BlueCross and BlueShield of Montana Medical Policy/Codes
Ipilimumab (Yervoy)
Chapter: Drugs - Medical Benefit
Current Effective Date: July 18, 2013
Original Effective Date: October 13, 2011
Publish Date: April 18, 2013
Revised Dates: April 18, 2013
Description

Melanoma is the most common serious form of skin cancer.  If recognized and treated early, it is almost always curable.  Approximately 84% of melanomas are diagnosed at a localized stage with five-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 is the process used to determine the size of a melanoma tumor, and where and how far it has spread or metastasized.  The following staging criteria from the 2002 American Joint Commission on Cancer are used to determine the stage of melanoma for the appropriate treatment or management of a melanoma diagnosis.  Additionally, the lesion may be assigned a Clark and Breslow number based on the measurements of the tumor penetration and thickness.

Stage

Characteristics

IA

Tumor ≤ 1.0 mm without ulceration; no lymph node involvement; no distant metastases

IB

Tumor ≤ 1.0 mm with ulceration or Clark level IV or V; tumor 1.01-2.0 mm without ulceration; no lymph node involvement; no distant metastases

IIA

Tumor 1.01-2.0 mm with ulceration; tumor 2.01-4.0 mm without ulceration; no lymph node involvement; no distant metastases

IIB

Tumor 2.01-4.0 mm with ulceration OR > 4.0 mm without ulceration; no lymph node involvement; no distant metastases

IIC

Tumor > 4.0 mm with ulceration; no nodal involvement; no distant metastases

IIIA

Tumor of any thickness without ulceration with one positive lymph node

IIIB

Tumor of any thickness without ulceration with two-three positive lymph nodes

IIIC

Tumor of any thickness and four more metastatic lymph nodes OR matted nodes OR in-transit met(s)/satellite(s) without metastatic lymph nodes, or combinations of in-transit met(s)/satellite(s), OR ulcerated melanoma and metastatic lymph node(s)

IV

Tumor of any thickness with any nodes and any distant metastases

Stage I, the tumor has not spread and can be surgically excised.  Stage II, the tumor has not spread, but is larger and possibly with greater penetration or depth to the surrounding area(s).  Stage III, the tumor has spread to the lymph nodes is greater than 4.0 mm, ulcerated, of any thickness and unresectable.  Stage IV, there is metastases to other regions of the body, irrespective of the tumor size or depth.

One new treatment option for unresectable or metastatic melanoma includes the U.S. Food and Drug Administration (FDA) approved agent ipilimumab (Yervoy ™).  Yervoy is a monoclonal antibody against cytotoxic T lymphocyte antigen-4 (CTLA-4) to potentiate an antitumor T-cell response.  CTLA-4 may play a role in slowing down or turning off the body’s immune system, affecting its ability to fight off cancerous cells.  Yervoy received its FDA approval on March 25, 2011.  To date, there is no known gene mutation test linked to the utilization of Yervoy for the treatment of melanoma.

Policy

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.

Medically Necessary

BCBSMT may consider ipilimumab (Yervoy™) medically necessary for the treatment of patients with the histological diagnosis of stage III or stage IV unresectable or metastatic melanoma.

Investigational

BCBSMT considers ipilimumab (Yervoy™) experimental, investigational and unproven for all other indications, including, but not limited to, stage I or stage II melanoma, prostate cancer, non-small cell lung cancer, chronic myeloid leukemia (CML), non-Hodgkin’s lymphoma (NHL), breast cancer, solid organ tumors, urothelial carcinoma, and metastatic renal cancer.

Policy guidelines

Drug dosing recommendations in the Medical Policy follow FDA approved dosage in the product label.  A prescription for doses that exceed the product label must be accompanied by citation of clinical studies that support a higher dose regimen.

The recommended FDA labeled dosing for ipilimumab (Yervoy™) states, “Yervoy 3 mg/kg is administered intravenously over 90 minutes every three weeks for a total of four doses.  NOTE:  The total Yervoy dose, in milligrams and given intravenously, equals the patient’s weight in kilograms multiplied by the prescribed dose in milligrams per kilograms”.  Before each dose, patients are assessed for signs and symptoms of enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy.  Clinical chemistry tests are done prior to Yervoy administration, including liver function testing and thyroid function tests, among others.

Rationale

Yervoy’s FDA-approval was based upon a recent pivotal Phase III, double-blind international study that randomized 676 patients with unresectable or metastatic melanoma.  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.  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 three-months thereafter.  The published study revealed the estimated overall survival at one-year was 46% in the Yervoy arm, 44% in the Yervoy and vaccine arm, and 25% in the vaccine alone arm.  At two-years, the overall survival was 24% in the Yervoy arm, 22% in the Yervoy and vaccine arm, and 14% in the vaccine alone arm. 

The FDA label comes with a label warning prompted by severe, life-threatening or fatal autoimmune-mediated adverse reactions (12.9% of patients treated with Yervoy) experienced during earlier phase II and III trials.  When the severe reactions occurred, Yervoy was stopped and corticosteroid treatment was started.  Due to the unusual and severe side effects associated with Yervoy, the therapy was approved with a Risk Evaluation and Mitigation Strategy informing health care professionals about these serious risks.

The National Comprehensive Cancer Network (NCCN) panel included Yervoy as a Category I recommendation for metastatic melanoma.  Category I designation of the NCCN Categories of Evidence and Consensus is that the therapy recommendation is based upon high-level evidence; the consensus is that the intervention is appropriate. 

Several unpublished trials have examined the use of Yervoy as monotherapy or in combination with chemotherapy or radiation therapy for the treatment of prostate cancer and non-small cell lung cancer.  Improved health outcomes have not been demonstrated.  The evidence is not sufficient to support the use of Yervoy beyond its FDA-approved indication.

Additional Information in 2012

A search of peer reviewed literature through March 2012 identified new clinical trial information regarding additional uses of Yervoy.  According to the National Cancer Institute, there are multiple clinical trials targeting the use of Yervoy, with or without other pharmaceutical preparations, in prostatic cancer (phases I to III), breast cancer (no specified phase established), solid organ tumors (phase I), urothelial cancer (phase II), and non-small cell lung cancer (phases I to III) (Clinical Trials, 2012).  According to the literature, Yervoy is also being investigated in a phase III trial for use in chronic myeloid leukemia (CML), non-Hodgkin’s lymphoma (NHL), and renal cell carcinoma.  Study results have not been found in published peer reviewed literature (Drugs, 2011; Tarhini, 2010; Morse, 2005).

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. 

Rationale for Benefit Administration
 
ICD-9 Codes

172.0, 172.1, 172.2, 172.3, 172.4, 172.5, 172.6, 172.7, 172.8, 172.9

ICD-10 Codes

C43.0, C430.1, C43.2, C43.3, C43.4, C43.5, C43.6, C43.7, C43.8, C43.9

Procedural Codes: J9228
References
  1. Morse, M.A.  Technology evaluation: ipilimumab, Medarex/Bristol-Myers Squibb.  Current Opinion in Molecular Therapy (2005 December) 7(6):588-97.
  2. Cranmer, L.D., and E. Hersh.  The role of the CTLA4 blockade in the treatment of malignant melanoma.  Cancer Investigation (2007 October) 25(7):613-31.
  3. Yang, J.C., Hughes, M., et al.  Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis.  Journal of Immunotherapy (2007 November-December) 30(8):825-30.
  4. O’Day, S.J., Hamid, O., et al.  Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies.  Cancer (2007 December 15) 110(12):2614-27.
  5. Weber, J.  Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with ipilimumab (MDX-010).  Oncologist (2008) 13 Supplement 4:16-25.
  6. Fong, L., and E.J. Small.  Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunodulatory antibodies for cancer treatment.  Journal of Clinical Oncology (2008 November 10) 26(32):5275-83.
  7. Weber, J.S., O’Day, S., et al.  Phase I/II study of ipilimumab for patients with metastatic melanoma.  Journal of Clinical Oncology (2008 December 20) 26(36):5950-6.
  8. Yuan, J., Gnjatic, S., et al.  CTLA-4 blockade enhances poly functional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit.  Proceedings of the National Academy of Sciences of the United States (2008 December 23) 105(51):20410.5.
  9. Ansell, S.M., Hurvitz, S.A., et al.  Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma.  Clinical Cancer Research (2009 October 15) 15(20):6446-53.
  10. Anonymous.  Ipilimumab.  Drugs – Research and Development (2010) 10(2):97-110.
  11. Hodi, F.S., O’Day, S.J., et al.  Improved survival with ipilimumab in patients with metastatic melanoma.  New England Journal of Medicine (2010 August 19) 363(8):711-23.
  12. Tarhini, A., Lo, E., et al.  Releasing the brake on the immune system: ipilimumab in melanoma and other tumors.  Cancer Biotherapy and Radiopharmaceuticals (2010 December) 25(6):601-13.
  13. Yervoy™ (ipilimumab) – Product Label Information.  Princeton, New Jersey: Bristol-Myers Squibb (2011 March).
  14. FDA – FDA approves new treatment for a type of late-stage skin cancer.  Food and Drug Administration – News & Events (2011 March 25).  Available at http://www.fda.gov accessed – 2011 November 16).
  15. FDA – YERVOY™ (ipilimumab) Prescribing Label.  Food and Drug Administration – News & Events (2011 March 25).  Available at http://www.fda.gov (accessed – 2012 March 25).
  16. FDA – Safety Information for Yervoy (ipilimumab): Risk Evaluation and Mitigation Strategy (REMS) – Severe Immune-Mediated Adverse Reactions.  Food and Drug Administration – Safety Alert for Human Medical Products (2011 April 6).  Available at http://www.fda.gov (accessed – 2011 November 16).
  17. Drugs – New Data from Bristol-Myers Squibb Oncology Portfolio to be presented at 2011 American Society of Clinical Oncology (ASCO) Annual Meeting (2011 May).  Prepared by Drug Information Online.  Available at http://www.drugs.com (accessed – 2012 April 16).
  18. Cameron, F., Whiteside, G., et al.  Ipilimumab: first global approval.  Drugs (2011 May 28) 71(8):1093-104.
  19. Ipilimumab (Yervoy™) Specialty Pharmacy combined Capacity (SPCC) Report #6-2011.  Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (2011 June):1-51.
  20. NCCN – Melanoma Version 2.2012 (2011 September 21).  National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines™).  Available at http://www.nccn.org (accessed on 2011 November 16).
  21. Clinical Trials – Ipilimumab (2012).  Prepared by the National Cancer Institute at the National Institutes of Health.  Available at http://www.cancer.gov (accessed – 2012 April 16).
  22. George, D., and J.W. Moul.  Emerging treatment options for patients with castration-resistant prostate cancer.  Prostate (2012 February) 72(3):338-49.
  23. Tomasini, P., Khobta, N., et al.  Ipilimumab: its potential in non-small cell lung cancer.  Therapeutic Advances in Medical Oncology (2012 March) 4(2):43-50.
  24. Drake, C.G., and E.S. Antonarakis.  Current status of immunological approaches for the treatment of prostate cancer.  Current Opinion in Urology (2012 May) 22(3):197-202.
History
October 2011 New Policy: HCPCS code C9284
April 2013 Restricted the Medically Necessary statement to include on stage III or stage IV unresectable or metastatic melanoma.  Formatting and language revised.  Removed HCPCs code C9284.
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Ipilimumab (Yervoy)