This document addresses the use of vaccines as a type of immunotherapy in the treatment of melanoma. Melanoma vaccines (also known as melanoma tumor vaccines) are designed to activate the immune system to respond to tumor antigens.

Note: For additional information, please see DRUG.00046 Ipilimumab (Yervoy^™₎

Investigational and Not Medically Necessary:

Melanoma vaccines are considered investigational and not medically necessary for any indication.

At the present time, no melanoma vaccine has received manufacturing approval from the U.S. Food and Drug Administration (FDA). A search of the National Institutes of Health's (NIH) clinical trials database reveals some phase III trials and many phase I and II trials investigating a variety of vaccines as monotherapy or in combination with other chemotherapy agents or adjuvants as treatment for melanoma.

On July 23, 2002, the FDA designated Antigenics' Oncophage^® (Agenus, Lexington, MA) as an orphan drug status for metastatic melanoma. The U.S. Orphan Drug Act of 1983 provides financial and practical incentives for the research and development of drugs to treat rare diseases (occurring in less than 200,000 people) or where there is little hope for recovery of development costs, so there is little financial incentive for industry to develop them. However, to date, the FDA has not conferred marketing approval status to Oncophage as an orphan drug.

The allogeneic whole-cell vaccine, Canvaxin^® (Cancer Vax Corp, Carlsbad, CA), was discontinued in 2005 after the results of clinical trials determined the vaccine was not likely to increase survival in stage III disease. Previous Canvaxin and Melacine^® (Ribi ImmunoChem Research, Inc., Hamilton, MT) trials have been discontinued. Sondak (2002) studied the effects of Melacine, an allogeneic melanoma cell lysate, on 600 participants with melanoma who were randomized to control or vaccinated groups. No difference in the 5-year estimated disease free survival or disease recurrence was found between the groups. This study was limited by inadequate power to detect small differences between groups and only a small percentage of participants were staged by sentinel node biopsy. Production of Melacine was discontinued in 2003, after the FDA required an additional phase III study.

In 2001, Kirkwood and colleagues conducted a randomized phase III trial comparing a ganglioside vaccine named GMK (Progenics Pharmaceuticals, Inc, Tarrytown, NY) with high dose interferon alpha 2b (IFNα2b). The trial was halted when the interim analysis of the data demonstrated a significant benefit in relapse free survival and overall survival with high dose IFNα2b versus GMK.

A phase III, randomized trial of 108 participants with stage IV metastatic melanoma closed at the first interim analysis due to the very low overall response rates (5.5% chemotherapy alone and 3.8% for chemotherapy and vaccine) between both cohorts. Schadendorf and colleagues (2006) identified the possibility of genetics affecting the response or lack of response to the vaccines. The authors noted the results were similar to a recent Italian study with 382 participants. Recommendations for new clinical trials include additional genetic criteria to assist in selection stratification.

In a multi-center phase II trial, 120 participants who had failed prior therapy for stage IV metastatic melanoma were randomized to receive a peptide vaccine with or without additional cytokines (i.e., granulocyte-monocyte colony-stimulating factor [GM-CSF] or interferon alpha-2b) (Kirkwood, 2009). The primary endpoint of this trial was the intermediate outcome of immune response. While secondary endpoints included survival outcomes, there was no control group of participants treated with conventional therapy. While the addition of cytokines did not enhance the immune response, at a median follow-up of 25.4 months, participants with an immune response to the peptide vaccine had a significantly longer survival (21.3 months) versus participants without an immune response (13.4 months; p=0.046). The authors concluded a "better understanding of the mechanisms that regulate immune responses to melanoma vaccines is necessary before larger phase III randomized vaccine trials are conducted".

Various agents are being studied to determine if the effects of vaccines can be potentiated when used in combination therapy. Oncolytic herpes virus encoding GM-CSF, monoclonal antibodies, and other immunotherapies are examples of adjuvants being evaluated along with melanoma vaccines.

The use of melanoma tumor vaccines is currently not included in the National Comprehensive Cancer Network's (NCCN^®₎ 2012 clinical practice guideline for the management of melanoma. The National Cancer Institute (NCI, 2011) encouraged clinical trial enrollment to study various treatment modalities, including vaccines. The American Cancer Society (ACS, 2012) noted "vaccines are experimental therapies that do not yet have proven benefit."

Hodi and colleagues (2010) reported results from a randomized, double-blind, phase 3 study of 676 individuals who were HLA-A*0201–positive with unresectable stage III or IV melanoma with progressive metastatic disease. Participants were randomized in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 individuals), ipilimumab alone (137), or gp100 alone. The primary endpoint was overall survival (OS) with the primary comparison being between the gp100 cohorts. Participants were followed for up to 55 months. The ipilumumab alone treatment group had significantly better best overall response rate (P=0.001) and disease control rate (P<0.001) versus the gp100 alone cohort. The median overall survival in the combination treatment group was 10.0 months (95% confidence interval [CI], 8.5 to 11.5), as compared to 6.4 months (95% CI, 5.5 to 8.7) in the gp100-alone cohort (hazard ratio for death, 0.68; P<0.001). The median overall survival in the cohort treated with ipilimumab alone was 10.1 months (95% CI, 8.0 to 13.8). The authors concluded the addition of the investigational vaccine, gp100, did not improve the efficacy or overall survival with Ipilimumab (Hodi, 2010).

There is currently no published, peer reviewed evidence to validate improved survival associated with any specific melanoma vaccine compared to usual treatment. There are ongoing clinical studies of vaccines and adjuvants to potentiate the effect of the vaccine. However, published results from randomized clinical trials are needed to determine the safety and long-term efficacy of vaccines as a treatment for melanoma.

Melanoma may occur on any skin surface, as well as in the eye. In men, melanoma is often found on the trunk or the head and neck. In women, it often develops on the lower legs. Melanoma is rare in individuals with very dark skin. When it does develop in dark-skinned people, it tends to occur under the fingernails or toenails, or on the palms or soles. Occasionally, melanoma may arise in the lining of the brain (meninges), the digestive tract, lymph nodes, or other areas where melanocytes are found.

Currently, the only preventive measures against the development of melanoma include avoiding prolonged exposure to direct sunlight, the use of sunscreen when exposure is unavoidable, the use of protective clothing and UV light absorbing sunglasses to protect the eyes. People at high risk for developing melanoma, include people with a personal or family history of the disease, people with fair skin, and people with weakened immune systems. Individuals with familial dysplastic nevus syndrome or with several dysplastic or atypical nevi have more than a fivefold greater risk of developing melanoma. Individuals at higher risk should speak to their physicians about their risk and what they can do to reduce the likelihood of developing the disease.

Primary treatment of melanoma includes surgical excision and usually involves additional testing to appropriately identify the severity of the disease, also called clinical staging. Treatment is based on the extent of the disease and may include single agent or combination chemotherapy, radiation therapy. FDA approved biologic agents include, but are not limited to kinase inhibitors, interleukin-2 (IL-2) and interferon alpha. More recently, ipilimumab, (Yervoy™, Bristol-Meyers Squibb, Princeton, NJ) a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody has been FDA approved for treatment of unresectable or metastatic melanoma. However, with high-dose biologic therapies there are significant side effects including, but not limited to flu-like symptoms, muscle aches, skin rash, fever, weakness, nausea and diarrhea. Currently, there are no melanoma vaccines approved for manufacturing by the FDA. There are ongoing clinical trials investigating the safety and effectiveness of different types of melanoma vaccines.

According to the NCI (2011), cancer vaccines are considered medications that are called biological response modifiers. The biological response modifiers stimulate or restore the ability of the individual's immune system to fight infections and disease. The broad categories for cancer vaccines are:

• Preventive (or prophylactic) vaccines, which are intended to prevent cancer from developing in healthy people; and
• Treatment (or therapeutic) vaccines, which are intended to treat already existing cancers by strengthening the body's natural defenses against cancer.

Cancer treatment vaccines are designed to treat cancers that have already occurred. Therapeutic cancer vaccines try to refresh the immune system's memory to recognize cancer cells for removal by the body. The cancer vaccine may contain inactivated cancer cells, viruses that express tumor antigens (unique proteins or protein bits that sit on the surface of cancer cells and can trigger some immune response), or any antigens that are overexpressed by cancer cells. The intent of cancer vaccine therapy is to delay or stop cancer cell growth; cause tumor shrinkage; prevent cancer from coming back; or eliminate cancer cells that are not killed by other forms of treatment, such as surgery, radiation therapy, or chemotherapy (NCI, 2011).

Melanoma vaccines are immunotherapies which attempt to stimulate and enhance the individual's own immune system to respond to tumor related antigens. They function by creating antibodies or activated T lymphocytes with intended destruction of tumor cells and regression of the melanoma. Melanoma vaccines can be generally categorized or prepared in the following ways:

• Purified antigen vaccines, consisting of single, purified proteins or gangliosides, or short, immunogenic peptide fragments of proteins;
• Cell lysate vaccines, in which allogeneic tumor cell lines are lysed by mechanical disruption or viral infection;
• Whole cell vaccines, consisting of whole killed allogeneic cells from tumor cell lines;
• Autologous whole-cell vaccines, in which tumor cells are harvested from the individual, irradiated, and modified with antigenic molecules to increase immunogenicity;
• Heat-shock protein-peptide complexes purified from autologous tumor cells;
• Shed antigen vaccines, consisting of a mixture of cell surface antigens shed into tissue culture supernatant by melanoma cell lines;
• Dendritic cell vaccines, consisting of autologous, dendritic cells pulsed with tumor-derived peptides, tumor lysates, antigen encoding RNA or DNA;
• Genetically modified tumor vaccines, consisting of autologous or allogeneic tumor cell lines transduced with retroviral vectors containing cytokine genes, tumor antigen genes, co-stimulatory molecules, or HLA proteins;
• Anti-idiotype vaccine, consisting of monoclonal antibodies with specificity for tumor antigen-reactive antibodies.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  A draft of future ICD-10 Coding (effective 10/01/2014) related to this document, as it might look today, is included below for your reference.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Garbe C, Eigentler TK, Keilholz U, et al. Systematic review of medical treatment in melanoma: current status and future prospects. Oncologist. 2011; 16(1):5-24.
2. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363(8):711-723.
3. Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol. 2001; 19 (9):2370-2380.
4. Kirkwood JM, Lee S, Moschos SJ, et al. Immunogenicity and antitumor effects of vaccination with peptide vaccine +/- granulocyte-monocyte colony-stimulating factor and/or IFN-α2b in advanced metastatic melanoma: Eastern Cooperative Oncology Group phase II trial E1696. Clin Cancer Res. 2009; 15(4):1443-1451.
5. Schadendorf D, Ugurel S, Schuler-Thurner B, et al. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol. 2006; 17(4):5563-570.
6. Slingluff CL, Petroni GR, Olson WC, et al. Effect of granulocyte/macrophage colony-stimulating factor on circulating CD8+ and CD4+ T-cell responses to a multipeptide melanoma vaccine: outcome of a multicenter randomized trial. Clin Cancer Res. 2009; 15(22):7036-7044.
7. Smith FO, Downey SG, Klapper JA, et al. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin Cancer Res. 2008; 14(17):5610-5618.
8. Sondak VK, Sabel MS, Mule JJ. Allogeneic and autologous melanoma vaccines: where have we been and where are we going? Clin Cancer Res. 2006; 12(7 Pt 2):2337s-2341s.

Government Agency, Medical Society, and Other Authoritative Publications:

1. National Cancer Institute (NCI). Cancer Vaccine Fact Sheet. Updated November 15, 2011. Available at: http://www.cancer.gov/cancertopics/factsheet/cancervaccine. Accessed on October 3, 2012.
2. National Cancer Institute (NCI). Melanoma (PDQ^®): Treatment. Updated May 11, 2012. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/melanoma/healthprofessional/allpages. Accessed on October 3, 2012.
3. National Comprehensive Cancer Network^® NCCN Clinical Practice Guidelines in Oncology™: Melanoma (V.1.2013). Revised July 12, 2012. © 2012 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on October 2, 2012.
4. National Institute of Health. Clinical Trials.gov. Available at: http://www.clinicaltrials.gov/. Accessed on October 2, 2012.

1. American Cancer Society (ACS). Available at: http://www.orgsites.com/ga/acs/. Accessed on September 26, 2012.
2. National Cancer Institute. What you need to know about melanoma and other skin cancers. Available at: http://www.cancer.gov/cancerinfo/wyntk/melanoma. January 11, 2011. Accessed on September 26, 2012.

Canvaxin
Melacine
Melanoma
Oncophage
Tumor vaccine
Vaccine

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.