Pending Policies - Prescription Drugs


Ipilimumab (Yervoy)

Number:RX502.053

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.

Ipilimumab (Yervoy™) may be considered medically necessary in adults and children (12 years and older) for the following indications:

Melanoma:

o Single agent first-line therapy or in combination with Opdivo® (see NOTE 1) for brain metastases if active against primary melanoma tumor for recurrent disease.

o Single agent therapy for brain metastases if active against primary melanoma tumor for recurrent stable systemic disease.

o Single agent as adjuvant treatment of patients with:

1. Stage III sentinel lymph node positive metastasis >1 millimeter (mm) following a complete lymph node dissection/resection;

2. Stage III disease with clinically positive lymph node(s) following wide excision of primary tumor and a complete therapeutic lymph node dissection/resection; or

3. Following complete lymph node dissection/resection and/or complete resection of nodal recurrence.

o Single agent first-line therapy in combination with Opdivo® (see NOTE 1) for treatment of a histological diagnosis of Stage III or Stage IV unresectable or metastatic melanoma.

o Single agent or in combination with Opdivo® (see NOTE 1) as second-line or subsequent therapy for disease progression of a histological diagnosis of Stage III or Stage IV unresectable or metastatic melanoma (if Yervoy™ not previously used). The patient must meet the 0-2 ECOG performance scale (see NOTE 2).

o Single agent or in combination with Opdivo® (see NOTE 1) following maximum clinical benefit from BRAF (serine/threonine-specific protein kinase gene) targeted therapy for unresectable or metastatic melanoma. The patient must meet the 0-2 ECOG performance scale (see NOTE 2).

o Single agent or in combination with Opdivo® (see NOTE 1) as re-induction therapy when the patient has experienced disease control and has no residual toxicity, but subsequently experience disease progression/relapse >3 months after treatment discontinuation for unresectable or metastatic melanoma. The patient must meet the 0-2 ECOG performance scale (see NOTE 2).

Small-Cell Lung Cancer (SCLC):

o Subsequent systemic therapy, in combination only with Opdivo® (see NOTE 1) when SCLC has relapsed 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).

Malignant Pleural Mesothelioma (MPM):

o Subsequent systemic therapy, in combination only with Opdivo® (see NOTE 1) for MPM. The patient must meet the 0-2 ECOG performance scale (see NOTE 2).

Renal Cell Carcinoma (RCC):

o First-line systemic therapy, in combination only with Opdivo® (see NOTE 1) for relapse or surgically unresectable stage IV (advanced) RCC.

o Subsequent systemic therapy, in combination only with Opdivo® (see NOTE 1) for relapse or surgically unresectable stage IV (advanced) RCC.

NOTE 1: For information regarding Opdivo®, refer to Medical Policy RX502.055, Nivolumab (Opdivo®).

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

NOTE 3: 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.

Ipilimumab (Yervoy™) is considered experimental, investigational and/or unproven for all other indications, including, but not limited to:

Autoimmune diseases requiring treatment with immunosuppressants,

Bladder cancer or urothelial carcinoma,

Breast cancer,

Cervical cancer,

Chronic myeloid leukemia,

Colorectal cancer,

Gastric cancer,

Glioblastoma,

Hodgkin lymphoma,

Non-Hodgkin lymphoma,

Non-small-cell lung cancer,

Ovarian cancer,

Pancreatic cancer,

Prostate cancer,

Salivary tumor,

Sarcomas,

Solid organ tumors,

Stage I or Stage II melanoma, and

Use in combination therapy with another checkpoint inhibitor agent, unless with Opdivo®.

NOTE 4: 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:

Ipilimumab (Yervoy™) is a programmed cell death protein (PD-1) checkpoint blocking inhibitor or antibody, in addition to actively attaching to the cytotoxic T-lymphocyte associated protein 4 (CTLA-4), 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.

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 (2, 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. (2, 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.

Overall, this new class of drugs have been shown to be helpful in treating several types of cancer, including melanoma of the skin, small-cell lung cancer, malignant pleural mesothelioma and other types of cancer that are currently being researched.

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. (5) Staging is based on non-invasive assessments (radiological) and/or invasive (surgical) techniques.

Malignant Pleural Mesothelioma (MPM)

Mesothelioma is a rare cancer that is estimated to occur in approximately 2500 individuals within the U.S. annually. (6) 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. (6)

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. (7) In 2018, the estimated number of new cases of RCC in the U.S. is approximately 65,000 with about 15,000 deaths. (8) 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. (7)

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. (9) 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 (9)

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

Yervoy™, manufactured by Bristol-Myers Squibb Co., Princeton, N.J., received its initial FDA approval on March 25, 2011. (10) The initial approval was for the treatment option for unresectable or metastatic melanoma. Since then, the FDA has approved expanded labeled indications, to include the adjuvant treatment of patients at risk for Stage III melanoma recurrence, including following lymph node resection. An expansion of the FDA labeling includes the treatment of patients with intermediate- or poor-risk, previously untreated advanced RCC, in combination with nivolumab (Opdivo®). 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. At this time, Yervoy™ was given orphan drug designation upon its initial FDA approval in 2011 for pediatric patients. (10) 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: (10)

For unresectable or metastatic melanoma: 3 milligrams/kilograms (mg/kg) administered intravenously (IV) over 90 minutes every 3 weeks for a total of 4 doses.

For adjuvant melanoma: 10 mg/kg administered IV over 90 minutes every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks up to 3 years or until documented disease recurrence or unacceptable toxicity.

For advanced RCC: following administration of Opdivo® 3 mg/kg IV over 30 minutes, 1 mg/kg of Yervoy™ is administered IV over 30 minutes on the same day, every 3 weeks for a maximum of 4 doses, then Opdivo® 240 mg every 2 weeks or 480 mg every 4 weeks IV over 30 minutes.

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 this medical policy. This policy continues to be based on the following:

The National Comprehensive Cancer Network (NCCN) Guidelines and Drugs & Biologics Compendium (4-7, 12, 13);

The U.S. Food and Drug Administration (FDA)-approved labeling of checkpoint-blocking inhibitors/antibody treatments (10); and

The Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Specialty Pharmacy Reports. (14)

A search of Medline, and 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.

In May 2011, BCBSA TEC released the Specialty Pharmacy Combined Capacity (SPCC) Report #6-2011 (14) concurrently to the release of the FDA-approved labeling of ipilimumab (Yervoy™). (10, 15) At that time, Yervoy™ was the sole pharmaceutical listed on this medical policy. The 2018 NCCN Drugs & Biologics Compendium maintained recommendations for the use of Yervoy™ for specific melanoma diagnoses and small-cell lung cancer (SCLC), malignant pleural mesothelioma (MPM), and added advanced renal cell carcinoma (RCC). (12)

Melanoma and Metastases to the Brain

Yervoy™’s FDA-approval was based upon a recent pivotal Phase 3, double-blind international study that randomized 676 patients with unresectable or metastatic melanoma, including metastases to the brain. (16) Hodi et al. reported all patients in the study had stopped responding to other FDA-approved or commonly used treatments of melanoma, such as aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. The study excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. According to the FDA, “The study was designed to measure overall survival, the length of time from when this treatment started until a patient's death. The randomly assigned patients received Yervoy™ alone, Yervoy™ plus an experimental tumor (peptide) vaccine called gp100, or the vaccine alone. (16) Those who received the combination of Yervoy™ plus the vaccine or Yervoy™ alone lived an average of about 10-months, while those who received only the experimental vaccine lived an average of 6.5-months.” The assessment of the tumor response was conducted at week 12 and 24, and every 3-months thereafter. The published study revealed the estimated overall survival at 1-year was 46% in the Yervoy™ arm, 44% in the Yervoy™ and vaccine arm, and 25% in the vaccine alone arm. At 2-years, the overall survival was 24% in the Yervoy™ arm, 22% in the Yervoy™ and vaccine arm, and 14% in the vaccine alone arm.

In October 2015, the FDA expanded the approved label for the adjuvant treatment of patients who are at risk of developing recurrence of Stage III melanoma after surgery as adjuvant therapy. This change was based upon a double-blind, Phase 3 trial reported by Eggermont et al. (17) The study purpose was to determine if Yervoy™ would be effective in the prevention or delay recurrence of Stage III melanoma, prolonging survival following complete resection by a full lymphadenectomy within 12-weeks prior to the study 1:1 randomization of 951 patients. ClinicalTrials.gov included trial parameters and results for this interventional study. (18) Staging was based according to the American Joint Committee on Cancer 2002 classification of Stage IIIA >1 mm nodal involvement, Stage IIIB with 1 to 3 involved lymph nodes, and Stage IIIC having ≥ 4 involved lymph nodes, which is found in the NCCN guidelines. (4) According to the FDA, patients were randomized to receive Yervoy™ 10 mg/kg (N=475) or placebo as an intravenous infusion (n=476) every 3-weeks for 4 doses, followed by Yervoy™ 10 mg/kg or placebo every 12-weeks from week 24 to week 156 (3 years) or until documented disease recurrence or unacceptable toxicity. (10) The outcomes were measured as recurrence-free survival from the time of randomization and the date of first recurrence (local, regional, or distant metastasis) or death. (This trial has yet to be published in a peer-reviewed journal.) The recurrence-free survival is shown on Table 4.

Table 4. Efficacy Results of Phase III Double Blind Randomized Trial (10)

Recurrence-Free Survival

Yervoy™

N=475

Placebo

N=476

Number of Events, N (%)

234 (49%)

294 (62%)

Recurrence

220

289

Death

14

5

Median (months)

26

17

(95% CI)

(19, 39)

(13, 22)

Hazard Ratio

0.75

(95% CI)

(0.64, 0.09)

p-value (stratified long-ranka)

P<0.002

Table Key:

N: number;

CI: confidence interval;

a: stratified by disease Stage.

Of the deaths during the trial, 5 (1%) were due to drug-related adverse events. (10) The balance was the result of colitis, myocarditis, and multi-organ failure with Guillain-Barre. The authors concluded that adjuvant Yervoy™ utilization for completely resected high-risk Stage III melanoma significantly improved recurrence-free survival. The adverse events profile was consistent when treated for advanced melanoma.

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, 12, 19) 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.

Malignant Pleural Mesothelioma (MPM)

The NCCN based their recommendation on the French IFCT-1501 MAPS2 (Intergroupe Francophone de Cancérologie Thoracique [French Cooperative Thoracic Intergroup]-1501 MPM patients) randomized Phase 2 trial, which is still ongoing according to ClinicalTrials.gov, published by Scherpereel et al., in 2017. (20, 21) This Phase 2 trial was a multi-center randomized, non-comparative study evaluating Opdivo® monotherapy and Opdivo® plus Yervoy™ combination therapy in patients with previously treated recurrent MPM. The premise was to determine if anti-PD-L1 therapy is effective compared to a combination of anti-PD-L1 and anti-cytotoxic T-lymphocyte-associated protein (CTL-4) agents.

From March to August 2016, 125 patients were enrolled in 21 centers in France. (20, 21) Eligible patients, previously treated by 1 or 2 systemic chemotherapy lines, were randomized into 2 treatment groups: patients received Opdivo® (3 mg/kg every 2-weeks) or Opdivo® (3 mg/kg every 2-weeks) combined with Yervoy™ (1 mg/kg every 6-weeks) until progression or unacceptable toxicity. The primary endpoint is disease control rate. Secondary endpoints include number of participants with treatment-related adverse events, progression-free survival, overall survival, quality of life, evaluation of predictive value of tumor PD-L1 score and prognostic value of biomarkers.

Per Scherpereel et al., to date, there is no treatment recommended for MPM patients progressing after first-line pemetrexed-platinum doublet therapy. (20, 21) Second-line therapy, disease control rate is <30%, with all chemotherapy agents. Following 12-weeks in the IFCT-1501 MAPS trial, the first 108 patients were assessed, 42.6% were treated with Opdivo® alone and 51.9% with Opdivo® plus Yervoy™. The overall response rate was 16.7% with Opdivo® alone and 25.9% with Opdivo® plus Yervoy™. Slightly increased toxicities were found with the combination therapy versus the monotherapy. Three treatment related deaths happened in the combination arm, in addition to other serious adverse events. With that, the authors suggest that immunotherapy may provide new options for MPM.

Renal Cell Carcinoma (RCC)

The FDA based their 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. (10, 22) 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 5.

Table 5. Efficacy Results – CHECKMATE-214 (10)

 

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 shown;

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.” (10) 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.” (22)

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. (7, 12, 13, 22) 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.” (7)

Ongoing and Unpublished Clinical Trials

Currently, there are 322 ongoing recruiting/active and/or unpublished completed trials, listed in ClinicalTrials.gov, focused on Yervoy™, with or without other pharmaceutical preparations to treat numerous conditions, including those which are FDA approved, e.g., prostatic cancer, breast cancer, solid organ tumors, urothelial cancer, non-small cell lung cancer, myelodysplastic syndromes, acute myeloid leukemia, head and neck cancers, glioblastoma and gliosarcoma, Merkel cell carcinoma, pancreatic cancer, post hematopoietic stem-cell transplantation (HSCT), etc. Some of the studies listed in ClinicalTrials.gov include Yervoy™ in combination with radiation therapy or radiosurgery, including stereotactic body radiation therapy.

Professional Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN) – Melanoma

The 2017 NCCN Guidelines and Drugs & Biologics Compendium continue to designate Yervoy™ as a Category I recommendation for Stage III melanoma disease with clinically positive lymph node(s) and close monitoring for adverse effect. (4, 10) The 2017 NCCN Drugs & Biologics Compendium recommends Yervoy™ as a Category 2A for Stage III sentinel lymph node positive metastases >1 mm and for the treatment of unresectable or metastatic melanoma (including brain metastases when the primary tumor is melanoma).

NCCN – Small-Cell Lung Cancer (SCLC)

The 2017 NCCN added treatment with Yervoy™ as a Category 2A recommendation for SCLC. (5, 10) The indications included subsequent systemic therapy with Yervoy™ for patients with ECOG performance status 0-2 when in combination with Opdivo®. (5, 10, 11)

NCCN – Malignant Pleural Mesothelioma (MPM)

The 2017 NCCN added treatment with Yervoy™ as a Category 2A recommendation for MPM when combined with Opdivo® as subsequent systemic therapy. (7, 10, 11)

NCCN – Renal Cell Carcinoma (RCC)

The 2018 NCCN added treatment with Opdivo® plus Yervoy™ as a Category 1 recommendation for RCC as 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™. (7, 12, 13)

Summary of Evidence

The evidence is sufficient to support the use of Yervoy™ 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 Yervoy™ beyond FDA approved indications. Therefore, the use of Yervoy™, 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, colorectal cancer, non-Hodgkin’s lymphoma, multiple myeloma, myelodysplastic syndrome, mycosis fungoides, non-Hodgkin’s lymphoma, Sézary syndrome, sarcomas, solid organ tumors, 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

J9228

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 1.2017 (November 10, 2016). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Available at: <http://www.nccn.org> (accessed on August 4, 2017).

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 – 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).

7. 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).

8. 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

9. 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).

10. FDA – Highlights of Prescribing Information (FDA-Approved Label) Yervoy™ (ipilimumab) Food and Drug Administration – Product Label. (April 16, 2018). Available at <http://www.fda.gov> (accessed on June 25, 2018).

11. ECRI Institute. Ipilimumab (Yervoy™) for Treating Metastatic Melanoma. Plymouth Meeting (PA): ECRI Institute; 2012 July. 8 p. (Health Technology Forecast).

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

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

14. Ipilimumab (Yervoy™) Specialty Pharmacy Combined Capacity (SPCC) Report #6-2011. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (June 2011):1-51.

15. FDA – FDA approves new treatment for a type of late-Stage skin cancer. Food and Drug Administration – News & Events (March 25, 2011). Available at <http://www.fda.gov> accessed – 2011 November 16).

16. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. Aug 19 2010; 363(8):711-23. PMID 20525992

17. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk Stage III melanoma (EORTC 18071): a randomized, double-blind, Phase 3 trial. Lancet Oncol. May 2015; 16(5):522-30. PMID 25840693

18. NIH – Efficacy study of ipilimumab versus placebo to prevent recurrence after complete resection of high risk Stage III melanoma (NCT00636168). (October 7, 2015) Prepared by the U.S. National Institutes of Health. Available at <http://www.clinicaltrials.gov> (accessed on November 3, 2015).

19. 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

20. 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).

21. 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.

22. 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

23. Yervoy™ – IBM Micromedex® DRUGDEX® (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: <www.micromedexsolutions.com> (accessed on June 26, 2018).

Policy History:

Date Reason
11/15/2018 Document updated with literature review. The following change was made to Coverage: Added conditional coverage for renal cell carcinoma to list of medically necessary indications. References 7, 8, and 22 added.
5/1/2018 New medical document. Yervoy™ may be considered medically necessary in adults and children (12 years and older) for the following indications, when meeting specific criteria: melanoma, small-cell lung cancer, and malignant pleural mesothelioma. Yervoy™ is considered experimental, investigational and/or unproven for all other indications, including, but not limited: autoimmune diseases requiring treatment with immunosuppressants, bladder cancer or urothelial carcinoma, breast cancer, cervical cancer, chronic myeloid leukemia, colorectal cancer, gastric cancer, glioblastoma, Hodgkin lymphoma, non-Hodgkin lymphoma, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, salivary tumor, sarcomas, solid organ tumors, Stage I or Stage II melanoma, and use in combination therapy with another checkpoint inhibitor agent, unless with Opdivo®. The following was added to coverage, “NOTE 1: For information regarding Opdivo®, refer to Medical Policy RX502.055, Nivolumab (Opdivo®)” and “NOTE 3: 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.” (The policy was originally included in RX502.033, Checkpoint-Blocking/Inhibitor Antibody Treatment for Select Cancers.)

Archived Document(s):

Title:Effective Date:End Date:
Ipilimumab (Yervoy)05-01-201811-14-2018
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