BlueCross and BlueShield of Montana Medical Policy/Codes
Melanoma Vaccines
Chapter: Medicine: Treatments
Current Effective Date: August 27, 2013
Original Effective Date: August 27, 2013
Publish Date: May 27, 2013
Description

Tumor vaccines are a type of immunotherapy that attempts to stimulate the patient’s own immune system to respond to tumor antigens. There are a number of different tumor vaccines for the treatment of malignant melanoma in various stages of development.

Vaccines using crude preparations of tumor material were first studied by Ehrlich over 100 years ago, (1) but the first modern report suggesting benefit using these in cancer patients did not appear until 1967. (2) Melanoma has been viewed as a particularly promising tumor for this type of treatment because of its immunologic features, which include the prognostic importance of lymphocytic infiltrate at the primary tumor site, the expression of a wide variety of antigens, and the occasional occurrence of spontaneous remissions. (3) Melanoma vaccines can be generally categorized or prepared in the following ways (4):

  • Whole cell vaccines, prepared using melanoma cells or crude sub-cellular fractions of melanoma cell lines:
  • Autologous whole-cell vaccines in which tumor cells are harvested from the tissues of excised cancers, irradiated, and potentially modified with antigenic molecules to increase immunogenicity and made into patient-specific vaccines (e.g., M-Vax®, AVAX Technologies); and
  • Autologous heat-shock protein-peptide complexes vaccines in which patient’s tumor cells are exposed to high temperatures and then purified into patient-specific vaccines (e.g., Oncophage®, Vitaspin, Antigenics, Inc.); and
  • Allogeneic whole-cell vaccines in which intact or modified allogeneic tumor cell lines from other patients are lysed by mechanical disruption or viral infection and used to prepare vaccine (e.g., Canvaxin®, CancerVaxCorp. or Melacine®, University of Southern California);
  • Dendritic cell vaccines in which  autologous dendritic cells are pulsed with tumor-derived peptides, tumor lysates, or antigen encoding Ribonucleic acid (RNA) or Deoxyribonucleic acid (DNA) to produce immunologically enhanced vaccines;
  • Peptide vaccines consisting of short, immunogenic peptide fragments of proteins (e.g., melanoma antigen E or MAGE; B Melanoma antigen or BAGE) used alone or in different combinations to create vaccines of varying antigenic diversity, depending on the peptide mix;
  • Ganglioside vaccines in which glycolipids present in cell membranes are combined with an immune adjuvant (e.g. GM2) to create vaccines;
  • DNA vaccines created from naked DNA expression plasmids;
  • Viral vectors in which DNA sequences are inserted into attenuated viruses for gene delivery to patient immune systems; and
  • Anti-idiotype vaccine, consisting of monoclonal antibodies with specificity for tumor antigen-reactive antibodies.

Regulatory Status

At the present time, no melanoma vaccine has received approval from the U.S. Food and Drug Administration (FDA). Melanoma vaccines are currently available only in clinical trials in the U.S.

Policy

Investigational

Blue Cross and Blue Shield of Montana (BCBSMT) considers melanoma vaccines experimental, investigational and unproven.

Federal Mandate

Federal mandate prohibits denial of any drug, device or biological product fully approved by the FDA as investigational for the Federal Employee Program (FEP). In these instances coverage of these FDA-approved technologies are reviewed on the basis of medical necessity alone. 

Rationale for Benefit Administration

This medical policy was developed through consideration of peer reviewed medical literature, FDA approval status, accepted standards of medical practice in Montana, Technology Evaluation Center evaluations, and the concept of medical necessity. BCBSMT reserves the right to make exceptions to policy that benefit the member when advances in technology or new medical information become available.

The purpose of medical policy is to guide coverage decisions and is not intended to influence treatment decisions. Providers are expected to make treatment decisions based on their medical judgment. BCBSMT recognizes the rapidly changing nature of technological development and welcomes provider feedback on all medical policies.

When using this policy to determine whether a service, supply or device will be covered, please note that member contract language will take precedence over medical policy when there is a conflict.

Rationale

The Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) evaluated the use of vaccines to treat melanoma in a 2001 TEC Special Report, “Vaccines for the Treatment of Malignant Melanoma.” (5) In spite of the fact that the literature contained hundreds of publications on this treatment at this time, there was a striking paucity of completed Phase III clinical trials available for evaluation. The 2001 report highlighted the importance of such studies to control for patient characteristic, disease, and treatment confounders. It also highlighted the value of long-term outcomes that measure disease progression or mortality instead of the use of less reliable surrogate measures of immune response. Of note, several Phase I or II studies of melanoma vaccines (Canvaxin®, Melacine®) have not been replicated in subsequent Phase II or III studies. (4)

In an article in Nature Medicine in 2004, Rosenberg et al. (6) noted that looking at the experience of the National Cancer Institute’s Surgery Branch in evaluating 450 patients treated for metastatic cancer with vaccines (the majority—422—with metastatic melanoma), only 2.6% exhibited a positive treatment response. Reviewing 35 carefully selected representative reports from the literature (one-third in melanoma patients) involving 765 patients, the objective response rate to this treatment was again surprisingly low (only 3.8%).

Rosenberg et al. (6) suggested that an important reason for this poor performance was the inability of T-cells generated by cancer vaccines to infiltrate tumors and become activated after an encounter with tumor antigen in vivo. He concluded “the lack of clinical effectiveness of currently available cancer vaccines should not be interpreted to mean that cancer vaccine approaches are at an investigational dead end. Rather, it emphasizes the need for profound changes in the application of this approach.” Among several suggestions proposed were mechanisms to increase the yield and activity of CD4+ cells and to eliminate-tumor induced or normally occurring lymphocyte-mediated immune suppressive mechanisms.

While more than 1,700 publications on melanoma vaccine use in both animals and humans have appeared since the 2001 TEC Special Report, there are currently only 12 Phase III clinical studies evaluating melanoma vaccines (7-18): 4 using allogeneic vaccines, 2 autologous whole-cell vaccines, 2 ganglioside vaccines, one autologous heat shock protein, and 3 peptide vaccines—one pulsed with dendritic cells, one administered with ipilimumab and one administered with concomitant IL-2. In 2 studies, (7, 10) vaccine treatments appeared to demonstrate superior performance in unique populations identified during post hoc data evaluation. However, no published study to date has shown a statistically significant survival benefit in the general population selected for study. In two reports, (9, 12) outcomes using vaccines appeared inferior to those observed in controls. A summary of trials showing lack of efficacy are provided in the table at the close of the Rationale section.

Hodi et al. (17) performed a Phase III study of ipilimumab, an agent that blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response. This agent was administered in a 3-arm study comparing ipilimumab to ipilimumab with gp100 peptide vaccine to gp100 peptide vaccine alone. Ipilimumab, when used alone or with gp100, exhibited improved overall survival compared to gp100 alone in patients with previously treated melanoma. Ipilimumab has subsequently been approved by the U.S. Food and Drug Administration (FDA) for this use.

Schwartzentruber et al. (15, 18) reported findings of their Phase III trial of gp100:209-217(210M) peptide vaccine plus high-dose IL-2 (vaccine) versus high-dose IL-2 alone (control). The vaccine arm showed significant improvement in response rate (RR; p=0.03) and progression-free survival (PFS; p=0.008) but not median overall survival (OS; p=0.06). The authors reached the guarded conclusion that “additional data are needed to ascertain whether the finding in our study was due to a direct effect of the vaccine or to the possibility that vaccinated patients were more responsive to salvage regimens or that the nature of progression differed between the two groups or that other factors were involved.”

A review of online site ClinicalTrials.gov accessed April 27, 2012 indicated 107 studies being performed under “melanomas, vaccines, Phase III.” Thirty-eight of these were listed as of unknown status and 41 as completed. They encompassed a broad range of studies looking at most of the vaccine types listed in the Description section of this policy and, in some cases, studies include a variety of efforts to provide for immunomodulation in an effort to improve results.

In a recent systematic review and meta-analysis of 4,375 patients in 56 Phase II and Phase III studies, no evidence was found that vaccine therapy provides better overall disease control or overall survival compared with other treatments. (19) However, in a second review of medical treatments in melanoma, 2 pending studies were highlighted. (20) The first is a Phase III vaccine trial of patients with stage IIIB melanoma whose tumors express MAGE-A3 antigen in lymph node metastasis. This allogeneic vaccine is unique in targeting a specific cancer germline family antigen. The second is a Phase III trivalent vaccine prepared using 3 peptides (gp100, MART-1/Melan, and tyrosine [human leukocyte antigen] HLA-A2). Preliminary reports suggest patients exhibiting antibodies to any of the 3 peptides had insignificantly improved survival. More definitive results from both studies are pending.

There are a variety of explanations as to why, to date, melanoma vaccines have not been able to produce clinically significant improvements in treatment outcomes. (21) One possible mechanism is immune ignorance and the ability of melanoma cells to escape detection through loss of antigens or loss of HLA expression. A second mechanism is immune tolerance. This may result from the ability of the melanoma tumor to prevent a local accumulation of active helper and/or effector T-cells as a result of high interstitial pressure in the tumor or lack of appropriate adhesion molecular on tumor vasculature. This may also occur as a result of normal down-regulation of the immune system at the site of T-cell tumor interaction. A wide range of immune-modulating techniques are being explored to find mechanisms for enhancing the immune response induced by tumor vaccines.

Gajewski (22) published a preliminary or exploratory report on the value of molecular profiling to identify relevant immune resistance in the tumor microenvironment. This approach toward identifying subsets of patients likely to benefit from specific treatment choices, if confirmed in future studies, may help improve treatment outcomes with the use of tumor vaccines.

Clinical Guidelines:

National Comprehensive Cancer Network Guidelines:

National Comprehensive Cancer Network (NCCN) Guidelines makes no recommendations as how to incorporate the use of melanoma vaccine into clinical practice. (23)

Summary

A wide range of vaccine choices are available including use of autologous tumor cells, allogeneic tumor cells, and tumor-specific moieties including peptides, gangliosides, and DNA plasmids. A variety of mechanisms appear to exist as possible obstacles to successful active immunotherapy using vaccines. Current studies are focused on the use of new and different vaccine preparations, as well as on various forms of immune-modulation as potential techniques for enhancing vaccine effectiveness.

Despite considerable interest and numerous studies over the past 20 years, to date no melanoma vaccine has been approved by FDA. One randomized clinical trial of a gp100 melanoma vaccine has reported a significant increase in RR and PFS, and many other trials are underway or in the planning stages. Therefore, the use of melanoma vaccines is considered experimental, investigational and unproven.

TABLE: Phase III randomized, controlled, clinical trials of vaccine therapy evaluating cancer outcomes.

Author

Patient

Population

Vaccine

Control

Results

Livingston et al., 1994 (7)  

Stage III n=122  

GM2/BCG (bacille Calmette-Guerin)  

BCG  

DFS and OS showed no statistically significant differences  

COMMENT: Patients with no pre-treatment anti-GM2 antibody showed improved PFS with vaccine  

Wallack

et al., 1998 (8)  

Stage III n=217  

Vaccinia melanoma oncolysate  

Vaccinia oncolysate from normal cell  

DFS and OS showed no statistically significant differences    

Kirkwood et al., 2001 (9)  

Stage IIB/III n=774  

Ganglioside GM2-KLH21 (GMK [guanylate kinase])  

Interferon alpha  

Trial closed after interim analysis indicated GMK inferiority    

 

Sondak

et al., 2002 (10)  

Stage II n=600  

Allogeneic melanoma vaccine (Melacine®)  

Observation  

No evidence of DFS 

COMMENT: Patients with 2 or more HLA matches showed improved PFS

Hersey

et al., 2002 (11)  

Stage IIB/III n=700  

Vaccinica melanoma oncolysate

Observation  

Recurrence-free and OS not statistically improved in vaccine patients

Morton

et al., 2006 (12)  

Stage III n=1,160  

Canvaxin® + BCG + placebo  

BCG + placebo  

Trial closed after interim analysis indicated Canvaxin® inferiority    

Morton

et al., 2006 (12)

Stage IV n=496  

Canvaxin®+ BCG + placebo  

BCG + placebo  

Trial closed after interim analysis showed lack of efficacy

Mitchell

et al., 2007 (13)  

Stage III n=604  

Allogeneic whole-cell lysate administered with Detox™ (Melacine®) + interferon alpha 

Interferon alpha  

No survival advantage but fewer adverse events in patients on vaccine    

 

Testori

et al., 2008 (14)  

Stage IV n=322  

Heat shock protein gp96 complex vaccine (Oncophage®)  

Physician’s choice of dacarbazine, temozolomide, IL-2 and/or resection

No survival advantage in patients on vaccine    

 

Schadendorf et al., 2006 (16)  

Stage IV n=108  

Peptide-pulsed dendritic cells  

Dacarbazine  

Trial closed after interim analysis showed lack of efficacy

Hodi

et al., 2010 (17)  

Stage III

or IV n=676  

Ipilimumab alone or with GP100  

GP100 peptide alone  

Ipilimumab showed improved OS with or without GP100 compared to GP100 treatment alone    

Schwar-zentruber

et al., 2011 (18)

Stage III/IV n=185  

GP100 peptide + IL2  

High-dose IL2  

Objective response and increased in patients on vaccine and IL2 treatment    

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. 

ICD-9 Codes
99.28, 172, 172.0, 172.1, 172.3, 172.4, 172.5, 172.6, 172.7, 172.8, 172.9
ICD-10 Codes

C43.0-C43.9, 3E01305, 3E02305, 3E03305, 3E033WK, 3E033WL, 3E043WK, 3E043WL, 3E053WK, 3E053WL, 3E063WK, 3E063WL

Procedural Codes: 86849
References
  1. Ray S, Chhabra A, Mehrotra S et al. Obstacles to and opportunities for more effective peptide-based therapeutic immunization in human melanoma. Clin Dermatol 2009; 27(6):603-13.
  2. Cunningham TJ, Olson KB, Laffin R et al. Treatment of advanced cancer with active immunization. Cancer 1969; 24(5):932-7.
  3. Eggermont AM. Therapeutic vaccines in solid tumours: can they be harmful? Eur J Cancer 2009; 45(12):2087-90.
  4. Lens M. The role of vaccine therapy in the treatment of melanoma. Expert Opin Biol Ther 2008; 8(3):315-23.
  5. Vaccines for the Treatment of Malignant Melanoma. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (2001 May) 16(4):1-45.
  6. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004; 10(9):909-15.
  7. Livingston PO, Adluri S, Helling F et al. Phase 1 trial of immunological adjuvant QS-21 with a GM2 ganglioside-keyhole limpet haemocyanin conjugate vaccine in patients with malignant melanoma. Vaccine 1994; 12(14):1275-80.
  8. Wallack, M.K., Sivanandham, M., et al. Surgical adjuvant active specific immunotherapy for patients with stage III melanoma: the final analysis of data from a phase III, randomized, double-blind, multicenter vaccinia melanoma oncolysate trial. Journal of the American College of Surgeons (1998) 187(1):69-79.
  9. Kirkwood, J.M., Ibrahim, J., et al. High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: results of the multicenter Eastern Cooperative Oncology Group phase II trial E2696. Journal of Clinical Oncology (2001) 19(5):1430-6.
  10. Sondak, V.K., Liu, P.Y., et al. Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: overall results of a randomized trial of the Southwest Oncology Group. Journal of Clinical Oncology (2002) 20(8):2058-66.
  11. Hersey, P., Coates, A.S., et al. Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: results of a randomized trial. Journal of Clinical Oncology (2002) 20(20):4181-90.
  12. Morton Dl MN, Thompson JF et al. An international, randomized phase III trial of bacillus Calmette-Guerin (BCG) plus allogenic melanoma vaccine (MCV) or placebo after complete resection of melanoma metastatic to regional or distant sites. J Clin Oncol 2007; 25(18S):8508.
  13. Mitchell, M.S., Abrams, J., et al. Randomized trial of an allogeneic melanoma lysate vaccine with low-dose interferon Alfa-2b compared with high-dose interferon Alfa-2b for Resected stage III cutaneous melanoma. Journal of Clinical Oncology (2007) 25(15):2078-85.
  14. Testori, A., Richards, J., et al. Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: the C-100-21 Study Group. Journal of Clinical Oncology (2008) 26(6):955-62.
  15. Schwartzentruber, D.J., Lawson, D., et al. A phase III multi-institutional randomized study of immunization with the gp100:209-217(210M) peptide followed by high-dose IL-2 compared with high-dose IL-2 alone in patients with metastatic melanoma. J Clin Oncol (2009) 27(18 suppl): abstract CRA9011.
  16. Schadendorf, D., Ugurel, S., 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. Annals of Oncology (2006) 17(4):563-70.
  17. 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):711-23.
  18. Schwartzentruber DJ, Lawson DH, Richards JM et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 2011; 364(22):2119-27.
  19. Chi M, Dudek AZ. Vaccine therapy for metastatic melanoma: systematic review and meta-analysis of clinical trials. Melanoma Res 2011; 21(3):165-74.
  20. 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.
  21. Chapman, P.B.  Melanoma vaccines. Seminars in Oncology (2007) 34(6):516-23.
  22. Gajewski TF. Molecular profiling of melanoma and the evolution of patient-specific therapy. Semin Oncol 2011; 38(2):236-42.
  23. National Comprehensive Cancer Network® NCCN Clinical Practice Guidelines in Oncology™: Melanoma (V.2.2013). Revised 2012 October 17. © 2012 National Comprehensive Cancer Network, Inc. Available at: http://www.nccn.org   (accessed – 2011 February 28) (confirmed on 2013 March 13)
  24. Melanoma Vaccines. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2012 June) Medicine 2.03.04.
History
May 2013  New 2013 BCBSMT medical policy.  Considered experimental, investigational and unproven. 
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Melanoma Vaccines