Subject:
Melanoma Vaccines
Description:
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IMPORTANT NOTE:
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Tumor vaccines are a type of active immunotherapy that attempts to stimulate the patient’s own immune system to respond to tumor cell antigens. A wide range of vaccine types 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 areas of investigation include new and different vaccine preparations, as well as various forms of immune modulation to enhance vaccine effectiveness.
Populations | Interventions | Comparators | Outcomes |
Individuals:
· With stage II-IV melanoma | Interventions of interest are:
· Melanoma vaccines | Comparators of interest are:
· Non‒vaccine therapies
· Observation | Relevant outcomes include:
· Overall survival
· Disease-specific survival
· Morbid events |
Background
Vaccines using crude preparations of tumor material were first studied by Ehrlich over 100 years ago.1 However, the first modern report to suggest benefit in cancer patients did not appear until 1967.2 Melanoma has been viewed as a particularly promising target for vaccine 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 ways4:
· Whole-cell vaccines prepared using melanoma cells or crude subcellular fractions of melanoma cell lines
o Autologous whole-cell vaccines in which tumor cells are harvested from the tissue of excised cancers, irradiated, and potentially modified with antigenic molecules to increase immunogenicity and made into patient-specific vaccines (eg, M-Vax®, AVAX Technologies)
o Autologous heat-shock protein-peptide complexes vaccines in which a patient’s tumor cells are exposed to high temperatures and then purified to make patient-specific vaccines (eg, Oncophage®, Antigenics Inc.), and
o 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 (eg, Canvaxin®, CancerVax Corp.; 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 RNA or DNA to produce immunologically enhanced vaccines.
· Peptide vaccines consisting of short, immunogenic peptide fragments of proteins (eg, melanoma antigen E [MAGE]; B melanoma antigen [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 (eg, 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.
· Anti-idiotype vaccines made from monoclonal antibodies with specificity for tumor antigen-reactive antibodies.
Regulatory Status
At the present time, no melanoma vaccine has received marketing approval from the U.S. Food and Drug Administration.
Related Policies
- Adoptive Immunotherapy (Policy #125 in the Treatment Section)
Policy:
(NOTE: For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)
Melanoma vaccines are considered investigational.
Medicare Coverage:
There is no National Coverage Determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a determination for this service. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy.
Medicaid Coverage:
For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.
FIDE SNP:
For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.
[RATIONALE: In a 2011 systematic review and meta-analysis of 4375 patients in 56 phase 2 and phase 3 studies, no evidence was found that vaccine therapy yields better overall disease control or overall survival (OS) compared with other treatments.6 Currently, there are 12 phase 3 clinical studies that have evaluated melanoma vaccines7-18: 4 using allogeneic vaccines, 2 autologous whole-cell vaccines, 2 ganglioside vaccines, 1 autologous heat shock protein, and 3 peptide vaccines—1 pulsed with dendritic cells, 1 administered with ipilimumab, and 1 administered with concomitant IL-2. In 2 studies, vaccine treatments appeared to demonstrate superior performance in unique populations identified during post hoc data evaluation.7,10 However, no published study to date has shown a statistically significant survival benefit in the general population selected for study. In 2 reports, outcomes using vaccines appeared inferior to those observed in controls.9,12 Table 1 provides a summary of trials that showed lack of efficacy of melanoma vaccines.
Several explanations have been offered as to why melanoma vaccines have not produced clinically significant improvements in clinical outcomes.19 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. One potential solution to this problem is to use molecular profiling to identify relevant immune resistance in the tumor microenvironment.20 If confirmed in future studies, this approach toward identifying subsets of patients likely to benefit from specific treatment choices may help improve treatment outcomes with the use of tumor vaccines.
Table 1. Phase 3 Randomized Controlled Trials of Vaccine Therapy Evaluating Cancer Outcomes
BCG: Bacille Calmette-Guérin; DFS: disease-free survival; GMK: guanylate kinase; HLA: human leukocyte antigen; IL-2: interleukin‒2; OS: overall survival.
No new phase 3 randomized controlled trial (RCT) evidence has been published in the period since the last evidence review. In single-arm series published in 2013-2015, combinations of immunotherapeutic agents (nivolumab, pegylated interferon) and study vaccines have been investigated in patients with unresectable or resected stage III and IV malignant melanoma.21-23 Results from these studies suggest combined immunotherapeutic approaches are tolerable and may have clinical efficacy reflected by tumor regression. However, no valid conclusions can be drawn from this evidence as to the effectiveness of the combinations relative to other treatments.
A randomized, phase 2 clinical trial published in 2014 evaluated the activity of interleukin-2 (IL-2) alone or IL-2 in combination with allogeneic large multivalent immunogen (LMI) vaccine in patients with stage IV melanoma.24 The primary objective of this trial was to evaluate the effect of the treatments on progression-free survival (PFS), with a secondary objective to evaluate median OS and 1- and 2-years rates of OS. The study was halted after enrolling 21 patients after a preplanned analysis established that it was unlikely to meet its primary objective of improved PFS with additional accrual. Per-protocol analysis of data from the 21 accrued patients showed median PFS of 2.20 months in the IL-2 plus LMI group versus 1.95 months in the IL-2 controls (p=NS). Median OS was 11.89 months in the IL-2 plus LMI group and 9.97 months in the IL-2 group (p=NS).
Ongoing and Unpublished Clinical Trials
A search of the online site www.ClinicalTrials.gov in June 2019 identified a number of phase 2 trials. Two of the ongoing phase 3 clinical trials are listed in Table 2. Approximately 32 phase 3 clinical trials were found in CT.gov, but in the handful with results, no clinical significance was found for the use of the vaccine.
Table 2. Summary of Key Trials
NCT No. | Trial Name | Planned Enrollment | Completion Date |
| Ongoing |  | | |
| NCT01546571a | A Multicenter, Double-blind, Placebo-controlled, Adaptive Phase 3 Trial of POL-103A Polyvalent Melanoma Vaccine in Post-resection Melanoma Patients With a High Risk of Recurrence (MAVIS) | 1059 | Oct 2018 - changed to June 30, 2019 |
| NCT01729663 | Randomized, Comparative Phase II/III Study Between Treatment With CSF470 Vaccine (Allogeneic, Irradiated) Plus BCG and MOLGRAMOSTIN (rhGM-CSF) as Adjuvants and Interferon-alfa 2b (IFN-ALPHA), in Stages IIB, IIC and III Post Surgery Cutaneous Melanoma Patients | 108 | Status Unknown |
NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.
Summary of Evidence
From a literature review and Clinicaltrials.gov overview, the evidence for melanoma vaccines in patients who have stage II-IV melanoma includes studies 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. Relevant outcomes include overall survival, disease-specific survival, and morbid events. Despite considerable activity in numerous studies over the past 20 years, no melanoma vaccine has received U.S. Food and Drug Administration marketing approval. One randomized controlled trial (RCT) of a gp100 melanoma vaccine has reported a significant increase in response rate and progression-free survival. However, several other RCTs have reported no improvements in disease-free survival or overall survival rates with the use of study vaccines. Additionally, other RCTs were closed early due to inferiority of results with study vaccines. Other phase 3 RCTs are underway or in the planning stages to further investigate vaccine preparations to treat malignant melanoma. For use of melanoma vaccines for treatment of patients with stage II-IV melanoma, the body of evidence is insufficient to conclude that anti‒melanoma vaccines of any type, alone or in combination with immunomodulating agents, significantly improve survival outcomes compared with non‒vaccine therapies. The evidence is insufficient to determine the effects of the technology on health outcomes.
Supplemental Information
Practice Guidelines and Position Statements
The National Comprehensive Cancer Network guideline on the treatment of melanoma (v.2.2019) does not reference the use of vaccines in clinical trials in any of its treatment algorithms. 25 The guidelines do discuss clinical trials that have reported inferiority in melanoma vaccine treatment arms.
U.S. Preventive Services Task Force Recommendations
Not applicable.]
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Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
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Index:
Melanoma Vaccines
Vaccines, Melanoma
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. Nov-Dec 2009;27(6):603-613. PMID 19880048
2. Cunningham TJ, Olson KB, Laffin R, et al. Treatment of advanced cancer with active immunization. Cancer. Nov 1969;24(5):932-937. PMID 4187652
3. Eggermont AM. Therapeutic vaccines in solid tumours: can they be harmful? Eur J Cancer. Aug 2009;45(12):2087-2090. PMID 19477117
4. Lens M. The role of vaccine therapy in the treatment of melanoma. Expert Opin Biol Ther. Mar 2008;8(3):315-323. PMID 18294102
5. Blue Cross and Blue Shield Association Technology Evalaution Center. Special Report: Vaccines for the Treatment of Malignant Melanoma. TEC Assessments. 2001;Volume 16, Tab 4. PMID
6. Chi M, Dudek AZ. Vaccine therapy for metastatic melanoma: systematic review and meta-analysis of clinical trials. Melanoma Res. Jun 2011;21(3):165-174. PMID 21537143
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. Nov 1994;12(14):1275-1280. PMID 7856291
8. Wallack MK, Sivanandham M, Balch CM, 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. J Am Coll Surg. Jul 1998;187(1):69-77; discussion 77-69. PMID 9660028
9. 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. May 1 2001;19(9):2370-2380. PMID 11331315
10. Sondak VK, Liu PY, Tuthill RJ, 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. J Clin Oncol. Apr 15 2002;20(8):2058-2066. PMID 11956266
11. Hersey P, Coates AS, McCarthy WH, et al. Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: results of a randomized trial. J Clin Oncol. Oct 15 2002;20(20):4181-4190. PMID 12377961
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. PMID
13. Mitchell MS, Abrams J, Thompson JA, 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. J Clin Oncol. May 20 2007;25(15):2078-2085. PMID 17513813
14. Testori A, Richards J, Whitman E, 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. J Clin Oncol. Feb 20 2008;26(6):955-962. PMID 18281670
15. Schwartzentruber DJ LD, Richards J et al. A Phase III multi-institutions 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. A Phase III multi-institutions 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. 2009 ASCO Annual Meeting. 2009. PMID
16. 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. Apr 2006;17(4):563-570. PMID 16418308
17. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. Aug 19 2010;363(8):711-723. PMID 20525992
18. Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. Jun 2 2011;364(22):2119-2127. PMID 21631324
19. Chapman PB. Melanoma vaccines. Semin Oncol. Dec 2007;34(6):516-523. PMID 18083375
20. Gajewski TF. Molecular profiling of melanoma and the evolution of patient-specific therapy. Semin Oncol. Apr 2011;38(2):236-242. PMID 21421113
21. Gibney GT, Kudchadkar RR, DeConti RC, et al. Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma. Clin Cancer Res. Feb 15 2015;21(4):712-720. PMID 25524312
22. Riker AI, Rossi GR, Masih P, et al. Combination immunotherapy for high-risk resected and metastatic melanoma patients. Ochsner J. Summer 2014;14(2):164-174. PMID 24940124
23. Weber JS, Kudchadkar RR, Yu B, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. Dec 1 2013;31(34):4311-4318. PMID 24145345
24. Jha G, Miller JS, Curtsinger JM, et al. Randomized phase II study of IL-2 with or without an allogeneic large multivalent immunogen vaccine for the treatment of stage IV melanoma. Am J Clin Oncol. Jun 2014;37(3):261-265. PMID 23241505
25. National Comprehensive Cancer Network N. Clinical Practice Guidelines in Oncology, Melanoma (v3.2016). https://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf. Accessed July 7, 2016.
26. UpToDate. Interleukin-2 and experimental immunotherapy approaches for advanced melanoma. Literature review current through July 2016. Topic last updated May 6, 2015.
27. Sosman JA. Interleukin-2 and experimental immunotherapy approaches for advanced melanoma. In: UpToDate, Atkins MB, Ross ME (Eds), UpToDate, Waltham , MA. (Accessed on July 3, 2017.)
28. Shoushtari AN, Wolchok J, Hellman M. Principles of cancer immunotherapy. In: UpToDate, Atkins MB, Ross ME (Eds), UpToDate, Waltham, MA. (Accessed on June 30, 2017.)
29. Sosman JA. Interleukin-2 and experimental immunotherapy approaches for advanced melanoma. In: UpToDate, Atkins MB, Ross ME (Eds), UpToDate, Waltham , MA. (Accessed on June 4, 2018)
30. Sosman JA. Interleukin-2 and experimental immunotherapy approaches for advanced melanoma. In: UpToDate, Atkins MB, Ross ME (Eds), UpToDate, Waltham , MA. (Accessed on June 6, 2019)
31. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), Cutaneous Melanoma (V2.2019 - March 12, 2019). NCCN.Org. (Accessed on June 6, 2019)
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