Treatment of Metastatic Melanoma: An Overview
By Shailender Bhatia, MD1, Scott S. Tykodi, MD, PhD2, John A. Thompson, MD3 |
May 12, 2009
1Instructor, Department of Medicine, Division of Medical Oncology 2Assistant Professor, Department of Medicine, Division of Medical Oncology 3Professor, Department of Medicine, Division of Medical Oncology, University of Washington School of Medicine, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, Washington
Novel Therapies Under Investigation in Treatment of Patients With Metastatic Melanoma
Multiple attempts to improve upon existing therapies for metastatic melanoma may not have been successful in phase III trials, but have added significantly to our understanding of the disease. The molecular alterations important to the pathogenesis of melanoma continue to be elucidated, and there has been a steady progress in our knowledge of the biology of this disease. Novel therapies, many of which target specific molecular pathways, are being tested. Some of these promising therapies that are currently being investigated in phase III trials are summarized in Table 3.
Some of the novel immunotherapeutic approaches deserve special mention, as promising antitumor activity has been observed.
The cytotoxic T-lymphocyte antigen (CTLA)-4 is expressed on activated T lymphocytes and counteracts positive stimulatory signals to these cells mediated through other T-cell receptors, hence acting as a negative regulator of T-cell activation. CTLA-4 is also constitutively expressed on regulatory T cells that inhibit excessive immune stimulation. Monoclonal antibodies that bind to CTLA-4 may potentiate immune responses against cancer cells. Anti-CTLA-4 antibodies (ipilimumab and tremelimumab) are currently being evaluated in clinical trials in melanoma (see Table 3) and have been associated with encouraging antitumor activity.
In a pooled analysis of two phase II trials of ipilimumab that enrolled 139 patients, objective responses were observed in 23 patients (17%), including three complete responses that were ongoing at last follow-up (23+, 52+, and 53+ months). The overall survival in this analysis was 15.7 months, which compares favorably to historical cohorts. Responses to anti-CTLA-4 antibodies are sometimes delayed in onset and are often associated with development of immune-related adverse events, primarily enterocolitis and hypophysitis. Results of a phase III trial comparing dacarbazine(Drug information on dacarbazine) plus ipilimumab vs dacarbazine alone are eagerly awaited. Anti-CTLA-4 antibodies may prove particularly useful in combination with other strategies designed to stimulate antitumor immune responses such as adoptive T-cell therapy or vaccination approaches.
Adoptive cell therapy (ACT) involves collection of lymphocytes from the patient (peripheral blood lymphocytes or tumor-infiltrating lymphocytes [TIL]), in vitro selection/expansion/ activation of collected lymphocytes, and subsequent infusion of processed lymphocytes back into the patient to induce an immune response against the cancer cells. A recent report that demonstrates the promise of ACT for metastatic melanoma investigated host lymphodepletion (using cyclophosphamide plus fludarabine with or without total-body irradiation) followed by autologous TIL transfer and HD IL‑2. An ORR of 56% was observed in 93 patients. Among the 10 patients who achieved a complete response, no relapses were reported with a median follow-up of 31 months.
Another example of successful use of ACT involved a novel approach that isolated and expanded autologous CD4+ T-cell clones with specificity for the melanoma-associated antigen NY-ESO-1. When these cells were infused into a patient with refractory metastatic melanoma, who had not undergone any previous conditioning or cytokine treatment, the transferred CD4+ T cells mediated a durable clinical remission and led to endogenous responses against melanoma antigens other than NY-ESO-1.
Various vaccination strategies to induce active immunity targeting cancer cells are currently being tested for the treatment of metastatic melanoma. These strategies have included vaccination with peptides (eg, gp100), dendritic cells, nucleic acids (eg, Allovectin-7), and heat shock protein complexes (eg, vitespen).
A phase III trial comparing the combination of HD IL-2 plus vaccination with gp100 peptides vs HD IL-2 alone has recently completed accrual, and results are awaited. Another phase III trial is comparing standard chemotherapy (dacarbazine or temozolomide) vs intralesional injections of Allovectin-7 (a plasmid DNA encoding the major histocompatibility complex [MHC] heavy chain class I antigen HLA-B7 and ß-2 microglobulin proteins that results in synthesis and expression of the complete MHC complex on the cell surface). This follows the encouraging results seen in a phase II study of intralesional Allovectin-7 in 127 patients, where the ORR was 12% with a median OS of 21.3 months.
In addition, multiple other approaches that target specific molecular pathways are in various stages of testing for metastatic melanoma. With the underlying heterogeneity in melanoma, it is unlikely that one approach will apply to all patients. As with most cancers, the key to the treatment of metastatic melanoma will be identification of specific subsets of the patient population that are more likely to respond to a specific therapy.
Treatment of metastatic melanoma remains a challenge. While surgery and radiation therapy may play a role in the palliation of symptoms from local tumor growth, systemic therapy is the mainstay of treatment for metastatic melanoma. Treatment with HD IL-2 may induce durable responses in a small subset of patients and should be considered in eligible patients. Chemotherapeutic approaches may have a palliative benefit. Single-agent chemotherapy is usually well tolerated. Combination chemotherapy and biochemotherapy have not improved survival but may lead to increased response rates at the cost of higher toxicity. Many novel therapeutic approaches appear promising, and participation in clinical trials should be considered the standard of care.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Acknowledgement: The authors thank Dr. Kim Margolin (Professor, University of Washington, Seattle) for her critical review of the manuscript and useful suggestions.
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