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 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.

Policy
Ipilimumab (Yervoy™) is considered MEDICALLY NECESSARY for treatment of adult and pediatric patients 12 years of age and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, in combination with nivolumab. Nivolumab 3 mg/kg followed by YERVOY 1 mg/kg on the same day every 3 weeks for 4 doses, then nivolumab 240 mg every 2 weeks.

Ipilimumab (Yervoy™) is considered MEDICALLY NECESSARY for treatment Esophageal carcinoma as first-line treatment of unresectable advanced or metastatic esophageal squamous cell carcinoma (in combination with nivolumab) in adults.

Ipilimumab (Yervoy™) dosed at 3 mg/kg once every 3 weeks (in combination with nivolumab) for up to 4 combination doses (unless disease progression or unacceptable toxicity occurs), followed by nivolumab monotherapy until disease progression or unacceptable toxicity is considered MEDICALLY NECESSARY for treatment of Hepatocellular carcinoma in patients who have been previously treated with sorafenib.

Ipilimumab (Yervoy™) is considered MEDICALLY NECESSARY as first-line treatment (in combination with nivolumab) of unresectable malignant pleural mesothelioma in adults.

Ipilimumab (Yervoy™) dosed at standard 3 mg/kg for four (4) infusions over ten (10) weeks may be considered MEDICALLY NECESSARY for adjuvant treatment of members with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection including total lymphadenectomy.

Ipilimumab (Yervoy™) dosed at standard 3 mg/kg for four (4) infusions over ten (10) weeks may be considered MEDICALLY NECESSARY for the treatment unresectable or metastatic melanoma in adult and pediatric patients ≥ 12 years of age as a single agent or in combination with nivolumab.

Ipilimumab (Yervoy™) is considered MEDICALLY NECESSARY for treatment of Non-small cell lung cancer, metastatic as first-line treatment (in combination with nivolumab) in adults whose tumors express PD-L1 (≥ 1%) as determined by an approved test, and with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

Ipilimumab (Yervoy™) is considered MEDICALLY NECESSARY for treatment of Non-small cell lung cancer, metastatic or recurrent: First-line treatment of metastatic or recurrent non-small cell lung cancer (in combination with nivolumab and 2 cycles of platinum doublet chemotherapy) in adults with no EGFR or ALK genomic tumor aberrations.

Ipilimumab (Yervoy™) dosed at 1 mg/kg once every 3 weeks (in combination with nivolumab) for up to 4 combination doses (unless disease progression or unacceptable toxicity occurs), followed by nivolumab monotherapy (refer to nivolumab monograph for Nivolumab dosing information) until disease progression or unacceptable toxicity is considered MEDICALLY NECESSARY for treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma.

Ipilimumab (Yervoy™) is investigational/unproven therefore considered NOT MEDICALLY NECESSARY for all other indications, including, but not limited to, stage I or stage II melanoma, prostate cancer, chronic myeloid leukemia (CML), non-Hodgkin’s lymphoma (NHL), breast cancer, solid organ tumors, and urothelial carcinoma.

BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be MEDICALLY NECESSARY if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and NOT MEDICALLY NECESSARY.

Policy Guidelines 
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
An international double-blind study that randomized 676 patients with unresectable or metastsic melanoma was instrumental in the FDA approval of Yervoy. The study by Hodi et al. reported that all patients in the study had ceased to respond to other FDA approved or commnly used melanoma treatments, including aldesleukin, dacarbazine, temozolomide, fotemustine or carboplatin. Patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation were excluded from the study. Participants in the study were randomized to receive Yervoy alone, Yervoy plus an experimental tumor (peptide) vaccine called gp 100 or the vaccine alone. Response to the randomized treatments indicated that the participants receiving Yervoy or Yervoy plus the vaccine lived an average of 10 months, those who received only the vaccine lived an average of 6.5 months. When published, the survival rate at one year was 46% in the Yervoy arm, 44% in the Yervoy and vaccine arm and 25% in the vaccine only arm.

References

1. National Comprehensive Cancer Network (NCCN) Guidelines Version 4.2011 Melanoma. Retrieved on May 23, 2011 from http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf
2. Food and Drug Administration (FDA). BLA Approval and REMS for Yervoy (Ipilimumab), 3/25/11. Retrieved on May 22, 2011 from http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377_REMS.pdf
3. National Institutes of Health (NIH). Clinical Trial NCT00094653. MDX-010 Antibody, MDX-1379 Melanoma Vaccine, or MDX-010/MDX-1379 Combination Treatment for Patients With Melanoma. Retrieved on May 22, 2011 from http://clinicaltrials.gov/ct2/show/NCT00094653?term=nct00094653&rank=1
4. 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.
5. Callahan MK, Wolchok JD, Allison JP. Anti-CTLA-4 Antibody Therapy: Immune Monitoring During Clinical Development of a Novel Immunotherapy. Semin Oncol. 2010 Oct;37(5):473-84. Retrieved on May 22, 2011 from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008567/?tool=pubmed
6. Wolchok JD, Weber JS, Hamid O, Lebbé C, et al. Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials. Cancer Immun. 2010 Oct 20;10:9. Retrieved on May 23, 2011 from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964017/?tool=pubmed
7. National Institutes of Health (NIH). Clinical Trial NCT01194271. Neoadjuvant Ipilimumab in Prostate Cancer. Retrieved on May 23, 2011 from http://clinicaltrials.gov/ct2/show/NCT01194271?term=ipilimumab&rank=5
8. National Institutes of Health (NIH). Clinical Trial NCT 00836407. Ipilimumab +/- Vaccine Therapy in Treating Patients With Locally Advanced, Unresectable or Metastatic Pancreatic Cancer. Retrieved on May 23, 2011 from http://clinicaltrials.gov/ct2/show/NCT00836407?term=ipilimumab&rank=7
9. Medical Director review 6/2011
10. Specialty Matched Consultant Advisory Panel 1/2012
11. Specialty Matched Consultant Advisory Panel – 3/2013
12. Specialty Matched Consultant Advisory Panel – 3/2014
13. Morse, M.A.  Technology evaluation: ipilimumab, Medarex/Bristol-Myers Squibb.  Current Opinion in Molecular Therapy (2005 December) 7(6):588-97.
14. 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.
15. 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.
16. 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.
17. Weber, J.  Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with ipilimumab (MDX-010).  Oncologist (2008) 13 Supplement 4:16-25.
18. 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.
19. 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.
20. 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.
21. 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.
22. Anonymous.  Ipilimumab.  Drugs – Research and Development (2010) 10(2):97-110.
23. 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.
24. 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.
25. Yervoy™ (ipilimumab) – Product Label Information.  Princeton, New Jersey: Bristol-Myers Squibb (2011 March).
26. 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).
27. FDA – YERVOY™ (ipilimumab) Prescribing Label.  Food and Drug Administration – News & Events (2011 March 25).  Available at http://www.fda.gov (accessed – 2012 March 25).
28. 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).
29. 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).
30. Cameron, F., Whiteside, G., et al.  Ipilimumab: first global approval.  Drugs (2011 May 28) 71(8):1093-104.
31. 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.
32. 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).
33. 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).
34. George, D., and J.W. Moul.  Emerging treatment options for patients with castration-resistant prostate cancer.  Prostate (2012 February) 72(3):338-49.
35. 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.
36. 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.

Coding Section 

HCPCS Coding:

ICD-9 Diagnoses Codes That Support Medical Necessity:

ICD-10 Diagnoses Codes That Support Medical Necessity: (Effective 10/01/15)

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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