).

o Single agent as palliative therapy for refractory/relapsed classical HL when patients are ≥ 60 years of age, if patient has been treated previously with brentuximab vedotin (Adcetris™).

Head and Neck Squamous Cell Cancer (HNSCC):

o Single agent first-line therapy for non-nasopharyngeal HNSCC if progression on or after platinum-containing chemotherapy in the following indications:

1. Newly diagnosed T4b, any N, M0 disease (see NOTE 6 for TNM [tumor, node, metastasis] information), unresectable nodal disease with no metastases, or for patients who are ineligible for surgery and meets 3 on the ECOG performance scale (see NOTE 2);

2. Metastatic (M1) disease at initial presentation or recurrent/persistent disease with distant metastases, or unresectable locoregional recurrence or second primary with prior radiation therapy. The patient must meet the 0-2 ECOG performance scale (see NOTE 2); or

3. Unresectable locoregional recurrence without prior radiation therapy. The patient must meet 3 on the ECOG performance scale (see NOTE 2).

Bladder Cancer (Urothelial Carcinoma):

o Single agent for locally advanced bladder cancer (clinical Stage T4b or T2-4a, N1-3 (see NOTE 6 for TNM information) disease, or for recurrence post-cystectomy, during or after platinum-containing chemotherapy OR disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum chemotherapy.

o Single agent subsequent systemic therapy for locally advanced metastatic disease (or metastatic recurrent disease) progression within 12 months of neoadjuvant or adjuvant treatment with platinum chemotherapy.

Merkel Cell Carcinoma (MCC):

o Single agent for treatment of disseminated, clinically distant metastatic MCC disease with or without surgery or radiation therapy.

Hepatocellular Carcinoma (HCC; Liver Cancer):

o Single agent for advanced, progressive, unresectable, primary liver cancer (HCC) following treatment of sorafenib (Nexavar®).

Nivolumab (Opdivo®) may be considered medically necessary for adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MIS-H) OR mismatch repair deficient (dMMR) for the following indication:

Colorectal Cancer (CRC):

o Single agent as initial therapy for CRC in patients who are not appropriate for intensive therapy.

o Single agent treatment of CRC when following adjuvant treatment with FOLFOX/fluoropyrimidine (such as, fluorouracil [Adrucil®] and oxaliplatin [Eloxatin®]), OR CapeOX (such as capecitabine [Xeloda®] and oxaliplatin [Eloxatin®]) within the past 12 months.

o Single agent subsequent therapy if Opdivo® or Keytruda® not previously given and following previous treatment with oxaliplatin (Eloxatin®), irinotecan (Campto®), and/or fluoropyrimidine (fluorouracil [Adrucil®])-based therapy.

NOTE 1: For some cancers, second-line treatments using checkpoint inhibitors may be administered for disease progression utilizing a different checkpoint inhibitor which was used as first-line therapy. For example, Opdivo® may be given for disease progression following treatment with Yervoy™, as second-line therapy for melanoma.

NOTE 2: Refer to the Description section for detailed information on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.

NOTE 3: Opdivo® may be given for disease progression with Yervoy™ as first-line therapy. For some indications, Opdivo® may be given for disease progression with Yervoy™ as subsequent systemic treatment. For information regarding Yervoy™, refer to Medical Policy RX502.053, Ipilimumab (Yervoy™).

NOTE 4: First-line therapy for melanoma using Opdivo®: Those patients should not have EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase) genomic tumor aberrations, ROS1 (proto-oncogene tyrosine-protein kinase or receptor tyrosine kinase gene), or BRAF (serine/threonine-specific protein kinase gene).

NOTE 5: Second-line therapy for non-squamous NSCLC using Opdivo®: Those patients with EGFR (epidermal growth factor receptor) or ALK (anaplastic lymphoma kinase) genomic tumor aberrations should have disease progression on FDA-approved therapies, e.g., docetaxel (Taxotere®) for these aberrations prior to receiving Opdivo®.

NOTE 6: TNM (T = primary tumor; N = regional lymph nodes; M = distant metastasis) refers to staging classification of some cancers, particularly when the tumor reaches beyond the initial site of the cancer itself. More information on staging can be found in the Description of this medical policy.

Table 1. Overall Tumor Staging Definitions

Stage

Characteristics

I

Tumor has not spread and can be surgically excised.

II

Tumor has not spread, but is larger and possibly with greater penetration or depth to the surrounding area(s).

III

Tumor has spread to the lymph nodes of any thickness and unresectable.

IV

There are metastases to other regions of the body, irrespective of the tumor size or depth.

NOTE 7: For information regarding Keytruda®, refer to Medical Policy RX502.054, Pembrolizumab (Keytruda®).

NOTE 8: For information regarding Tecentriq™, refer to Medical Policy RX502.056, Atezolizumab (Tecentriq™).

Nivolumab (Opdivo®) is considered experimental, investigational and/or unproven for all other indications, including, but not limited to:

Breast cancer,

Cervical cancer,

Gastric cancer,

Glioblastoma,

Multiple myeloma,

Myelodysplastic syndrome,

Mycosis fungoides,

Non-Hodgkin lymphoma,

Ovarian cancer,

Sarcomas,

Sézary syndrome,

Solid organ tumors,

Squamous cell cancer,

Stage I or Stage II melanoma,

Use in combination therapy with another checkpoint inhibitor agent, unless addressed above with Yervoy®.

NOTE 9: There are some checkpoint inhibitors that may have been granted orphan drug designation by the U.S. Food and Drug Administration (FDA) for specific indications. Refer to the FDA approved labeling of this drug for more information.

Description:

Nivolumab (Opdivo®) is a programmed death receptor-1 (PD-1) checkpoint blocking inhibitor or antibody used to treat specific cancer types.

Background

According to the American Cancer Society, the crucial part of the immune system is its ability to distinguish between normal cells in the body and those it sees as “foreign.” This lets the immune system attack the foreign cells while leaving the normal cells alone. To accomplish this, the immune system uses “checkpoints”, molecules on certain immune cells that need to be activated (or inactivated) to start an immune response. Cancer cells sometimes find ways to use these checkpoints to avoid being attacked by the immune system, being hidden or masked. However, a new class of drugs targets these “checkpoints” and hold a lot of promise as anti-cancer treatments or therapies. (1)

Programmed cell death protein 1 (PD-1), is a cell surface receptor that plays an important role in down-regulating the immune system and promoting self-tolerance by suppressing T-cell inflammatory activity. PD-1 is an immune checkpoint or a checkpoint protein on theses immune cells identified as T-cells. PD-1 guards against autoimmunity through a dual mechanism of promoting programmed cell death in antigen specific T-cells in lymph nodes while simultaneously reducing programmed cell death in regulatory T-cells (anti-inflammatory, suppressive T-cells). PD-1 acts as a type of “off-switch” that helps to keep the T-cells from attacking other normal cells within the body.

Microsatellite (MS) Instability (MSI)-High (MSI-H) Solid Tumors

According to the National Institutes of Health, MSI is a biomarker occurring in certain types of cancers when cells are unable to repair DNA (deoxyribonucleic acid; a molecule that contains the cell’s genetic code) sequencing errors that then proliferate with future cell division, a genetic instability. (2) This flawed replication may lead to a cancer. Essentially, a change that occurs in the DNA of certain cells (such as tumor cells) in which the number of repeats of microsatellites (short, repeated sequences of DNA) is different than the number of repeats that was in the DNA when it was inherited. The cause of MSI may be a defect in the ability to repair mistakes, similar to a “spellcheck” function identifying the error and removing, made when the DNA is copied in the cell. The proteins correcting the DNA error are known as mismatch repair (MMR). When the MMR can’t repair the error, this activity is known as dMMR (mismatch repair deficient). This is primarily a sporadic, or nonheritable, event. When this repair system is faulty, microsatellites in the DNA develop short nucleotide repeats that lead to frame-shift mutations. MSI is genetic instability in short nucleotide repeats (microsatellites) due to a high mutation rate as a result of abnormal DNA mismatch repair, a hypermutation of uncorrected DNA replication. When there are 2 or more markers, the tumor is classified as MSI-High (MSI-H). Other MSI errors can be stratified to MSI-Low (MSI-L) or MS-Stable (MSS). MSI may result in cancer development in the following solid organs: colon, gastric, endometrium, ovarian, hepatobiliary tract, urinary tract, brain, and skin. MSI is most prevalent as the cause of colon cancers.

Overall, this new class of drugs have been shown to be helpful in treating several types of cancer, including melanoma of the skin, non-small-cell lung cancer (NSCLC), kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma (HL). They are also being studied for use against many other types of cancer.

This policy addresses the blockade of co-inhibitory molecules, checkpoint antibodies or inhibitors, such as CTLA-4, PD-1, PD-L1, and MSI-H, among others; studies are continuing for another T-cell down regulator or immune checkpoint receptor, known as LAG-3 (lymphocyte-activation gene 3).

Tumor Staging

Cancer staging is the process of determining the extent to which a cancer has developed by spreading. Contemporary practice is to assign a number (stage) from I to IV to the tumor which is based on tumor progression as shown in Table 2. The cancer Stage generally takes into account the size of a tumor, whether it has invaded adjacent organs, how many regional (nearby) lymph nodes it has spread to (if any), and whether it has appeared in more distant locations (metastasized). Staging is useful for the determination of which checkpoint inhibitor would be used for a select tumor indication.

Table 2. Overall Tumor Staging Definitions (3)

Stage

Characteristics

I

Tumor has not spread and can be surgically excised.

II

Tumor has not spread, but is larger and possibly with greater penetration or depth to the surrounding area(s).

III

Tumor has spread to the lymph nodes of any thickness and unresectable.

IV

There are metastases to other regions of the body, irrespective of the tumor size or depth.

For some tumors, the most clinical useful staging may be accessed by the tumor, node, and metastasis (TNM) classification or staging system developed by the American Joint Committee on Cancer (AJCC) in collaboration with the Union for International Cancer Control (UICC), herein referred to as the AJCC TNM staging system. (3) The AJCC TNM system classifies cancers by:

T – The size and extent of primary tumor,

N – The involvement of regional lymph nodes, and

M – The presence or absence of distant metastases.

Additional numbering and lettering may be assigned to any of the TNM categories to more accurately describe the pathological stage (e.g., cT3N1M0 or pT2N0). There is a TNM staging algorithm for cancers of virtually every anatomic site and histology, with the primary exception of pediatric cancers, brain tumors, and hematological malignancies. TNM is useful for treatment considerations, including the use of checkpoint inhibitors.

Melanoma

Melanoma is the most common serious form of skin cancer. (4) If recognized and treated early, it is almost always curable. Approximately 84% of melanomas are diagnosed at a localized Stage with 5-year survival of 98%. However, melanoma is more likely than other skin tumors to metastasize. Five-year survival for patients with regional metastasis is 62%, and for patients with distant metastasis 15%. Staging for a melanoma tumor is based on the overall staging classifications discussed earlier, with expansion of Stages II and III to indicate the if ulceration has occurred and size of the lesion(s), its penetration and thickness. (4)

Small-Cell Lung Cancer (SCLC)

Neuroendocrine tumors account for approximately 20% of lung cancers, with roughly 14% as SCLC. (5) According to the National Comprehensive Cancer Network (NCCN), an estimated 31,000 new cases of SCLC were diagnosed in 2015 in the United States (U.S.). Nearly all of these new cases are attributed to cigarette smoking. Although the number of lung cancers are decreasing overall, the incidence in women is increasing and the male-to-female incidence ratio is nearly equal. SCLC is characterized by a rapid doubling time, high growth fraction, and early development of widespread metastases. Staging for lung cancer, both SCLC and NSCLC, uses the TNM classification discussed earlier. Staging is based on non-invasive assessments (radiological) and/or invasive (surgical) techniques. (5)

Non-Small-Cell Lung Cancer (NSCLC)

According to the NCCN, lung cancer is the leading cause of cancer deaths in the U.S. (6) In 2015, an estimated 221,200 new cases of lung and bronchial cancer will be diagnosed, with 158,040 deaths estimated resulting from this disease. With the progress being made for screening, minimally invasive techniques for diagnosis and management, only 16.8% of all patients with lung cancer will survive to 5 years or more following the initial diagnosis. NSCLC is the most common form of lung cancer. It includes three sub-types: adenocarcinoma, large-cell carcinoma, and squamous cell carcinoma. Therefore, the literature confirms that non-squamous NSCLC is considered to include adenocarcinoma and large-cell carcinoma. The difference between squamous and non-squamous NSCLC is a key distinction for some U.S. Food and Drug Administration (FDA) approved checkpoint-blocking antibody agents. Staging for NSCLC utilizes the same staging as SCLC, as described above. (6)

Malignant Pleural Mesothelioma (MPM)

Mesothelioma is a rare cancer that is estimated to occur in approximately 2500 individuals within the U.S. annually. (7) The most common type of mesothelioma is MPM. In addition to the lung, MPM can be found in other areas of the body, but those are extremely rare and difficult to treat, as the disease is advanced at the time of initial diagnosis. Median survival is approximately 1 year, and cure is very rare. According to the NCCN Guidelines for MPM, the incidence of MPM is leveling off in the U.S. as a result of the decline of asbestos use since the 1970s; however, the U.S. still leads with the number of cases and deaths worldwide. Staging for MSM uses the basic TNM classification described above, with enhancements from the International Mesothelioma Interest Group (IMIG) with focus on MPM. (7)

Renal Cell Carcinoma (RCC)

RCC is the most common type of kidney cancer, which accounts for 3% of all adult malignancies, with a steadily increasing rate of about 2.5% annually. (8) In 2018, the estimated number of new cases of RCC in the U.S. is approximately 65,000 with about 15,000 deaths. (9) Most people who have RCC are older, usually between the ages of 50 to 70 years of age. Approximately 90% of renal tumors are RCC, and approximately 80% of these are clear-cell histology. Generally, RCC begins as one tumor in the tubules of a single kidney, sometimes there are 2 or more tumors in 1 kidney or even diagnosed in both kidneys. RCC may be known as hypernephroma or renal cell adenocarcinoma. Cancer that originates in the ureters or in the renal pelvis is not considered as RCC. Although most adults are diagnosed with localized tumors, approximately one-third of patients present with metastatic disease. Staging for RCC uses the TNM classification described above, focused on the kidney. (8)

Hodgkin Lymphoma (HL)

HL is an uncommon malignancy involving lymph nodes and the lymphatic system. (10) Most patients are diagnosed between 15 and 30 years of age, followed by another peak in adults aged 55 years or older. The NCCN reports for 2015, over 9000 patients will be diagnosed with classical HL (cHL) in the U.S., with over 1100 patients dying from the same disease. The World Health Organization (WHO) Classification divides HL into 2 main types: cHL and nodular lymphocyte-predominant HL (NLPHL). In Western countries, cHL accounts for 95% and NLPH accounts for 5% of all HL. Staging for HL is based on the Ann Arbor staging system, according to the NCCN. Each Stage is divided into A and B categories. “A” indicates that no systemic symptoms are present and “B” is assigned to patient with unexplained weight loss of >10% of their body weight, unexplained fevers, or drenching night sweats. Patients with HL are usually classified into 3 groups: early-Stage favorable (Stage I-II with no unfavorable factors); early-Stage unfavorable (Stage I-II with any of the unfavorable factors such as large mediastinal adenopathy; >2-3 nodal sites of disease; B symptoms; extranodal involvement; or significantly elevated erythrocyte sedimentation rate ≥50) and advanced-Stage disease (Stage III-IV). (10)

Head and Neck Squamous Cell Cancers (HNSCC)

The NCCN Guidelines for HNSCCs address tumors arising in the lip, oral cavity, pharynx, larynx, and paranasal sinuses. (11) In 2014, it is estimated that about 55,070 new cases of oral cavity, pharyngeal, and laryngeal cancers will occur, which account for about 3% of new cancer cases in the U.S. An estimated 12,000 deaths from HNSCCs will occur during the same time period. Squamous cell carcinoma or a variant is the histologic type in more than 90% of these tumors. Alcohol and tobacco abuse are common etiologic factors in cancers of the oral cavity, oropharynx, hypopharynx, and larynx. Human papillomavirus (HPV) infection is now well accepted as a risk factor for the development of squamous cancers of the oropharynx, particularly cancers of the lingual and palatine tonsils and base of the tongue. The overall incidence of HPV-positive HNSCCs is increasing in the U.S. Staging for HNSCC cancers uses the basic TNM classification described above, with changes particularly to primary tumor descriptions for moderately advanced local disease (T4a) and very advanced local disease (T4b). (11)

Bladder Cancer (Urothelial Carcinoma)

According to the NCCN, bladder cancer is the sixth most common cancer and is 3 times more prevalent in men than in women in the U.S. (12) In 2015 alone, approximately 74,000 new cases have been diagnosed in the U.S. Urothelial carcinoma, also known as transitional cell carcinoma (TCC) is the most common type of bladder cancer. Bladder cancers are rarely diagnosed in individuals younger than 40 years old, with a median age of 65 years. Bladder cancer is divided into 3 categories: non-muscle-invasive tumors, muscle-invasive tumors, and metastatic lesions. Bladder preservation is key throughout prognosis, management and therapeutic aims by providers. Staging of bladder cancer uses the TNM classification described above, focused on the bladder. (12)

Merkel Cell Carcinoma (MCC)

MCC, also known as primary cutaneous neuroendocrine carcinoma of the skin, is a rare type of skin cancer that usually appears as a flesh-colored or bluish-red nodule. (13) MCC tends to grow quickly and metastasizes to other areas of the body, with most recurrences after 2 years following initial diagnosis of the primary tumor. While the disease is 30 times rarer than melanoma (an estimated 0.24 cases per 100,000 persons in the U.S.), patient death occurs 1 in 3 patients compared with 1 in 6 for melanoma. MCC most often arises on sun-exposed areas in fair-skinned individuals over age 50. Its name comes from the similarity of these cancer cells to normal Merkel cells in the skin that are thought to be associated with touch sensation. Staging of MCC uses the TNM classification described above, focused on the skin. (13)

Hepatocellular Carcinoma (HCC; Liver Cancer)

HCC is considered within the spectrum of hepatobiliary cancer, which are the most lethal cancers as reported by the NCCN. (14) Overall, the incidence and mortality rates for cancer are in decline; however, both the incident and mortality rates for liver cancer is increasing. Risk factors for liver cancer include the following: viral infections caused by hepatitis B virus (HBV) and/or hepatitis C virus (HVC), particular comorbidities or conditions, and certain external sources. Non-viral causes of associated with heightened risk of HCC include cirrhosis from any cause (e.g., alcoholic cirrhosis), inherited errors of metabolism, Wilson’s disease, and stage IV primary biliary cirrhosis. Metabolic disorders (e.g., obesity, diabetes, impaired glucose metabolism) may be contributing factors to the increased risk of HCC. Unfortunately, HCC is asymptomatic for much of its natural history. Non-specific symptoms associated with HCC may be attributed to other disease states. Staging of HCC uses the TNM classification described above, but also taking in to account assessment of liver function through scoring evaluations, such as the Child-Pugh Score to evaluate portal hypertension or Model of End-Stage Liver Disease (MELD) to evaluate the liver reserve. (14)

Colorectal Cancer (CRC)

The NCCN Guidelines for colon cancer stated that CRC is the fourth most frequently diagnosed cancer and second leading cause of cancer death in the U.S. (15, 16) In 2016, an estimated 95,270 new cases of colon cancer and approximately 39,220 cases of rectal cancer will occur. During the same year, an estimated 49,190 patients will die of colon and rectal cancer combined. The incidence of CRC has decreased at a rate of 3% per year between 2003 and 2012. In addition, the mortality from CRC has decreased by almost 35% from 1990 to 2007, and is currently down by about 50% from peak mortality rates. Each year, there are over 500,000 CRC cases worldwide. Based on findings, reported by Popet et al., from over 7000 patients stratified for MSI-H, MSI-L, or MSS colon cancers, those with MSI-H had a more positive prognosis by 15% to MSI-L or MSS tumors. (14) Colorectal tumors with MSI are found in the right colon, associated with poor differentiated tissue, high mucinogens, tumor infiltrating lymphocytes, and a presence of a Crohn's-like host response. MSI-H tumors contributing to CRC exhibit less metastasis than another derived CRC. This is demonstrated by previous research showing that MSI-H tumors are more representative in Stage II rather than Stage III cancer. Staging of CRC uses the TNM classification described above, focused on the colon and rectum. (15-18)

Eastern Cooperative Oncology Group (ECOG) Performance Scale

Assessment of the patient’s daily living abilities, also known as the patient’s performance status, including their ability to take care of themselves, daily activity, and physical ability, such as walking, working, etc., is required for a new treatment method, as well continued or repeated therapy. (19) One such measurement tool is the ECOG Performance Scale, developed in 1982. The following Table 3 displays the grade levels and performance scale descriptions.

Table 3. Eastern Cooperative Oncology Group (ECOG) Performance Scale (19)

Grade

ECOG Performance Status

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.

Regulatory Status

Nivolumab (Opdivo®):

Opdivo®, manufactured by Bristol-Myers Squibb Co., Princeton, N.J., received its initial FDA approval on December 22, 2014. (20) This approval was for the treatment of advanced, unresectable or metastatic melanoma. Since then, the FDA has approved expanded labeled indications, to include the treatment of:

1) BRAF V600 wild-type or mutation-positive unresectable or metastatic melanoma;

2) Treatment of metastatic non-squamous NSCLC when the tumor has expressed the PD-L1 determined by an FDA-approved test (along with the FDA allowance for the treatment of patients with epidermal growth factor receptor [EGFR]) or anaplastic lymphoma kinase [AL]) genomic tumor aberrations when disease has progressed on prior FDA-approved treatments);

3) Treatment of advanced RCC who have received prior anti-angiogenic therapy;

4) Treatment of cHL that has relapsed or progressed after autologous hematopoietic stem-cell transplantation and post-transplantation brentuximab vedotin; and

5) The combination therapy with Yervoy™ for treatment of unresectable or metastatic melanoma. (21)

In November 2016, the FDA approved Opdivo® for the treatment of recurrent or metastatic HNSCC with disease progression on or after a platinum-based chemotherapy. (20) According to the NCCN, this type of carcinoma is “very advanced or recurrent/persistent.” (12) In February 2017, the FDA approved Opdivo® for the treatment of “locally advanced or metastatic urothelial carcinoma with disease progression or after platinum-containing chemotherapy or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum chemotherapy.” (20) An expansion of the FDA labeling includes the treatment of patients with intermediate- or poor-risk, previously untreated advanced RCC, in combination with ipilimumab (Yervoy™). As a PD-1 checkpoint inhibitor®, Opdivo® was given orphan drug designation upon its FDA approvals for treatment of gastric cancer and gastroesophageal junction cancer, hepatocellular carcinoma, SCLC, glioblastoma, esophageal cancer, Hodgkin lymphoma, Stage IIb-IV malignant melanoma, and combination therapy with Yervoy™ to treat Stage IIb-IV melanoma or gastric cancer and gastroesophageal junction cancer. (20) There may be pending orphan drug designations for additional indications, refer to the FDA approved labeling of this drug for more information.

Recommended FDA labeled dosing: (20)

  • For unresectable or metastatic melanoma: 240 milligrams (mg) administered intravenously (IV) every 2 weeks.
  • For Opdivo® with ipilimumab (Yervoy™) for unresectable or metastatic melanoma: first Opdivo® 1 mg/kg (kilogram), followed by Yervoy™ on the same day, every 3-weeks for 4 doses, then Opdivo® 240 mg every 2-weeks or 480 mg every 4-weeks, all given IV.
  • For adjuvant treatment of melanoma: 240 mg administered IV every 2-weeks or 480 mg every 4-weeks.
  • For metastatic NSCLC: 240 mg administered IV every 2-weeks or 480 mg every 4-weeks.
  • For advanced RCC: 240 mg administered IV every 2-weeks or 480 mg every 4-weeks.
  • For Opdivo® with ipilimumab (Yervoy™) for advanced RCC: first Opdivo® 3 mg/kg, followed by Yervoy™ 1 mg/kg on the same day, every 3-weeks for 4 doses, then Opdivo® 240 mg every 2-weeks or 480 mg every 4-weeks, all given IV.
  • For cHL: 3 mg/kg administered IV every 2-weeks or 480 mg every 4-weeks.
  • For recurrent or metastatic HNSCC: 3 mg/kg administered IV every 2-weeks or 480 mg every 4-weeks.
  • For advanced or metastatic UC: 240 mg administered IV every 2-weeks or 480 mg every 4-weeks.
  • For HCC: 240 mg administered IV every 2-weeks or 480 mg every 4-weeks.
  • For MSI-H or dMMR metastatic CRC: 240 mg administered IV every 2-weeks.

Rationale:

This medical policy was created in January 2018 and previously noted on RX502.033 - Checkpoint-Blocking/Inhibitor Antibody Treatment for Select Cancers, which has been archived. The archived document can be located at the end of RX502.053 - Ipilimumab (Yervoy). This policy continues to be based on the following:

The National Comprehensive Cancer Network (NCCN) Guidelines and Drugs & Biologics Compendium (4-8, 10-16, 21, 22);

The U.S. Food and Drug Administration (FDA)-approved labeling of checkpoint-blocking inhibitors/antibody treatments (20); and

The Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Specialty Pharmacy Reports. (23)

A search of the Medline, the NCCN Guidelines and Drugs & Biologics Compendium, and the FDA-approved labeling was conducted through January 1, 2018. Each drug treatment is summarized individually below with a focus on recommended use, including off-label indications, from the NCCN Drugs & Biologics Compendium.

Medical policies assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function--including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

The FDA approved nivolumab (Opdivo®) in December 2014 followed by an expanded approval to treat NSCLC in March 2015; and, the NCCN panel updated their Guidelines on the treatment of melanoma in January 2015 and NSCLC in March 2015. (21) These changes lead to inclusion of Opdivo® to the medical policy. Recent FDA approved changes in 2017, expanded utilization of Opdivo® to treat urothelial carcinoma, malignant pleural mesothelioma (MPM), and microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic CRC. The FDA approved a 2018 change for Opdivo® when using in combination with Yervoy™ for treatment of advanced renal cell carcinoma (RCC) (20) Since then, the FDA has continued to expand the approved indications, particularly for the treatment of melanoma and dosage information for all indications.

Melanoma

The FDA approval for treatment of unresectable or metastatic melanoma using Opdivo® or the investigator’s chemotherapy selection was based upon a multi-center, open-label randomized Phase 3 trial of patients following treatment with Yervoy™ and BRAF inhibitors. (20, 24) Weber et al. performed tumor assessments at 9-weeks after the randomization then every 6-weeks for the first year, and every 12-weeks thereafter. (25) Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the first 120 patients who received Opdivo® and in whom the minimum duration of follow-up was 6-months. The major efficacy outcome measured the objective response rate using the RECIST v1.1 (26) and duration of response. The objective response rate was 32% (95% CI: 23, 41), consisting of 4 complete responses and 34 partial responses in the Opdivo®-treated patients. Of the 38 patients with responses, 33 patients (87%) had ongoing responses with durations ranging from 2.6+ to 10+ months, which included 13 patients with ongoing response of 6-months or longer. (25)

Although not included in the 2016 NCCN Guidelines or by the FDA, Robert et al. reported Opdivo® studied in patients previously untreated without the BRAF mutation, as this treatment option had not been tested in a Phase 3 controlled study (CHECKMATE-066). (24) Four hundred eighteen patients with advanced melanoma without BRAF mutation were randomly assigned to either Opdivo® or dacarbazine. The primary endpoint was overall survival. At 1-year, the overall rate of survival was 72.9% (95% CI: 65.5, 78.9) in the Opdivo® group compared to 42.1% (95% CI: 33.0, 50.9) in the dacarbazine group. The median progression free survival was 5.1-months in the Opdivo® group versus 2.2-months in the dacarbazine group. The objective response rate was 40.0% (95% CI, 33.3, 47.0) for the Opdivo® group compared to the 13.9% (95% CI: 9.5, 19.4) in the dacarbazine group. The conclusion by the authors was Opdivo® was associated with significant improvements in overall survival and progression-free survival among those patients previously untreated.

Table 4 provides the efficacy results from the CHECKMATE-066 Phase 3 trial, which demonstrated the statistically significant improvement of the overall survival for the Opdivo® arm compared with the dacarbazine arm in an interim analysis based on 47% of the total planned events. (20, 24)

Table 4. Efficacy Results (20, 24)

Endpoints

Opdivo® (n=210)

Dacarbazine (n=208)

Overall Survival (OS)

Events (%)

50 (24)

96 (46)

Median, months (95% CI)

Not reached

10.8 (9.3, 12.1)

Hazard ratio (95% CI)

0.42 (0.30, 0.60)

p-value

<0.0001a

Progression-free Survival (PFS)

Events (%)

108 (51)

163 (78)

Median, months (95% CI)

5.1 (3.5, 10.8)

2.2 (2.1, 2.4)

Hazard ratio (95% CI)

0.43 (0.34, 0.56)

p-value

<0.0001a

Objective Response Rate (ORR)

34%

9%

(95% CI)

(28, 41)

(5, 13)

Complete response rate

4%

1%

Partial response rate

30%

8%

Table Key:

n: number;

CI: confidence interval;

a: p-value is compared with the allocated alpha of 0.0021 for this interim analysis.

The authors claim that at the time of the analysis, 88% (63/72) of the Opdivo® treated patients had ongoing responses, which included 43 patients with ongoing response of 6 months or longer. (24) The trial had been stopped early as the evidence was showing the overall survival was superior in the Opdivo® arm when compared to the control/dacarbazine arm. As a result, the patients were unblinded; those patients in the control arm were then allowed to receive Opdivo®. Results of those patients have not been published as yet. (20) However, this study was the basis for the November 2015 FDA-approval and label change.

The FDA approved adjuvant treatment of melanoma following the result of the CHECKMATE-238 randomized, double-blind phase 3 trial that enrolled patients with completely resected Stage IIIB/C or Stage IV melanoma. (20) The study, published in 2017 from Weber et al., was designed to determine the efficacy of Opdivo® versus Yervoy™ for adjuvant therapy in patients with resected advanced melanoma. (27) Nine hundred six patients were enrolled and were randomized based on PD-L1 status (positive versus negative/indeterminate) and the American Joint Committee on Cancer staging system (stage IIIB [34%], IIIC [47%], or IV [19%] melanoma): 453 to Opdivo® and 453 to Yervoy™. The major efficacy outcome measure was recurrence-free survival (RFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis), new primary melanoma, or death, from any cause, whichever occurs first. The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. Patients underwent imaging for tumor recurrence every 12 weeks for the first 2 years then every 6 months thereafter. At a minimum follow-up of 18 months, the 12-month rate of RFS was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the Opdivo® group and 60.8% (95% CI, 56.0 to 65.2) in the Yervoy™. Table 5 provides the efficacy results of the CHECKMATE-238 study.

Table 5. Efficacy Results in CHECKMATE-238 (20, 27)

Recurrence-Free Survival

Opdivo® (n=453)

Yervoy™ (n=453)

Number of Events, n (%)

154 (34.0%)

206 (45.5%)

Median (months) (95% CI)

Not reacheda

Not reacheda

Hazard ratiob (95% CI)

0.65 (0.53, 0.80)

p-value

<0.0001

Table Key:

n: number;

CI: confidence interval;

a: not reached;

b: based on stratified proportional hazards model;

c: based on stratified log-rank test;

d: p-value is compared with 0.0244 of the allocated alpha for this analysis.

The study authors concluded that among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with Opdivo® resulted in significantly longer RFS and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with Yervoy™. (27)

Small-Cell Lung Cancer (SCLC)

In 2017, the NCCN added treatment of relapsed SCLC with a combination of Yervoy™ and Opdivo®, which was based on a recent Phase 1/2 study published by Antonia, et al. (5, 21, 28) The patients received either Opdivo® alone or Opdivo® with Yervoy™. This was a multi-center, multi-arm, open-trial for patients 18-years of age or older. Patients had disease progression after at least 1 prior platinum-containing regimen. Two hundred sixteen patients were enrolled and treated, 98 patients receiving Opdivo® alone and 118 divided into 3 groups of various escalating doses of both agents. Response rates were 10% (10 of 98) for the Opdivo® alone, 19% (14 of 61) for Opdivo® with Yervoy™ (dose escalating for Yervoy™), and 19% (10 of 54) Opdivo® with Yervoy™ (dose escalating for Opdivo®). The NCCN panel did note that the response rate did not correlate with the PD-L1 expression. The study authors concluded that Opdivo® monotherapy and Opdivo® with Yervoy™ combined therapy showed anti-tumor activity with durable responses and manageable safety profiles in previously treated SCLC patients.

Non-Small Cell Lung Cancer (NSCLC)

A second trial (CHECKMATE-063) presented to the American Society of Clinical Oncology late in 2014 by Penrod et al. was utilized by the FDA as part of their priority review program to expand approval to include squamous NSCLC. (20, 29) The expanded approval was completed 3-months prior to the initial goal date by both the FDA and manufacturer as a combined early submission and review late in December 2014. The CHECKMATE-063 was randomized (Opdivo® group versus docetaxel; 1:1), open-label study enrolling 272 patients with metastatic squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen. (29) This study included patients regardless of the PD-L1 status. The first tumor assessments were conducted at 9-weeks after randomization and continued every 6-weeks thereafter. The outcome was evaluated using RECIST v1.1. (26) At approximately 11-months of follow-up, the objective response rate was 15% (95% CI: 8.7, 22.21). The estimated 1-year survival was 41% (95% CI: 6.05, 10.91). Historically the expected 1-year survival rate for third-line squamous NSCLC patients is approximately 5.5% to 18%, which is based upon prior studies. (29)

The third trial discussed on the FDA approved label was the study used by the NCCN to make their recommendation of adding Opdivo® as an added treatment option for patients with NSCLC. (6) Rizvi et al. completed a single-arm trial for 117 patients that had progressed after having received a platinum-based therapy and at least 1 additional systemic treatment regimen, some of which had as many as 4 prior treatments. (30) This study included patient regardless of their PD-L1 status. As with the previous discussed above, the objective response rate was based upon RECIST v1.1 (19), which as 15% (95% CI: 9, 22), all were partial responses. The median time to onset of response was 3.3-months. Duration of response ranged from 1.9+ to 11.5+ months for 13 of 17 patients; 10 of these 17 patients had durable response of 6-months or longer. The authors concluded that the data supported the use of Opdivo® for first-line and second-line treatment is effective for squamous NSCLC.

The October 2015 FDA-approval of Keytruda® preceded the expansion of Opdivo® to treat patients diagnosed with non-squamous NSCLC, as Opdivo® also targets the cellular pathway known as PD-1/PD-L1. (20) This change was based upon a randomized, open-label, international Phase 3 study reported on by Borghaei, et al. (31) Patients diagnosed with non-squamous NSCLC that had progressed during or after platinum-based chemotherapy. The 2 arm 1:1 study assigned the 582 patients to either Opdivo® at a dose of 3 mg/kg every 2-weeks (n=292) or docetaxel at a dose of 75 mg/m2 every 3-weeks (n=290). According to the FDA, appropriate prior target therapy for patients with known sensitizing EGFR (epidermal growth factor receptor) or ALK (anaplastic lymphoma kinase) translocation were allowed. (31) Table 6 demonstrates the statistically significant improvements in overall survival for the Opdivo® arm.

Table 6. Efficacy Results of Overall Survival and Progression Free Survival Improvements Opdivo® versus Docetaxel (20, 31)

Endpoints

Opdivo® (n=292)

Docetaxel (n=290)

Overall Survival

Deaths (%)

190 (65%)

223 (77%)

Median (months)

12.2

9.4

(95% CI)

(9.7, 15.0)

(8.0, 10.7)

p-valuea,b

0.0015

Hazard ratio

0.73

(95% CI)c

(0.60, 0.89)

Objective Response Rate

56 (19%)

36 (12%)

(95% CI)

(15, 24)

(9, 17)

p-valued

0.02

Complete response

4 (1.4%)

1 (0.3%)

Partial response

52 (18%)

35 (12%)

Median duration of response (months)

17

6

Progression-Free Survival

Disease progression of death (%)

234 (80%)

245 (84%)

Median (months)

2.3

p-valuea

0.39

Hazard ratio

0.92

(95% CI)

(0.77, 1.11)

Table Key:

n: number;

CI: confidence interval;

a: based on stratified log-rank test;

b: p-value is compared with 0.0408 of the allocated alpha for this interim analysis;

c: based on a stratified proportional hazards model;

d: based on the stratified Cochran-Mantel-Haenszel test.

As shown above in Table 6, the median overall survival for those treated with Opdivo® was 12.2 months. At 1-year for the same study arm, 51%, followed by 39% at 18-months. The same intervals for the docetaxel arm were 9.4-months, 39 % at 1-year, with 23% at the 18-month evaluation. The study authors concluded that among patients with advanced non-squamous NSCLC that had progressed during or after platinum-based chemotherapy, the overall survival was longer when treated with Opdivo® than with docetaxel. (31)

Malignant Pleural Mesothelioma (MPM)

In 2017, the NCCN added treatment of MPM with a combination of Opdivo® and Yervoy™, which was based on the recent ongoing French IFCT-1501 MAPS2 (Intergroupe Francophone de Cancérologie Thoracique [French Cooperative Thoracic Intergroup]-1501 malignant pleural mesothelioma patients) randomized Phase 2 trial published by Scherpereel et al., discussed earlier in this Rationale. (7, 32, 33)

Renal Cell Carcinoma (RCC)

The FDA based their approval of Opdivo® to treat advanced RCC following prior treatment with anti-angiogenic therapy on an open-label study from Motzer et al., the CHECKMATE-025 trial (20, 34) A total of 821 patients were randomized (1:1 ratio) to receive Opdivo® or everolimus for advanced clear-cell RCC, despite prior treatment with 1 or 2 regimens of anti-angiogenic therapy, such as vascular endothelial growth factors. The patients had to have a Karnofsky performance score of 70%. The first tumor assessment was done at 8-weeks following randomization and continued every 8-weeks thereafter for the first year. Following 1-year, assessments were done every 12-weeks until disease progression or treatment discontinuation, whichever occurred later.

The major efficacy outcome measure was overall survival, which for this study was 25.0-months (95% CI, 21.8 to not estimable). (20, 34) Table 7 provides the efficacy results from this open-label trial, which includes the confirmed objective response rates. The trial demonstrated a statistically significant improvement in overall survival for patients treated with Opdivo®.

Table 7. Efficacy Results (20, 34)

Endpoints

Opdivo® (n=410)

Everolimus (n=411)

Overall Survival

Events (%)

183 (45)

215 (52)

Median, months (95% CI)

25.0 (21.7, NE)

19.6 (17.6, 23.1)

Hazard ratio (95% CI)

0.73 (0.60, 0.89)

p-value

<0.0018a

Confirmed Objective Response Rate (95% CI)

21.5% (17.6, 25.8)

3.9% (2.2. 6.2)

Median duration of response in months (95% CI)

23.0 (12.0, NE)

13.7 (8.3, 21.9)

Median time to onset of confirmed response in months (min, max)

3.0 (1.4, 13.0)

3.7 (1.5, 11.2)

Table Key:

n: number;

CI: confidence interval;

NE: not estimable;

min: minimum;

max: maximum;

a: p-value is obtained from a two-sided log-rank test stratified by Memorial Sloan Kettering Cancer Center risk group, number of prior antiangiogenic therapies, and regions.

The authors concluded that among patients previously treated for advanced RCC, overall survival was longer and fewer more significant adverse events occurred with Opdivo® than with everolimus. There was no cross-over from the everolimus group to the Opdivo® group. (34)

The FDA based their April 16, 2018 approval on the CHECKMATE-214 (NCT; National Clinical Trial 02231749) clinical trial, which was a randomized (1:1), open-label study in patients with previously untreated advanced RCC, published by Motzer et al. (20, 35) Intermediate- or poor-risk patients were randomized to Opdivo® 3 mg/kg plus Yervoy™ 1 mg/kg (n=425 of 1096 total enrolled patients) every 3-weeks for 4 doses followed by Opdivo® as monotherapy 3 mg/kg every 2-weeks or sunitinib malate (Sutent®) (n=422) administered orally 50 mg daily for 4-weeks. The efficacy results from this trial are shown in Table 8.

Table 8. Efficacy Results – CHECKMATE-214 (20, 35)

Intermediate-/Poor-Risk

Opdivo® plus Yervoy™

(number=425)

Sutent®

(number=422)

Overall Survival

Deaths (%)

140 (32.9)

188 (44.5)

Median Survival (months)

NE

25.9

Hazard Ratio (99.8% CI)a

0.63 (0.44, 0.89)

p-valueb,c

<0.0001

Confirmed Objective Response Rate (95% CI)

41.6% (36.9, 46.5)

26.5% (22.4, 31.0)

p-valued,e

<0.0001

Complete Response (CR)

40 (9.4)

5 (1.2)

Partial Response (PR)

137 (32.2)

107 (25.4)

Median duration of response in months (95% CI)

NE (21.8, NE)

18.2 (14.8, NE)

Progression-Free Survival

Disease progression or death (%)

228 (53.6)

228 (54.0)

Median (months)

11.6

8.4

Hazard Ratio (99.8% CI)a

0.82 (0.64, 1.05)

p-valueb

NSf

Table Key:

NE: not evaluated;

NS: not significant;

CI: confidence interval;

a: Based on a stratified proportional hazards model;

b: Based on a stratified log-rank test;

c: p-value is compared to alpha 0.002 in order to achieve statistical significance;

d: Based on the stratified DerSimonian-Laird test;

e: p-value is compared to alpha 0.001 in order to achieve statistical significance;

f: Not significant at alpha level of 0.009.

In the CHECKMATE-214 study, patients who were favorable-risk were also randomized (n=249) to Opdivo® plus Yervoy™ (n=125) or to Sutent® (n=124). These patients were not evaluated as part of the efficacy analysis population. Overall survival in favorable-risk patients receiving Opdivo® plus Yervoy™ compared to Sutent® has a hazard ratio of 1.45 (95% CI: 0.75, 2.81). The conclusion of the FDA-approved labeling stated, “The efficacy of nivolumab [Opdivo®] plus Yervoy™ in previously untreated renal cell carcinoma with favorable-risk disease has not been established.” (20) The study authors concluded, “Overall survival and objective response rates were significantly higher in nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal cell carcinoma.” (35)

The NCCN cited the Motzer et al. 2018 CHECKMATE-214 study in their recommendation for Opdivo® plus Yervoy™ as a treatment option for first-line therapy for intermediate- and poor-risk patients with previously untreated, relapsed, or medically unresectable predominantly clear-stage IV RCC. (8, 21, 22, 35) The 2018 NCCN Guideline for Kidney Cancer included the following statement on the restricted FDA approval of Opdivo® plus Yervoy™, “The FDA approval for nivolumab plus ipilimumab is narrower, only for patients with intermediate- or poor-risk RCC.” (8)

Hodgkin Lymphoma (HL)

The FDA based approval of Opdivo® on 2 studies assessing classical HL (cHL). (19) Opdivo® was evaluated as a single agent in patients with cHL following the failure of autologous HSCT and post-transplantation brentuximab vedotin. The first trial was a single-arm, open-label, multi-center, multi cohort of cHL. (20) (This trial has yet to be published in a peer-reviewed journal.) The second trial was not a single-arm, but rather a dose escalation study. (20, 36)

According to the FDA, both studies included patients regardless of their tumor PD-L1 status and excluded patients with ECOG performance status of 2 or greater, autoimmune disease, symptomatic interstitial lung disease, hepatic transaminases more than 3 times ULN (upper limit of normal), creatinine clearance less than 40 mL/min, prior allogeneic HSCT, or chest irradiation within 24-weeks. (20) In addition, both studies required an adjusted diffusion capacity of the lungs for carbon monoxide (DLCO) of over 60% in patients with prior pulmonary toxicity.

Patients received 3 mg/kg of Opdivo® administered intravenously over 60-minutes every 2-weeks until disease progression, maximal clinical benefit, or unacceptable toxicity. A cycle consisted of one dose. Dose reduction was not permitted. Efficacy was evaluated by objective response rate as determined by an independent radiographic review committee. Additional outcome measures included duration of response. Efficacy was evaluated in 95 patients in both trials combined who had received brentuximab vedotin after failure of autologous HSCT. The median age was 37 years (range: 18 to 72). The majority were male (64%) and white (87%). Patients had received a median of 5 prior systemic regimens (range: 3 to 15).

Results are shown in Table 9. Patients received a median of 17 doses of Opdivo® (range 3 to 48), with a median duration of therapy of 8.3-months (range 1.9 to 24 months). (20)

Table 9. Efficacy in cHL after Autologous HSCT with Adcetris® (20, 36)

Endpoints

Both Trials (n = 95 patients)

Objective Response Rate, n (%) a (95% CI)

62 (65%) (55, 75)

Complete Remission Rate (95% CI)

7 (7%) (3, 15)

Partial Remission Rate (95% CI)

55 (58%) (47, 68)

Median Duration of Response (months) (95% CI) Range

8.7 (6.8, NE) 0.0+, 23.1+

Median Time to Response (months) Range

2.1 0.7, 5.7

Table Key:

n: number.

CI: confidence interval.

NE: not evaluated

a: Per 2007 revised International Working Group criteria.

Head and Neck Squamous Cell Cancers (HNSCC)

The FDA approval for Opdivo® was based upon on an open-label clinical trial of 361 patients with metastatic or recurrent HNSCC who had experienced disease progression during or within 6 months of receiving platinum-based therapy. (20) While not published as of August 17, 2017, trial 9 was randomized (2:1), 240 patients were given Opdivo® and 121 patients were given the investigators’ choice (45% received docetaxel, 43% received methotrexate, and 12% received cetuximab). The first tumor assessments were conducted 9-weeks after randomization and continued every 6-weeks thereafter. The major efficacy outcome measure was overall survival. Additional efficacy outcome measures were progression-free survival and objective response rate. Outcomes summary for HNSCC treatment with Opdivo® displays survival results in Table 10.

Table 10. Overall Survival of Trial 9 (20)

Endpoint

Opdivo®

Number of patients = 240

Investigator’s Choice

Number of patients = 121

Overall Survival (OS)

Deaths (%)

133 (55%)

85 (70%)

Median (months) (95% CI)

7.5 (5.5, 9.1)

5.1 (4.0, 6.0)

Hazard ratio (95% CI)a

0.70 (0.53, 0.92)

p-valueb,c

0.0101

Table Key:

CI: Confidence Interval;

a: Based on stratified proportional hazards model;

b: Based on stratified log-rank test;

c: p-value is compared with 0.0227 of the allocated alpha for this interim analysis.

Archival tumor specimens were retrospectively evaluated for PD-L1 expression using the PD-L1 IHC 28-8 pharmDx assay. Across the study population, 28% (101/361) of patients had non-quantifiable results. Among the 260 patients with quantifiable results, 43% (111/260) had PD-L1 negative HNSCC, defined as <1% of tumor cells expressing PD-L1, and 57% (149/260) had PDL1 positive HNSCC, defined as ≥1% of tumor cells expressing PD-L1. In pre-specified exploratory subgroup analyses, the hazard ratio (HR) for survival was 0.89 (95% CI: 0.54, 1.45) with median survivals of 5.- and 5.8-months for the Opdivo® and chemotherapy arms, respectively, in the PD-L1 negative subgroup. The HR for survival was 0.55 (95% CI: 0.36, 0.83) with median survivals of 8.7- and 4.6-months for the Opdivo® and chemotherapy arms, respectively, in the PD-L1 positive HNSCC subgroup. (20)

Bladder Cancer (Urothelial Carcinoma)

The clinical trial used for the FDA-approval was documented in the FDA-approved label. (20) The study, described below from the FDA-approved label, has yet to be published.

In Trial 10, 270 patients with locally advanced or metastatic urothelial carcinoma who had disease progression during or following platinum-containing chemotherapy or who had disease progression within 12-months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen were treated with Opdivo®. (20) Patients were excluded for active brain or leptomeningeal metastases, active autoimmune disease, medical conditions requiring systemic immunosuppression, and ECOG performance status >1. Patients received an intravenous infusion of 3 mg/kg of Opdivo® every 2-weeks until unacceptable toxicity or either radiographic or clinical progression. Tumor response assessments were conducted every 8-weeks for the first 48 weeks and every 12-weeks thereafter. Major efficacy outcome measures included confirmed objective response rate as assessed by independent radiographic review committee using RECIST v1.1 (19) and duration of response.

The median age was 66 years (range 38 to 90), 78% were male, 86% of patients were white. Twenty-seven percent had non-bladder urothelial carcinoma and 84% had visceral metastases. Thirty-four percent of patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy. Twenty-nine percent of patients had received ≥2 prior systemic regimens in the metastatic setting. Thirty-six percent of patients received prior cisplatin only, 23% received prior carboplatin only, and 7% were treated with both cisplatin and carboplatin in the metastatic setting. Forty-six percent of patients had an ECOG performance status of 1. Eighteen percent of patients had a hemoglobin <10 g/dL, and twenty-eight percent of patients had liver metastases at baseline. Patients were included regardless of their PD-L1 status.

Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory and the results were used to define subgroups for pre-specified analyses. Of the 270 patients, 46% were defined as having PD-L1 expression of ≥1% (defined as ≥1% of tumor cells expressing PD-L1). The remaining 54% of patients, were classified as having PD-L1 expression of <1% (defined as <1% of tumor cells expressing PD-L1). Confirmed objective response rate in all patients and the two PD-L1 subgroups are summarized in Table 11. (20) Median time to response was 1.9-months (range; 1.6-7.2). In 77 patients who received prior systemic therapy only in the neoadjuvant or adjuvant setting, the objective response rate was 23.4% (95% CI: 14.5%, 34.4%).

Table 11. Efficacy of Trial 10 (20)

Endpoints

All Patients

PD-L1 <1%

PD-L1 ≥1%

n=270

n=146

n=124

Confirmed Objective Response Rate,

n (%) (95% CI)

53 (19.6%) (15.1, 24.9)

22 (15.1%) (9.7, 21.9)

31 (25.0%) (17.7, 33.6)

Complete Response Rate

7 (2.6%)

1 (0.7%)

6 (4.8%)

Partial Response Rate

46 (17.0%)

21 (14.4%)

25 (20.2%)

Median Duration of Responsea (months) (range)

10.3

(1.9+, 12.0+)

7.6

(3.7, 12.0+)

NE

(1.9+, 12.0+)

Table Key:

PD-L1: Programmed death receptor-1 ligand;

n: number;

CI: confidence interval;

NE: not estimable;

a: Estimated from the Kaplan-Meier Curve.

Merkel Cell Carcinoma (MCC)

In the 2018 NCCN Drugs & Biologics Compendium, the recommendation is single agent treatment for disseminated metastatic disease with or without surgery or radiation therapy. (13) This 2A recommendation comes as preliminary data from non-randomized trials in patients with MCC demonstrating that rates of durable response are improved with PD-1/PD-L1 blockade with cytotoxic safety. The NCCN stated, “The safety profiles for checkpoint immunotherapies are significantly different from cytotoxic therapies.”. However, one 2017 anecdotal study from Mantripragada and Birnbaum was found in a Medline database search, reporting promising response following 4 cycles of Opdivo® to treat metastatic MCC. (37) Results from the non-randomized trials mentioned in the 2A NCCN recommendation have not been published as of January 16, 2018.

Hepatocellular Carcinoma (HCC)

Results from the CHECKMATE-040 trial was the basis for the FDA-approval of Opdivo® to treat patients with HCC who have progressed on or were intolerant to sorafenib. (20) The 154-patient subgroup multicenter, open-label phase I/II trial was published by El-Khoueiry et al., in 2017. (38)

Additional eligibility criteria included histologic confirmation of HCC and Child-Pugh Class A: 48 patients with advanced HCC in a dose-escalation phase and the balance in dose-expansion phase. All patients had received prior sorafenib, of whom 36 (23%) were unable to tolerate sorafenib; 19% of patients had received 2 or more prior systemic therapies. Tumor assessments were conducted every 6 weeks for 48 weeks and every 12 weeks thereafter. The major efficacy outcome measure was confirmed overall response rate. The study authors concluded that Opdivo® had a manageable safety profile and no new signals were observed in patients with advanced HCC. Durable objective responses show the potential of Opdivo® for treatment of advanced HCC. Efficacy results are summarized in Table 12.

Table 12. Efficacy Results of CHECKMATE-040 (20, 38)

Response Results

Opdivo® (n=154)

BICR - Assessed Overall Response Ratea, n (%), RECIST v1.1

22 (14.3%)

(95% CI)b

(9.2, 20.8)

Complete Response

3 (1.9%)

Partial Response

19 (12.3%)

BICR - Assessed Duration of Response, RECIST v1.1

(n=22)

Range (months)

(3.2, 38.2+)

% with duration ≥ 6 months

91%

% with duration ≥ 12 months

55%

BICR - Assessed Overall Response Ratea, n (%), mRECIST

28 (18.2%)

(95% CI)

(12.4, 25.2)

Complete response

5 (3.2%)

Partial response

23 (14.9%)

Table Key:

n: number;

CI: confidence interval;

BICR: Blinded Independent Central Review;

a: Overall response rate confirmed by BICR;

b: Confidence interval is based on the Clopper and Pearson method.

Microsatellite Instability-High (MSI-H) Colorectal Cancer (CRC)

The efficacy of Opdivo® was evaluated for CRC and presented to the FDA for approval. (20, 39) Patients diagnosed with MSI-H or dMMR metastatic CRC who had disease progression during, after, or were intolerant to, prior treatment with 1 of several agents. The CHECKMATE-142 trial was published by Overman et al. in 2017, as an open-label, multi-center, Phase 2 study. (19, 37) The 74 adult patients had received 3 or more prior treatments before receiving Opdivo®. Opdivo® was given every 2-weeks until disease progression, death, unacceptable toxic effect, or withdrawal from the study. At the median follow up of 12-months, 51 patients had disease control for 12-weeks or longer. Table 13 provides the efficacy results of the CHECKMATE-142 trial. (20, 40)

Table 13. Efficacy of the CHECKMATE-142 Trial (20, 40)

Endpoint

All Patients

(n=74)

Prior Treatment

(n=53)

Objective Response Rate (95% CI)

24 (32%) (22, 44)

15 (28%) (17, 42)

Complete Remission Rate

2 (2.7%)

1 (1.9%)

Partial Remission Rate

22 (30%)

14 (26%)

Duration of Response (median in months) Range

NR (1.4+, 26.5+)

NR (2.8+, 22.1+)

Table Key:

n: number;

CI: confidence interval;

NR: not reached;

+: denotes ongoing.

The CHECKMATE-142 study authors concluded that Opdivo® had provided durable responses and disease control in pre-treated patients with dMMR/MSI-H metastatic CRC, and could be a new treatment option for those patients that have been diagnosed. (40)

Ongoing and Unpublished Clinical Trials

According to the National Cancer Institute (NCI)/ClinicalTrials.gov, there are multiple clinical trials targeting the use of Opdivo®, with or without other pharmaceutical preparations, such as to treat colorectal cancer, pancreatic cancer, gastric cancers, hepatocellular cancer, prostatic cancer, breast cancer, solid organ tumors, small-cell lung cancer, acute myeloid leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, non-Hodgkin lymphoma, glioblastoma and gliosarcoma, ovarian cancer, HIV associated tumors, etc. Some of the studies listed in ClinicalTrials.gov include Keytruda® in combination with radiation therapy or radiosurgery, including stereotactic radiation therapy.

Professional Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN) - Melanoma

The 2018 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 1 recommendation for first-line or in combination with Yervoy™ for the treatment of unresectable or metastatic melanoma. (4, 21, 22) The 2018 NCCN Drugs & Biologics Compendium recommends Opdivo® as a Category 2A for second-line, subsequent or re-induction therapy to treat unresectable or metastatic disease, for patients with ECOG performance status 0-2. In 2018, adjuvant therapy of melanoma with Opdivo® as a single agent has been added as a Category 2A recommendation.

NCCN – Small-Cell Lung Cancer (SCLC)

The 2017 NCCN added treatment with Yervoy™ as a Category 2A recommendation for SCLC. (5, 21) The indications included subsequent systemic therapy with Opdivo® for patients with ECOG performance status 0-2 when in combination with Yervoy™.

NCCN – Non-Small-Cell Lung Cancer (NSCLC)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 1 recommendation to treat metastatic NSCLC for patients with ECOG performance scale 0-2 as subsequent therapy following progression on a first-line therapy cytotoxic regiment or as a Category 2A for further progression on other systemic therapy. (6, 21)

NCCN – Malignant Pleural Mesothelioma (MPM)

The 2017 NCCN added treatment with Opdivo® as a Category 2A recommendation for MPM without any qualifications. (7, 21)

NCCN – Renal Cell Carcinoma (RCC)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 1 for the treatment of clear cell RCC as the preferred subsequent therapy and a 2A for non-clear cell RCC histology as systemic therapy, when the disease has relapsed or classified as Stage IV. (8, 21)

The 2018 NCCN added treatment with Opdivo® plus Yervoy™ as a Category 1 recommendation for RCC as a systemic therapy for first-line therapy for predominant clear-cell histology and intermediate- or poor-prognosis risk group. As a Category 2A recommendation, based on high-level evidence, there is uniform NCCN consensus for subsequent therapy with Opdivo® plus Yervoy™. (8, 21, 22)

NCCN – Hodgkin Lymphoma (classical HL)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 2A recommendation for patients ≥18 years for refractory cHL following prior chemotherapy or as palliative therapy for older adult patients >60 years of age with relapsed or refractory disease. (10, 21)

NCCN – Head and Neck Squamous Cell Cancer(HNSCC)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 2A recommendation as a single agent for non-nasopharyngeal HNSCC if disease progression on or after platinum containing chemotherapy, which includes newly diagnosed or metastatic disease. (11, 21) For use in newly diagnosed disease or for unresectable locoregional recurrent, the NCCN recommends the patient must meet ECOG performance status 3; however, for initial presentation of metastatic disease or other metastatic indications, the patient must meet ECOG performance status 0-2.

NCCN – Bladder Cancer (Urothelial Carcinoma)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 2A recommendation for the treatment, locally advanced, for recurrence post-cystectomy bladder cancer or metastatic disease. (12, 21) Additionally, the NCCN has as a 2A recommendation for the treatment using Opdivo® of urothelial carcinoma found in the urethra, upper genitourinary tract, and prostate.

NCCN – Merkel Cell Carcinoma (MCC)

The 2018 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 2A recommendation for the systemic treatment of disseminated MCC disease. (13, 21)

NCCN – Hepatocellular Cancer (HCC)

The 2018 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 2A recommendation for the treatment option for progression on or after sorafenib therapy of HCC (Child-Pugh Class A or B7 only). (14, 21)

NCCN – Colorectal Cancer (CRC)

The 2017 NCCN Guidelines and Drugs & Biologics Compendium designated Opdivo® as a Category 2A recommendation for the following CRC treatments: (15, 16, 21)

Primary therapy for unresectable metachronous metastases following prior specific adjuvant treatment within last 12 months,

Initial therapy for unresectable advanced or metastatic disease when not appropriate for intensive therapy(s), and

Subsequent therapy for unresectable advance or metastatic disease following prior specific treatment.

Summary of Evidence

The evidence is sufficient to support the use of Opdivo® for its U.S. Food and Drug Administration (FDA) approved indications, which is based on the clinical trial outcomes documented in the published labeling, and the indications listed within the National Comprehensive Cancer Network (NCCN) Guidelines and Drugs & Biologics Compendium.

The evidence is insufficient to support the use of Opdivo® beyond FDA approved indications. Therefore, the use of Opdivo®, a checkpoint-blocking/inhibitor agent, is considered experimental, investigational and/or unproven for the following indications including, not limited to, breast cancer, chronic myeloid leukemia, non-Hodgkin’s lymphoma, multiple myeloma, myelodysplastic syndrome, and stage I or stage II melanoma.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

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.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

J9299

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. ACS – Immune Checkpoint Inhibitors to Treat Cancer (May 1, 2017). American Cancer Society. Available at: <http://www.cancer.org> (accessed on August 2, 2017).

2. NIH – FDA approves pembrolizumab for tumors with specific tumor genetic features (June 20, 2017). National Cancer Institute of the National Institutes of Health. Available at: <https://www.cancer.gov> (accessed on August 17, 2017).

3. NIH – Staging (March 19, 2015). National Cancer Institute of the National Institutes of Health. Available at: <https://www.cancer.gov> (accessed on August 17, 2017).

4. NCCN – Melanoma Version 1.2018 (October 11, 2017). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Available at: <http://www.nccn.org> (accessed on January 16, 2018).

5. NCCN – Small Cell Lung Cancer Version 3.2017 (February 23, 2017). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Available at: <http://www.nccn.org> (accessed on August 4, 2017).

6. NCCN – Non-Small Cell Lung Cancer Version 8.2018 (July 14, 2017). National Comprehensive Cancer Network Practice Guidelines in Oncology (NCCN Guidelines™). Available at: <http://www.nccn.org> (accessed on August 4, 2017).

7. NCCN – Malignant Pleural Mesothelioma Version 2.2017 (July 7, 2017). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Available at: <http://www.nccn.org> (accessed on August 4, 2017).

8. NCCN – Kidney Cancer Version 4.2018 (April 23, 2018). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Available at: <http://www.nccn.org> (accessed on June 26, 2018).

9. Alsharedi M, Katz H. Check point inhibitors a new era in renal cell carcinoma treatment. Med Oncol. May 4 2018; 35(6):85. PMID 29728867

10. NCCN – Hodgkin Lymphoma Version 1.2017 (March 1, 2017). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Available at: <http://www.nccn.org> (accessed on August 4, 2017).

11. NCCN – Head and Neck Cancers Version 2.2017 (May 18, 2017). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Available a: <http://www.nccn.org> (accessed on August 4, 2017).

12. NCCN – Bladder Cancer Version 5.2017 (May 25, 2017). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Available at: <http://www.nccn.org> (accessed on August 4, 2017).

13. NCCN – Merkel Cell Carcinoma Version 1.2018 (September 18, 2017). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Available at: <http://www.nccn.org> (accessed on January 16, 2018).

14. NCCN – Hepatobiliary Cancers Version 4.2017 (October 9, 2017). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Available at: <http://www.nccn.org> (accessed on January 15, 2018).

15. NCCN – Colon Cancer Version 2.2017 (March 13, 2017). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Available at: <http://www.nccn.org> (accessed on August 4, 2017).

16. NCCN – Rectal Cancer Version 3.2017 (March 13, 2017). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Available at: <http://www.nccn.org> (accessed on August 4, 2017).

17. Popat SL, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. Jan 20 2005; 23(3):609-18. PMID 15659508

18. Buecher BI, Cacheux W, Rouleau E, et al. Role of microsatellite instability in the management of colorectal cancers. Dig Liver Dis. Jun 2013; 45(6):441-9. PMID 23195666

19. ECOG Performance Scale/Status (1982). Developed by the Eastern Cooperative Oncology Group, Comis RL, Group Chair. Available at: <http://www.ecog-acrin.org> (accessed on August 17, 2016).

20. FDA – Highlights of Prescribing Information (FDA-Approved Label) for Opdivo® (nivolumab). Food and Drug Administration – Product Label. (April 16, 2018). Available at: <http://www.fda.gov> (accessed on June 27, 2018).

21. NCCN – Nivolumab (2018). National Comprehensive Cancer Network Drugs & Biologics Compendium. Available at: <http://www.nccn.org> (accessed on June 26, 2018).

22. NCCN – Ipilimumab (2018). National Comprehensive Cancer Network Drugs & Biologics Compendium. Available at: <http://www.nccn.org> (accessed on June 26, 2018).

23. Nivolumab (Opdivo®) Specialty Pharmacy Report #1-2015. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (January 2015):1-28.

24. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. Jan 22 2015; 372(4):320-30. PMID 25399552

25. 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. Apr 2015; 16(4):375-84. PMID 25795410

26. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). EJC. Jan 2009; 45(2):228-47. PMID 19097774

27. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. Sep 2017; 377(19):1824-35. PMID 28891423

28. Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CHECKMATE-032) a multi-center, open-label, phase 1/2 trial. Lancet Oncol. Jul 2016; 17(7):883-95. PMID 27269741

29. Penrod JR. Phase 2 objective response rate and survival data for opdivo (novilumab) in heavily pre-treated advanced squamous cell non-small-cell lung cancer. Presented at 2014 Chicago, Illinois Multidisciplinary Symposium on Thoracic Oncology, sponsored by American Society of Clinical Oncology (October 30, 2014). Produced by Bristol-Myers Squibb. Available at <http://news.bms.com> (accessed on April 27, 2015).

30. Rizvi NA, Mazieres J, Plandchard 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. Mar 2015; 16(3):257-65. PMID 25704439

31. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced non-squamous non-small cell lung cancer. N Engl J Med. Oct 22 2015; 373(17):1627-39. PMID 26412456

32. IFCT – Encouraging disease control rates observed with nivolumab alone on in combination with ipilimumab in refractory or relapsing malignant pleural mesothelioma patients: results from the IFCT-1501 MAPS-2 trial (June 8, 2017). Intergroupe Fracncophone de Cancerolgie Thoracique with Bristol-Myers Squibb. Available at <http://www.ifct.fr> (accessed on August 15, 2017).

33. Scherpereel A, Mazieres 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 MPAPS-2 randomized phase II trial. J Clin Oncol. 2017;35(18):Epub ahead of print.

34. Motzer RF, Escudier DF, McDermott S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. Nov 5 2015; 373(19):1803-13 PMID 26406148

35. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. Apr 5 2018; 378(14):1277-90; Epub Mar 21 2018. PMID 29562145

36. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. Jan 22 2015; 372(4):311-9. PMID 25482239

37. Mantripragada K, Birnbaum A. Response to anti-PD-1 therapy in metastatic Merkel cell carcinoma metastatic to the heart and pancreas. Cureus. Dec 13 2013; 7(12):e403. PMID 26824006

38. 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. Jun 24 2017; 389(10088):2492-502. PMID 28434648

39. FDA – FDA grants nivolumab accelerated approval for MSI-H or dMMR colorectal cancer (July 31, 2017). U.S. Food and Drug Administration – News Release. Available at: <http://www.fda.gov> (accessed on August 1, 2017).

40. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CHECKMATE-142): an open-label, multi-center, phase 2 study. Lancet Oncol. July 19, 2017:Epub ahead of print. PMID 28734759

41. Opdivo® – IBM Micromedex® DRUGDEX® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: <www.micromedexsolutions.com> (accessed on June 28, 2018).

Policy History:

Date Reason
11/15/2018 Document updated with literature review. The following change was made to Coverage: 1) Added conditional coverage for renal cell carcinoma to list of medically necessary indications; and 2) changed from first-line to second-line or subsequent for treatment of melanoma in combination with Yervoy, “Single agent or in combination with Yervoy™ as second-line or subsequent therapy (see NOTE 3) of unresectable or metastatic melanoma, when patient has the BRAF V600 mutation-positive with disease progression following treatment with a BRAF inhibitor (see NOTE 4) (such as vemurafenib [Zelboraf®] or dabrafenib [Tafinlar®]).” References 9, 22, and 35 were added.
5/1/2018 New medical document. Opdivo® may be considered medically necessary in patients with the following indications, when meeting specific criteria: melanoma, small-cell lung cancer, non-small-cell lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck squamous cell cancer, bladder cancer (urothelial carcinoma), Merkel cell carcinoma, and hepatocellular carcinoma. Opdivo® is considered experimental, investigational and/or unproven for all other indications, including, but not limited to: breast cancer, cervical cancer, gastric cancer, glioblastoma, multiple myeloma, myelodysplastic syndrome, mycosis fungoides, non-Hodgkin lymphoma, ovarian cancer, sarcomas, Sézary syndrome, solid organ tumors, squamous cell cancer, stage I or stage II melanoma, use in combination therapy with another checkpoint inhibitor agent, unless addressed above with Yervoy®. The following was added to coverage, “NOTE 3: Opdivo® may be given for disease progression with Yervoy™ as first-line therapy. For information regarding Yervoy™, refer to Medical Policy RX502.053, Ipilimumab (Yervoy™)”; “NOTE 7: For information regarding Keytruda®, refer to Medical Policy RX502.054, Pembrolizumab (Keytruda®)”; “NOTE 8: For information regarding Tecentriq™, refer to Medical Policy RX502.056, Atezolizumab (Tecentriq™)”; and “NOTE 9: There are some checkpoint inhibitors may have been granted orphan drug designation by the U.S. Food and Drug Administration (FDA) for specific indications. Refer to the FDA approved labeling of this drug for more information.” (The policy was originally included in RX502.033, Checkpoint-Blocking/Inhibitor Antibody Treatment for Select Cancers.)

Archived Document(s):

Title:Effective Date:End Date:
Nivolumab (Opdivo)05-01-201811-14-2018
Back to Top