Coverage Policy Manual
Policy #: 2011006
Category: Pharmacy
Initiated: April 2011
Last Review: August 2018
  Ipilimumab (Yervoy™)

Description:
Melanoma is a cancer that begins in skin cells called melanocytes. Melanomas can occur anywhere on the skin, but are more likely to start in certain locations. The trunk (chest and back) is the most common site in men. The legs are the most commonly affected site in women. The neck and face are other common sites. Melanomas can also form in other parts of your body such as the eyes, mouth, and vagina, but these are much less common than melanoma of the skin. Melanoma is much less common than basal cell and squamous cell skin cancers, but it is far more dangerous. Like basal cell and squamous cell cancers, melanoma is almost always curable in its early stages. But it is much more likely than basal or squamous cell cancer to spread to other parts of the body if not caught early. Melanoma accounts for less than 5% of skin cancer cases but causes a large majority of skin cancer deaths.
 
Treatment of melanoma may include surgery, chemotherapy, immunotherapy or radiation therapy.  Surgery is the main treatment option for most stages of melanoma.  However, once the melanoma has metastasized to other organs it is very unlikely to be cured by surgery.  Several chemotherapy drugs have been used to treat metastatic melanoma including dacarbazine, cisplatin, temozolomide and paclitaxel. However, no therapy has been proven to improve overall survival (Hodi, 2010).
 
In March, 2011, the FDA approved ipilimumab (Yervoy™) for the treatment of unresectable or metastatic melanoma. Ipilimumab (Yervoy™) is a recombinant monoclonal antibody that blocks a molecule known as cytotoxic T-lymphocyte antigen (CTLA-4), a down regulator of T-cell activation.  Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation.  The proposed mechanism of action of ipilimumab is by blocking CTLA-4, T-cells may be allowed to proliferate and attack melanoma cancer cells.
 
The FDA approved ipilimumab (Yervoy™) with a Risk Evaluation and Mitigation Strategies (REMS) and included a “black box warning” in the labeling, indicating that ipilimumab (Yervoy™) can result in sever and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system.  Thirteen percent of patients in the Yervoy trial had severe or fatal autoimmune reactions (allergic). Other common side effects included diarrhea, skin rash, fatigue and colitis. These severe side effects led to the FDA’s requirement of a REMS program consisting of a communication plan to inform potential prescribers and supportive healthcare providers about serious adverse reactions associated with Yervoy.
 
Effective January 1, 2012 there is a specific HCPS code for ipilimumab: J9228.

Policy/
Coverage:
Effective July 2018
 Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Ipilimumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed indications:
 
    1. Treatment of Unresectable or Metastatic Melanoma in adults and pediatric patients 12 yrs and older.
    2. As adjuvant treatment of patients with Cutaneous Melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.
    3. For the treatment of patients with intermediate or poor risk, previously Untreated Advanced Renal Cell Carcinoma, in combination with nivolumab (Opdivo).
    4. For the treatment of adult and pediatric (12 years and older) patients with colorectal cancer that is microsatellite instability high (MSI-H) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and iriniotecan, given as a single agent or in combination with ipilmumab
    5. NCCN 2A and 2B Recommendations in accordance with Coverage Policy #2000030.
 
Dosing Guidelines:
Dosing should be in accordance with FDA labeling:
    1. For unresectable or metastatic melanoma, the recommended dosing is 3mg/kg IV over 90 mins every 3 weeks for a maximum of 4 doses.  
    2. For adjuvant treatment of melanoma, the recommended dosing is 10mg/kg IV over 90 mins every 3 wks for 4 doses, followed by 10 mg/kg every 12 wks for up to 3 yrs.  
    3. For renal cell carcinoma, the recommended dose is 1 mg/kg IV over 30 mins, every 3 wks for 4 doses, on the same day as nivolumab, followed by nivolumab as a single agent.   
    4. For colorectal cancer, the recommended dose is 1mg/kg IV over 30 minutes every 3 weeks for up to 4 doses or until intolerable toxicity or disease progression, given on the same day as nivolumab.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Any other use of Ipilimumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, any other use of Ipilimumab is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Combination therapy of ipilimumab (Yervoy™) and vemurafenib (Zelboraf) for the treatment of
melanoma does not meet member benefit certificate primary coverage criteria that there be scientific
evidence of effectiveness.
 
For members with contracts without primary coverage criteria, combination therapy of ipilimumab
(Yervoy™) and vemurafenib (Zelboraf) for the treatment of melanoma is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of
coverage.
 
Effective April 2013
Therapy with the human cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody, ipilimumab (Yervoy™) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in the treatment of patients with unresectable or metastatic melanoma.
 
Therapy with ipilimumab (Yervoy™) is being studied in clinical trials to determine effectiveness in conditions other than metastatic melanoma and does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in any indication other than unresectable or metastatic melanoma.
 
For members with contracts without primary coverage criteria, therapy with ipilimumab (Yervoy™) in conditions other than metastic melanoma is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Combination therapy of ipilimumab (Yervoy™) and vemurafenib (Zelboraf) for the treatment of melanoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, combination therapy of ipilimumab (Yervoy™) and vemurafenib (Zelboraf) for the treatment of melanoma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective prior to April 2013
Therapy with the human cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody, ipilimumab (Yervoy™) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in the treatment of patients with unresectable or metastatic melanoma.
 
Therapy with ipilimumab (Yervoy™) is being studied in clinical trials to determine effectiveness in conditions other than metastatic melanoma and does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in any indication other than unresectable or metastatic melanoma.
 
 

Rationale:
The FDA approval of ipilimumab was based on a phase 3 randomized controlled trial assessing the safety and effectiveness of ipilimumab (3mg/kg) with or without the tumor vaccine (gp100) or gp100 alone (Hodi, 2010). Gp100 was used as an active control in lieu of an accepted standard of care following first-line treatment of stage III-IV melanoma.
 
A total of 676 patients with unresectable stage III or IV melanoma whose disease progressed while on therapy were randomized to receive one of the three treatments every 3 weeks for up to four treatments.  The primary endpoint was overall survival. The median overall survival was 10.0 months for patients who received ipilimumab plus gp100 compared with 6.4 months among patients who received gp100 alone. There was no difference in overall survival in the group that received ipilimumab plus gp100 and the ipilimumab alone group.
 
Ten to 15% of patients that received treatment with ipilimumab experienced grade 3 or 4 immune-related events, including 7 out of 14 study treatment related deaths.
 
The data from the phase III study is consistent with the results of the phase II studies in the same population ( Weber, 2009) (Wolchok, 2010) (O’Day, 2010). Wolchok and colleagues published results of a phase II, randomized, double-blind, multicenter dose-ranging trial.  In this study, 217 patients were assigned to receive ipilimumab 10mg/kg, 3mg/kg or 0.3mg/kg every 3 weeks for four cycles.  The primary endpoint was best overall response ( the percentage of patients with a complete or partial response). The best overall response was 11.1% for the 10mg/kg group, 4.2% for 3 mg/kg group and 0% for the 0.3 mg/kg group.  
 
O’Day and colleagues reported on the phase II study evaluating the safety and efficacy of ipilimumab monotherapy (10mg/k every 3 weeks for four cycles) in patients with unresectable stage III/IV melanoma. Induction treatment was followed by maintenance therapy every 3 months.  The primary end point was best overall response rate (BORR) using modified World Health Organization criteria. BORR was 5.8% with a disease control rate of 27%. One and two year survival rates were 47.2% and 32.8%, respectively.  The authors reported that immune-related events were manageable and generally reversible with corticosteroids.
 
In another phase II study, investigators randomized both previously treated and treatment-näive patients with unresectable stage III or IV melanoma to receive ipilimumab 10mg/kg every 3 weeks for four doses with either budesonide or placebo Weber, 2009).  The trial was conducted to determine whether budesonide reduced the rate of immune-related adverse events.  Prophylactic treatment with budesonide did not affect the rate of grade 2 or greater diarrhea.  The median overall survival rate in the group treated with ipilimumab plus prophylactic budesonide was 17.7 months compared with 19.3 months in the group treated with ipilimumab plus placebo.  In this study there were no treatment related deaths.
 
Studies are currently being conducted on ipilimumab for the treatment of various other cancers including prostate, small cell lung cancer, non-small cell lung cancer, advanced or refractory solid tumors, recurrent or refractory lymphoma, colon cancer and renal cell cancer (clinicaltrials.gov). There is insufficient evidence that ipilimumab improves health outcomes in any form of cancer other than the FDA approved indication of unresectable or metastatic melanoma.
 
2013 Update
Ribas and colleagues in a letter to the editor of the NEJM reported on a phase 1 study of the concurrent administration of vemurafenib and ipilimumab for patients with metastatic melanoma with a BRAF V600 mutation who had not received previous therapy BRAF or MEK inhibitor or with CTLA-4 or programmed cell death protein 1 (PD-1)–blocking antibodies. Two cohorts (six patients each) were enrolled. Hepatic adverse events occurred in 8 of 10 patients who received both drugs. Two patients in the 2nd cohort received only vemurafenib. The study was closed to further patient accrual due to the liver toxic effects. All hepatic adverse events in the two cohorts were asymptomatic and reversible with either temporary discontinuation of the study drugs or administration of glucocorticoids.
 
2014 Update
A search of the MEDLINE database conducted through March 2014 did not reveal any new information that would prompt a change in the coverage statement.
  
2015 Update
A literature search conducted through March 2015 did not reveal any new information that would prompt a change in the coverage statement.
   
2016 Update
A literature search conducted through March 2016 did not reveal any new information that would prompt a change in the coverage statement.

CPT/HCPCS:
96365Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96413Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug
J3590Unclassified biologics
J9228Injection, ipilimumab, 1 mg

References: American Cancer Society. Melanoma Skin Cancer. Available at http://www.cancer.org. Last accessed April 13, 2011.

Hodi FS, O’Day SJ, McDermott DF et al.(2010) Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med. 2010;363:711-23.

O’Day SJ, Maio M, chiarion-Sileni V, et al.(2010) Efficacy and safety of ipilimumab monotherapy in patients with previously treated, advanced melanoma: a multicenter, single-arm phase II study. Ann Oncol 2010 February 10 (Epub ahead of print).

Ribas A, Hodi FS, Callahan M, et al.(2013) Hepatotoxicity with Combination of Vemurafenib and Ipilimumab. N Engl J Med 2013; 368:1365-1366.

Weber J, Thompson JA, Hamid O, et al.(2009) A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 2009;15:5591-8.

Wolchok JD, Neyns B, Linette G, et al.(2010) Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomized, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010;11:155-64.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2019 American Medical Association.