- freely available
Cancers 2010, 2(2), 955-969; doi:10.3390/cancers2020955
Abstract: In advanced metastatic melanoma (non-resectable stage III/IV), the prognosis still remains poor, with median survival times between six and twelve months. Systemic therapeutic approaches for metastatic melanoma include chemotherapy, immunotherapy, immunochemotherapy, small molecules and targeted therapy. In this review, we will focus on the various treatment modalities as well as new agents used for targeted therapy.
Melanoma is an aggressive tumor with a continuously growing incidence worldwide. Depending on tumor thickness, ulceration and lymphocytic infiltration at the time of diagnosis, 20–25% of all primary melanoma will spread [1,2]. In case of distant metastatic melanoma, with the exception of rare cases of surgery for oligometastatic disease, the prognosis is fatal with median survival times between six and twelve months. It has a three-year survival rate of only 10–15% . Here we summarize therapeutic options in distant metastatic disease.
In cases of non-resectable metastatic melanoma, systemic chemotherapy is a therapeutic option, besides radiotherapy. Chemotherapeutic agents are cytotoxic anticancer drugs that impair cell division, resulting in the death of rapidly dividing cells.
Single-agent chemotherapy produces responses in 10–25% of patients with advanced melanoma, although there is no evidence that this translates into a survival advantage. We see complete responses only in about 2% of the cases. The median survival associated with chemotherapy is nine months. 13% of patients are alive at two years . Compounds including dacarbazine (DTIC), temozolomide, fotemustine and vindesine are commonly used (see Table 1).
|Dacarbazine (DTIC)||200–250 mg/m2/day i. v., 5 daily doses
800–1200 mg/m2 i. v., every 3–4 weeks
|Temozolomide||150–200 mg/m2 p. o. 5 daily doses (day 1–5), every 4 weeks
150 mg/m2 p. o., day 1–7, then 7 days pause (biweekly)
|Fotemustine||100 mg/m2 i. V. day 1 and 8 and 15, then 5 weeks pause, continuation every 3 weeks|
|Vindesine||3 mg/m2 i. v., every 2 weeks|
|Carboplatin/ Paclitaxel||Carboplatin AUC 6 i. v. day 1
Paclitaxel 225 mg/m2 i. v. day 1
every 3 weeks
|Gemcitabine/ Treosulfan||Gemcitabine 1000 mg/m2 i. v. day 1 and 8
Treosulfan 3500 mg/m2 i. v. day 1 and 8
every 3 weeks
|BHD||BCNU 150 mg/m2 i. v. day 1, every 2 cycles
Hydroxyurea 1500 mg/m2 p. o. day 1–5
Dacarbazine 150 mg/m2 i. v. day 1–5
every 4 weeks
|BOLD||Bleomycin 15 mg/m2 i. v., day 1 and 4
Vincristine 1 mg/m2 i. v. day 1 and 5
CCNU 80 mg/m2 p. o. day 1
Dacarbazine 200 mg/m2 i. v. day 1–5
every 4 weeks
|DVP||Dacarbazine 450 mg/m2 i. v., day 1 and 8
Vindesine 3 mg/m2 i. v., day 1 and 8
Cisplatin 50 mg/m2 i. v., day 1 and 8,
every 3–4 weeks
2.1. Dacarbazine (DTIC)
In 1975, dacarbazine (DTIC) became the first US Food and Drug Administration (FDA) approved chemotherapeutic agent for the treatment of metastatic melanoma. As a single agent, dacarbazine was most commonly used even when it had not been formally compared with other agents or with observation alone. The usual dose is 800–1200 mg/m2 every 3–4 weeks (given either in one dose or in five doses of 200–250 mg/m2 on different days). The response rates with dacarbazine are 15–25%, with the median response duration of 5–6 months, but less than 5% of complete responses. Long-term follow-up of patients treated with dacarbazine alone shows less than 2% survival rate for six years [5,6].
Dacarbazine can also be substituted with temozolomide, an orally available analog of dacarbazine, because of its convenience of adminstration. This substance has the advantage of central nervous system penetration. Temozolomide has shown an equal efficacy to that of dacarbazine in a phase III trial at a dose of 200 mg/m2/day for five days every 28 days. Recent results from a large, randomized phase III trial showed no differences in overall survival, progression-free survival and overall response rate between temozolomide arm and dacarbazine arm. This trial examined the efficacy of an extended schedule of temozolomide (week on–week off, 150 mg/m2/day for seven days, repeated every 14 days) compared with standard dose single-agent dacarbazine. Temozolomide was very well tolerated and showed an improvement in the quality of life, resulting in large use of temozolomide for the treatment of metastatic melanoma .
Fotemustine, a nitrosourea, is probably the most active one of this group in metastatic melanoma. The nitrosoureas can cross the blood-brain barrier. Fotemustine has been widely tested in Europe and has shown an overall response of 20–25%, including 5–8% of complete response rates. It was the first drug showing significant efficacy in brain metastases [8,9]. In a study comparing foremustine to dacarbazine, fotemustine produced a higher overall response rate than dacarbazine. However, response duration (time to disease progression and overall survival) was not statistically significant. Interestingly, in patients without brain metastasis at inclusion, the median time to brain metastasis was longer in fotemustine comparing to dacarbazine (22.7 months versus 7.2 months). This trial showed no significant difference in terms of quality of life between both arms .
Vindesine is a vinca alkaloid used as a single agent therapy as well as in polychemotherapy in patients with metastatic melanoma. The vinca alkaloids block cell division in metaphase. The main side effects of vindesine are nephrotoxicity and neurotoxicity. A mild myelosuppression is another side effect of vindesine .
The poor efficacy of the single agent chemotherapy led to the evaluation of polychemotherapy in the 1980s to improve outcome and enhance response rates in patients with metastatic melanoma. The first combinations added nitrosourea, vinca alkaloids or platinum to dacarbazine, failing to result in any significant benefit compared with dacarbazine alone, except for a slight increase of response rates. Other more aggressive polychemotherapy regimens such as BHD (BCNU, hydroxyurea, and dacarbazine) and BOLD (bleomycin, vincristine, CCNU, and dacarbazine) were used, and resulted in higher response rates without any survival advantage. In a phase II trial with the combination of dacarbazine, cisplatinum and vindesine (DVP or CVD), a response rate of 40% was obtained, including 4% of complete response . In a randomized study on 150 patients comparing CVD to dacarbazine, the response rate was higher in the CVD arm as compared to the dacarbazine arm (19% to 14%), without any differences in either response duration or survival. However, increased toxicity has been observed . The combination of tamoxifen and dacarbazine was tested in a small phase III study. It demonstrated an improvement of response and survival compared to dacarbazine alone . However, other large randomized studies did not support this result. The reported efficacy of the combination of paclitaxel and carboplatin used in the therapy of metastatic melanoma in recent years was one of the more unexpected developments.
The other chemotherapy combination is gemcitabine and treosulfan. To evaluate an in vitro test system providing information on the drug sensitivity profile of melanoma cells, Ugurel et al. examined tumor tissue specimens from metastatic melanoma patients with an ATP-based chemosensitivity assay (ATP-TCA). In the chemosensitivity testing in 31 metastatic melanoma patients, the highest sensitivity was detected for this combination. 76% of the tissue samples revealed high sensitivity and 10% resistance . Chemosensitive patients showed an increased overall survival of 14.6 months compared with 7.4 months in chemoresistant patients .
Huncharek et al. reported in a meta-analysis comparing two or three drug combination regimens with dacarbazine alone, that there was no advantage for the combination chemotherapy in terms of response or survival. Treatment decisions remain controversial, and quality of life and toxicity issues from treatment assume greater importance .
As a first-line therapy, polychemotherapy did not show significant advantages for prolongation of survival compared to single agent therapy; hence it is more toxic. As treatment in metastatic non-operable malignant melanoma is primarily palliative, the effect of any regimen on the quality of life must be carefully weighed .
The Term “immunotherapy” is used for non-specific as well as specific immunomodulation that encompasses a number of different approaches, summarized below.
The most widely used immunomodulating drugs in metastatic melanoma are Interleukin 2 (IL-2) and Interferon α (IFN-α). An overall objective response rate of 16% and a complete response in 6% of patients treated with high-dose IL-2 have been reported . IL-2 can cause severe hypotension and vascular leak syndrome, resulting in interstitial and pulmonary edema, renal and hepatic dysfunction, cardiovascular failure, neurological disturbances, nausea, vomiting and thrombocytopenia . The significant toxicity of the treatment with IL-2 (Proleukin) has limited its use to selected patients with good organ function who are treated by experienced clinicians at selected specialized centers .
Numerous studies have demonstrated that IFN-α has antiproliferative and immunomodulatory effects, including the inhibition of angiogenesis , the increase of major histocompatibility complex class I antigen expression and the infiltration of CD4+ T cells into melanomas . In a metastatic situation, single agent IFN-α showed approximately 15% of responses with less than 5% of complete response rates and median response duration between six and nine months, with a maximum of twelve months for the best studies . These response rates, while encouraging, were not significant enough to lead to its widespread use in the treatment of metastatic melanoma. However, observations that patients with non-visceral disease were more likely to response suggested that the use of IFN-α may demonstrate a greater impact in patients with micrometastasis [23,24].
3.2. Monoclonal Antibodies
Anti-cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4)
Activation of naïve T cells requires recognition of the antigen by the T cell receptor (TCR) and provision of costimulatory signals. CTLA-4 is expressed on the surface of Helper T cells and transmits an inhibitory signal to T cells. The pivotal role of CTLA-4 in regulating T-cell function is established, and a series of preclinical studies provided proof-of-concept evidence of the antitumor activity of anti-CTLA-4 antibodies in combination with vaccines or chemotherapy. Subsequently, anti-CTLA-4 antibodies have shown encouraging results in clinical trials in advanced melanoma. Recent progress in the understanding of melanoma genetics and tumorgenesis has led to potential new therapeutic targets. Molecular targeted agents that inhibit the proliferation and survival of metastatic melanoma cells offer potential partners for anti-CTLA-4 antibodies in combined modality regimens . Two monoclonal antibodies recognizing CTLA-4, ipilimumab (MDX 010) and tremelimumab (CP-675, 206), have been examined in many trials.
Activity of ipilimumab in patients with metastatic melanoma has been examined with and without chemotherapy. In a randomized phase II trial, ipilimumab was given alone or in combination with dacarbazine. The median overal survival (OS) for the monotherapy group was 351 and for the combination group 389 days, respectively. Approximately 10% of the patients were alive after two to more than four years of follow-up in both therapy arms. This fact indicates that the therapy can achieve a long-term control of the disease.
The activity of ipilimumab in combination with a vaccine (two modified HLA-A* 0201.restricted peptides) was tested in a randomized study (phase II) in 56 patients . The overall response rate was 13%. Patients with grade 3/4 autoimmune toxicity show better clinical responses. It is reported that some of the immune-related adverse events were observed in 62% of 139 overall treated patients and were associated with a greater probability of objective antitumor response . Colitis or diarrhea and also dermatitis were the most common grade 3/4 immune-related adverse events [28,29,30]. The induction of manageable autoimmunity in patients with metastatic melanoma treated with ipilimumab could be a marker of objective and durable clinical response.
Tremelimumab (CP-675, 206) is another fully human monoclonal antibody specific for human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD 152) in clinical development for patients with cancer . In a single-arm phase II trial with 246 previously treated patients, assessing the activity of tremelimumab as a single agent shows the objective response rate of only 6.6%. The duration of response was 8.9 to 29.8 months. Clinical benefit rate (overall response + stable disease) was 21% (16 partial responses and 35 stable disease), and median overall survival was 10.0 months. Progression-free survival at six months was 15%, and survival was 40.3% at 12 months and 22% at 24 months. This indicates a role for tremelimumab in these patients . A randomized study investigating tremelimumab as a single agent in comparison with a standard chemotherapy (decarbazine or temozolomide) in previously untreated patients concluded that the antibody failed to demonstrate an improvement in OS as a first-line treatment in patients with metastatic melanoma . An overall response rate of 19% for a combination therapy with tremelimumab and high-dose Interferon-α2b was shown in a phase II trial of 16 previously treated patients . Early-Phase clinical trials demonstrated acceptable toxicity of tremelimumab (diarrhea/colitis, dermatitis, fatigue, pancreatitis, Grave’s disease) .
In trials involving 440 metastatic cancer patients (96% melanoma) receiving cancer vaccine, the objective response was very low (2.6%). The other 40 studies with 756 patients have showed a comparable result of 4.0% response rate . It is discussable that the vaccines may only be suitable for immune-competent patients (after full resection of their tumors, adjuvant setting). However, large adjuvant trials after tumor resection (stage II-IV melanoma) have not demonstrated positive results.
3.3.1. Allogeneic and Autologous Vaccines
The autologous vaccines are prepared from tumors of individual patients. Vitespen is a tumor-derived, HSP-peptide complex vaccine that was tested in a study with 64 metastatic melanoma patients. A phase III study with 322 previously untreated metastatic melanoma patients compared Vitespen with a physician choice therapy. A similar overall survival (OS) was found in both arms . In two large trials, more than 1400 patients were randomized to Canvaxin + BCG (bacillus Calmette-Guerin) or placebo + BCG after resectional surgery. The five-year survival rate in stage III was 59% for the Canvaxin patients and 68% for the placebo patients. In the stage IV study, the median survival was 32 months for the Canvaxin patients and 39 months for the placebo patients. The five-year survivals were 40% (Canvaxin) and 45% (placebo) [38,39].
Tumor regression in melanoma patients has been documented in several trials involving antigens encoded by genes of the MAGE family, particularly MAGE-3. Low-level cytolytic lymphocyte (CTL) responses mediate these tumor regressions . A randomized, open trial with the MAGE-A3 protein combined with different immunological adjuvants- AS02B or AS15- assessed the adjuvants for toxicity and clinical and immunological responses. 68 patients with unresectable stage III or stage IV M1a melanoma got the MAGE-A3 protein as first-line treatment. In combination with AS15, it yielded higher anti-MAGE-3 antibody titer, stronger T cell induction and long-lasting clinical response .
4. Small Molecules and Targeted Therapies
Another interesting starting point in the therapy of metastatic melanoma is the selected blocking of targeted structures. Several signal pathways related to survival of cancer cells are frequently deregulated in melanoma (RAS-RAF-MEK-ERK pathway, p16INK4A-CDK4-RB pathway, ARF-p53 pathway, PI3K-AKT pathway and the canonical Wnt signaling pathway). Inhibition of these signal transduction pathways, as well as of tumor angiogenesis, adhesion mechanisms or apoptosis induction, can be the action point of these new molecules (summarized in Table 2, see also ).
|Receptor tyrosinase kinase (RTK) inhibitors|
|RAS-RAF-MEK-ERK signal pathway inhibitors|
|PLX4032, PLX4720||Mutant B-Raf||[48,49]|
|Sorafenib||B-Raf, c-Kit, C-Raf Flt-3, PDGF, VEGF-2 , VEGF -3||[50,51,52]|
|Tanespimycin||Hsp90, as well as B-Raf, Akt, and others)|||
|PI3K-AKT signal pathway inhibitors|
|Targeting anti-apoptotic proteins|
|Targeting the neovasculature|
|Elesclomol||oxidative stress induction|||
Sorafenib is a multikinase inhibitor with selectivity for B-Raf, C-Raf, VEGFR-2 and -3, platelet-derived growth factor receptor (PDGFR) and c-Kit. Because of the high rate of activating B-Raf mutations in melanoma, sorafenib is an agent to treat metastatic melanoma. As a single agent, it has been shown to stabilize the disease in 19% of metastatic melanoma patients . In contrast to sorafenib, PLX4032 is a selective inhibitor of the oncogenic V600E mutant BRAF kinase. V600E BRAF is the most common kinase mutation in melanoma (60%). Promising results in distant metastatic melanoma were recently shown for this substance [71,72].
Another interesting target is the receptor tyrosine kinase KIT. Activating Kit mutations have been found in mucosal and acral-lentiginous melanomas. Targeting Kit by receptor tyrosine-kinase inhibitors (imatinib, dasatinib, sunitinib) have shown some dramatic responses in patients with very high c-KIT expression and/or documented activating mutations [73,74,75]. This fosters the belief that focused studies in patients selected on the basis of c-KIT mutational status will yield more encouraging results.
The prognosis of patients with metastatic malignant melanoma remains poor. Only low response rates from 10% to 25% have been achieved by the most effective single-agent chemotherapies. More aggressive chemotherapy regimens (polychemotherapies) have reached response rates of about 40% but there was no significant benefit in overall survival compared to single-agent chemotherapies. Single-agent or combination chemotherapy, new agents or biologic response modifiers alone have not yet shown response rates of durable remissions that are high enough to affect median survival. There is an urgent need for more effective agents and developing new innovative treatment options to achieve higher response rates in treatment of metastatic melanoma. There are many opportunities for improving the treatment of patients with melanoma, including novel immunotherapy approaches, molecular targeted and antiangiogenic therapies. Further efforts are needed to select treatments for patients based on tumor and host molecular and genetic features. These new substances need to be evaluated in clinical trials.
None of the authors has financial or proprietary interests in any material or method mentioned.
- Rass, K.; Hassel, J.C. Chemotherapeutics, chemoresistance and the management of melanoma. G. Ital. Dermatol. Venereol. 2009, 144, 61–78. [Google Scholar]
- Schadendorf, D.; Algarra, S.M.; Bastholt, L.; Cinat, G.; Dreno, B.; Eggermont, A.M.; Espinosa, E.; Guo, J.; Hauschild, A.; Petrella, T.; Schachter, J.; Hersey, P. Immunotherapy of distant metastatic disease. Ann. Oncol. 2009, 20 (Suppl. 6), vi41–50. [Google Scholar] [CrossRef]
- Balch, C.M.; Buzaid, A.C.; Soong, S.J.; Atkins, M.B.; Cascinelli, N.; Coit, D.G.; Fleming, I.D.; Gershenwald, J.E.; Houghton, A., Jr.; Kirkwood, J.M.; McMasters, K.M.; Mihm, M.F.; Morton, D.L.; Reintgen, D.S.; Ross, M.I.; Sober, A.; Thompson, J.A.; Thompson, J.F. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J. Clin. Oncol. 2001, 19, 3635–3648. [Google Scholar]
- Lee, M.L.; Tomsu, K.; Von Eschen, K.B. Duration of survival for disseminated malignant melanoma: results of a meta-analysis. Melanoma Res. 2000, 10, 81–92. [Google Scholar]
- Comis, R.L. DTIC (NSC-45388) in malignant melanoma: a perspective. Cancer Treat. Rep. 1976, 60, 165–176. [Google Scholar]
- Hill, G.J., 2nd; Metter, G.E.; Krementz, E.T.; Fletcher, W.S.; Golomb, F.M.; Ramirez, G.; Grage, T.B.; Moss, S.E. DTIC and combination therapy for melanoma. II. Escalating schedules of DTIC with BCNU, CCNU, and vincristine. Cancer Treat. Rep. 1979, 63, 1989–1992. [Google Scholar]
- Mouawad, R.; Sebert, M.; Michels, J.; Bloch, J.; Spano, J.P.; Khayat, D. Treatment for metastatic malignant melanoma: Old drugs and new strategies. Crit. Rev. Oncol. Hematol. 2009. [Google Scholar] [CrossRef]
- Jacquillat, C.; Khayat, D.; Banzet, P.; Weil, M.; Fumoleau, P.; Avril, M.F.; Namer, M.; Bonneterre, J.; Kerbrat, P.; Bonerandi, J.J.; et al. Final report of the French multicenter phase II study of the nitrosourea fotemustine in 153 evaluable patients with disseminated malignant melanoma including patients with cerebral metastases. Cancer 1990, 66, 1873–1878. [Google Scholar] [CrossRef]
- Khayat, D.; Giroux, B.; Berille, J.; Cour, V.; Gerard, B.; Sarkany, M.; Bertrand, P.; Bizzari, J.P. Fotemustine in the treatment of brain primary tumors and metastases. Cancer Invest. 1994, 12, 414–420. [Google Scholar] [CrossRef]
- Avril, M.F.; Aamdal, S.; Grob, J.J.; Hauschild, A.; Mohr, P.; Bonerandi, J.J.; Weichenthal, M.; Neuber, K.; Bieber, T.; Gilde, K.; Guillem Porta, V.; Fra, J.; Bonneterre, J.; Saiag, P.; Kamanabrou, D.; Pehamberger, H.; Sufliarsky, J.; Gonzalez Larriba, J.L.; Scherrer, A.; Menu, Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J. Clin. Oncol. 2004, 22, 1118–1125. [Google Scholar] [CrossRef]
- Garbe, C.; Eigentler, T.K. Therapy of malignant melanoma at the stage of distant metastasis. Hautarzt 2004, 55, 195–213. [Google Scholar] [CrossRef]
- Legha, S.S.; Ring, S.; Papadopoulos, N.; Plager, C.; Chawla, S.; Benjamin, R. A prospective evaluation of a triple-drug regimen containing cisplatin, vinblastine, and dacarbazine (CVD) for metastatic melanoma. Cancer 1989, 64, 2024–2029. [Google Scholar] [CrossRef]
- Buzaid, A.C.; Legha, S.S.; Winn, R.; Belt, R.; Pollock, T.; Wiseman, C.; Ensign, L.G. Cisplatin, vinblastine and dacarbazine (CVD) versus dacarbazine alone in metastatic melanoma: preleminary results of a phase II Cancer Community Oncology Program (CCOP) Trial. J. Clin. Oncol. 1993, 12, 389. [Google Scholar]
- Cocconi, G.; Bella, M.; Calabresi, F.; Tonato, M.; Canaletti, R.; Boni, C.; Buzzi, F.; Ceci, G.; Corgna, E.; Costa, P.; et al. Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N. Engl. J. Med. 1992, 327, 516–523. [Google Scholar] [CrossRef]
- Ugurel, S.; Tilgen, W.; Reinhold, U. Chemosensitivity testing in malignant melanoma. Recent Results Cancer Res. 2003, 161, 81–92. [Google Scholar] [CrossRef]
- Ugurel, S.; Schadendorf, D.; Pfohler, C.; Neuber, K.; Thoelke, A.; Ulrich, J.; Hauschild, A.; Spieth, K.; Kaatz, M.; Rittgen, W.; Delorme, S.; Tilgen, W.; Reinhold, U. In vitro drug sensitivity predicts response and survival after individualized sensitivity-directed chemotherapy in metastatic melanoma: a multicenter phase II trial of the Dermatologic Cooperative Oncology Group. Clin. Cancer Res. 2006, 12, 5454–5463. [Google Scholar] [CrossRef]
- Huncharek, M.; Caubet, J.F.; McGarry, R. Single-agent DTIC versus combination chemotherapy with or without immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients from 20 randomized trials. Melanoma Res. 2001, 11, 75–81. [Google Scholar] [CrossRef]
- Garbe, C.; Hauschild, A.; Volkenandt, M.; Schadendorf, D.; Stolz, W.; Reinhold, U.; Kortmann, R.D.; Kettelhack, C.; Frerich, B.; Keilholz, U.; Dummer, R.; Sebastian, G.; Tilgen, W.; Schuler, G.; Mackensen, A.; Kaufmann, R. Evidence-based and interdisciplinary consensus-based German guidelines: systemic medical treatment of melanoma in the adjuvant and palliative setting. Melanoma Res. 2008, 18, 152–160. [Google Scholar] [CrossRef]
- Atkins, M.B.; Lotze, M.T.; Dutcher, J.P.; Fisher, R.I.; Weiss, G.; Margolin, K.; Abrams, J.; Sznol, M.; Parkinson, D.; Hawkins, M.; Paradise, C.; Kunkel, L.; Rosenberg, S.A. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J. Clin. Oncol. 1999, 17, 2105–2116. [Google Scholar]
- Tsao, H.; Atkins, M.B.; Sober, A.J. Management of cutaneous melanoma. N. Engl. J. Med. 2004, 351, 998–1012. [Google Scholar] [CrossRef]
- Slaton, J.W.; Perrotte, P.; Inoue, K.; Dinney, C.P.; Fidler, I.J. Interferon-alpha-mediated down-regulation of angiogenesis-related genes and therapy of bladder cancer are dependent on optimization of biological dose and schedule. Clin. Cancer Res. 1999, 5, 2726–2734. [Google Scholar]
- Hakansson, A.; Gustafsson, B.; Krysander, L.; Hakansson, L. Effect of IFN-alpha on tumor-infiltrating mononuclear cells and regressive changes in metastatic malignant melanoma. J. Interferon Cytokine Res. 1998, 18, 33–39. [Google Scholar] [CrossRef]
- Agarwala, S.S.; Kirkwood, J.M. Interferons in melanoma. Curr. Opin. Oncol. 1996, 8, 167–174. [Google Scholar] [CrossRef]
- Agarwala, S.S.; Kirkwood, J.M. Potential uses of interferon alpha 2 as adjuvant therapy in cancer. Ann. Surg. Oncol. 1995, 2, 365–371. [Google Scholar] [CrossRef]
- Agarwala, S.S. Novel immunotherapies as potential therapeutic partners for traditional or targeted agents: cytotoxic T-lymphocyte antigen-4 blockade in advanced melanoma. Melanoma Res. 2010, 20, 1–10. [Google Scholar] [CrossRef]
- Attia, P.; Phan, G.Q.; Maker, A.V.; Robinson, M.R.; Quezado, M.M.; Yang, J.C.; Sherry, R.M.; Topalian, S.L.; Kammula, U.S.; Royal, R.E.; Restifo, N.P.; Haworth, L.R.; Levy, C.; Mavroukakis, S.A.; Nichol, G.; Yellin, M.J.; Rosenberg, S.A. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J. Clin. Oncol. 2005, 23, 6043–6053. [Google Scholar] [CrossRef]
- Downey, S.G.; Klapper, J.A.; Smith, F.O.; Yang, J.C.; Sherry, R.M.; Royal, R.E.; Kammula, U.S.; Hughes, M.S.; Allen, T.E.; Levy, C.L.; Yellin, M.; Nichol, G.; White, D.E.; Steinberg, S.M.; Rosenberg, S.A. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin. Cancer Res. 2007, 13, 6681–6688. [Google Scholar] [CrossRef]
- Beck, K.E.; Blansfield, J.A.; Tran, K.Q.; Feldman, A.L.; Hughes, M.S.; Royal, R.E.; Kammula, U.S.; Topalian, S.L.; Sherry, R.M.; Kleiner, D.; Quezado, M.; Lowy, I.; Yellin, M.; Rosenberg, S.A.; Yang, J.C. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J. Clin. Oncol. 2006, 24, 2283–2289. [Google Scholar] [CrossRef]
- O'Day, S.J.; Maio, M.; Chiarion-Sileni, V.; Gajewski, T.F.; Pehamberger, H.; Bondarenko, I.N.; Queirolo, P.; Lundgren, L.; Mikhailov, S.; Roman, L.; Verschraegen, C.; Humphrey, R.; Ibrahim, R.; de Pril, V.; Hoos, A.; Wolchok, J.D. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann. Oncol. 2010. [Google Scholar] [CrossRef]
- Wolchok, J.D.; Neyns, B.; Linette, G.; Negrier, S.; Lutzky, J.; Thomas, L.; Waterfield, W.; Schadendorf, D.; Smylie, M.; Guthrie, T., Jr.; Grob, J.J.; Chesney, J.; Chin, K.; Chen, K.; Hoos, A.; O'Day, S.J.; Lebbe, C. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010, 11, 155–164. [Google Scholar] [CrossRef]
- Ribas, A.; Hanson, D.C.; Noe, D.A.; Millham, R.; Guyot, D.J.; Bernstein, S.H.; Canniff, P.C.; Sharma, A.; Gomez-Navarro, J. Tremelimumab (CP-675,206), a cytotoxic T lymphocyte associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer. Oncologist 2007, 12, 873–883. [Google Scholar] [CrossRef]
- Kirkwood, J.M.; Lorigan, P.; Hersey, P.; Hauschild, A.; Robert, C.; McDermott, D.; Marshall, M.A.; Gomez-Navarro, J.; Liang, J.Q.; Bulanhagui, C.A. Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. Clin. Cancer Res. 2010, 16, 1042–1048. [Google Scholar] [CrossRef]
- Ribas, A.; Hauschild, A.; Kefford, R.; Punt, C.J.; Haanen, J.B.; Marmol, M.; Garbe, C.; Gomez-Navarro, J.; Pavlov, D.; Mars, M. Phase III, open-lable, randomized, comparative study of tremelimumab (CP-675, 206) and chemotherapy (temozolomide [TMZ] or dacarbazine [DTIC] in patients with advanced melanoma. ASCO annual proceedings Part I. J. Clin. Oncol. 2008, 26, Abstr. LBA9011. [Google Scholar]
- Tarhini, A.A.; Moschos, S.S.; Schlesselman, J.J.; Shope-Spotloe, J.; Demark, M.; Kirkwood, J.M. Phase II trial of combination biotherapy of high-dose interferon alfa-2b and tremelimumab for recurrent inoperable stage III or stage IV melanoma. ASCO Annual proceedings Part I. J. Clin. Oncol. 2008, 26, Abstr. 9009. [Google Scholar]
- Ribas, A.; Antonia, S.; Sosman, J. Results of a phase II clinical trial of 2 doses and schedules of CP-675, 206, an anti-CTLA4 monoclonal antibody, in patients (pts) with advanced melanoma. ASCO Annual Meeting Proceedings Part I. J. Clin. Oncol. 2007, 25, Abstr. 3000. [Google Scholar]
- Rosenberg, S.A.; Yang, J.C.; Restifo, N.P. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 2004, 10, 909–915. [Google Scholar] [CrossRef]
- Testori, A.; Richards, J.; Whitman, E.; Mann, G.B.; Lutzky, J.; Camacho, L.; Parmiani, G.; Tosti, G.; Kirkwood, J.M.; Hoos, A.; Yuh, L.; Gupta, R.; Srivastava, P.K. 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. 2008, 26, 955–962. [Google Scholar] [CrossRef]
- Chung, M.H.; Gupta, R.K.; Hsueh, E.; Essner, R.; Ye, W.; Yee, R.; Morton, D.L. Humoral immune response to a therapeutic polyvalent cancer vaccine after complete resection of thick primary melanoma and sentinel lymphadenectomy. J. Clin. Oncol. 2003, 21, 313–319. [Google Scholar] [CrossRef]
- Hsueh, E.C.; Essner, R.; Foshag, L.J.; Ollila, D.W.; Gammon, G.; O'Day, S.J.; Boasberg, P.D.; Stern, S.L.; Ye, X.; Morton, D.L. Prolonged survival after complete resection of disseminated melanoma and active immunotherapy with a therapeutic cancer vaccine. J. Clin. Oncol. 2002, 20, 4549–4554. [Google Scholar] [CrossRef]
- Coulie, P.G.; Karanikas, V.; Colau, D.; Lurquin, C.; Landry, C.; Marchand, M.; Dorval, T.; Brichard, V.; Boon, T. A monoclonal cytolytic T-lymphocyte response observed in a melanoma patient vaccinated with a tumor-specific antigenic peptide encoded by gene MAGE-3. Proc. Natl. Acad. Sci. USA 2001, 98, 10290–10295. [Google Scholar]
- Kruit, W.H.; Suciu, S.; Dreno, B.; Chiarion-Sileni, V.; Mortier, L.; Robert, C.; Maio, M.; Brichard, V.G.; Lehmann, F.; Keilholz, U. immunization with recombinant MAGE-A3 protein combined with adjuvant systems AS15 or AS02B in patients with unresectable and progressive metastatic cutaneous melanoma: a randomized open-lable phase II study of the EORTC Melanoma Group (16032-18031). ASCO Annual Proceedings Part I. J. Clin. Oncol. 2008, 26, Abstr. 9065. [Google Scholar]
- Hersey, P.; Bastholt, L.; Chiarion-Sileni, V.; Cinat, G.; Dummer, R.; Eggermont, A.M.; Espinosa, E.; Hauschild, A.; Quirt, I.; Robert, C.; Schadendorf, D. Small molecules and targeted therapies in distant metastatic disease. Ann. Oncol. 2009, 20 (Suppl. 6), vi35–40. [Google Scholar] [CrossRef]
- Hodi, F.S.; Friedlander, P.; Corless, C.L.; Heinrich, M.C.; Mac Rae, S.; Kruse, A.; Jagannathan, J.; Van den Abbeele, A.D.; Velazquez, E.F.; Demetri, G.D.; Fisher, D.E. Major response to imatinib mesylate in KIT-mutated melanoma. J. Clin. Oncol. 2008, 26, 2046–2051. [Google Scholar] [CrossRef]
- Woodman, S.E.; Trent, J.C.; Stemke-Hale, K.; Lazar, A.J.; Pricl, S.; Pavan, G.M.; Fermeglia, M.; Gopal, Y.N.; Yang, D.; Podoloff, D.A.; Ivan, D.; Kim, K.B.; Papadopoulos, N.; Hwu, P.; Mills, G.B.; Davies, M.A. Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. Mol. Cancer Ther. 2009, 8, 2079–2085. [Google Scholar] [CrossRef]
- Puri, N.; Ahmed, S.; Janamanchi, V.; Tretiakova, M.; Zumba, O.; Krausz, T.; Jagadeeswaran, R.; Salgia, R. c-Met is a potentially new therapeutic target for treatment of human melanoma. Clin. Cancer Res. 2007, 13, 2246–2253. [Google Scholar] [CrossRef]
- Adjei, A.A.; Cohen, R.B.; Franklin, W.; Morris, C.; Wilson, D.; Molina, J.R.; Hanson, L.J.; Gore, L.; Chow, L.; Leong, S.; Maloney, L.; Gordon, G.; Simmons, H.; Marlow, A.; Litwiler, K.; Brown, S.; Poch, G.; Kane, K.; Haney, J.; Eckhardt, S.G. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J. Clin. Oncol. 2008, 26, 2139–2146. [Google Scholar] [CrossRef]
- Ciuffreda, L.; Del Bufalo, D.; Desideri, M.; Di Sanza, C.; Stoppacciaro, A.; Ricciardi, M.R.; Chiaretti, S.; Tavolaro, S.; Benassi, B.; Bellacosa, A.; Foa, R.; Tafuri, A.; Cognetti, F.; Anichini, A.; Zupi, G.; Milella, M. Growth-inhibitory and antiangiogenic activity of the MEK inhibitor PD0325901 in malignant melanoma with or without BRAF mutations. Neoplasia 2009, 11, 720–731. [Google Scholar]
- Halaban, R.; Zhang, W.; Bacchiocchi, A.; Cheng, E.; Parisi, F.; Ariyan, S.; Krauthammer, M.; McCusker, J.P.; Kluger, Y.; Sznol, M. PLX4032, a Selective BRAF(V600E) Kinase Inhibitor, Activates the ERK Pathway and Enhances Cell Migration and Proliferation of BRAF(WT) Melanoma Cells. Pigment Cell Melanoma Res. 2010, 23, 190–200. [Google Scholar] [CrossRef]
- Tsai, J.; Lee, J.T.; Wang, W.; Zhang, J.; Cho, H.; Mamo, S.; Bremer, R.; Gillette, S.; Kong, J.; Haass, N.K.; Sproesser, K.; Li, L.; Smalley, K.S.; Fong, D.; Zhu, Y.L.; Marimuthu, A.; Nguyen, H.; Lam, B.; Liu, J.; Cheung, I.; Rice, J.; Suzuki, Y.; Luu, C.; Settachatgul, C.; Shellooe, R.; Cantwell, J.; Kim, S.H.; Schlessinger, J.; Zhang, K.Y.; West, B.L.; Powell, B.; Habets, G.; Zhang, C.; Ibrahim, P.N.; Hirth, P.; Artis, D.R.; Herlyn, M.; Bollag, G. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc. Natl. Acad. Sci. USA 2008, 105, 3041–3046. [Google Scholar] [CrossRef]
- Amaravadi, R.K.; Schuchter, L.M.; McDermott, D.F.; Kramer, A.; Giles, L.; Gramlich, K.; Carberry, M.; Troxel, A.B.; Letrero, R.; Nathanson, K.L.; Atkins, M.B.; O'Dwyer, P.J.; Flaherty, K.T. Phase II Trial of Temozolomide and Sorafenib in Advanced Melanoma Patients with or without Brain Metastases. Clin. Cancer Res. 2009, 15, 7711–7718. [Google Scholar] [CrossRef]
- Hauschild, A.; Agarwala, S.S.; Trefzer, U.; Hogg, D.; Robert, C.; Hersey, P.; Eggermont, A.; Grabbe, S.; Gonzalez, R.; Gille, J.; Peschel, C.; Schadendorf, D.; Garbe, C.; O'Day, S.; Daud, A.; White, J.M.; Xia, C.; Patel, K.; Kirkwood, J.M.; Keilholz, U. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J. Clin. Oncol. 2009, 27, 2823–2830. [Google Scholar] [CrossRef]
- Hong, D.S.; Sebti, S.M.; Newman, R.A.; Blaskovich, M.A.; Ye, L.; Gagel, R.F.; Moulder, S.; Wheler, J.J.; Naing, A.; Tannir, N.M.; Ng, C.S.; Sherman, S.I.; El Naggar, A.K.; Khan, R.; Trent, J.; Wright, J.J.; Kurzrock, R. Phase I trial of a combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in advanced malignancies. Clin. Cancer Res. 2009, 15, 7061–7068. [Google Scholar] [CrossRef]
- Kefford, R.; Millward, M.; Hersey, P.; Brady, B.; Graham, M.; Johnson, R.G.; Hannah, A.L. Phase II trial of tanespimycin (KOS-953), a heat shock protein-90 (Hsp90) inhibitor in patients with metastatic melanoma. ASCO Annual Meeting Proceedings Part I. J. Clin. Oncol. 2007, 25 (18S, June 20 Supplement), 8558. [Google Scholar]
- Mita, M.M.; Britten, C.D.; Poplin, E.; Tap, W.D.; Carmona, A.; Yonemoto, L.; Wages, D.S.; Bedrosian, C.L.; Rubin, E.H.; Tolcher, A.W. Deforolimus trial 106- A Phase I trial evaluating 7 regimens of oral Deforolimus (AP23573, MK-8669). J. Clin. Oncol. 2008, 26, Abstr. 3509. [Google Scholar]
- Thallinger, C.; Werzowa, J.; Poeppl, W.; Kovar, F.M.; Pratscher, B.; Valent, P.; Quehenberger, P.; Joukhadar, C. Comparison of a treatment strategy combining CCI-779 plus DTIC versus DTIC monotreatment in human melanoma in SCID mice. J. Invest. Dermatol. 2007, 127, 2411–2417. [Google Scholar] [CrossRef]
- Ernst, D.S.; Eisenhauer, E.; Wainman, N.; Davis, M.; Lohmann, R.; Baetz, T.; Belanger, K.; Smylie, M. Phase II study of perifosine in previously untreated patients with metastatic melanoma. Invest. New Drugs 2005, 23, 569–575. [Google Scholar] [CrossRef]
- Lopez-Fauqued, M.; Gil, R.; Grueso, J.; Hernandez-Losa, J.; Pujol, A.; Moline, T.; Recio, J.A. The dual PI3K/mTOR inhibitor PI-103 promotes immunosuppression, in vivo tumor growth and increases survival of sorafenib-treated melanoma cells. Int. J. Cancer 2010, 126, 1549–1561. [Google Scholar]
- Smalley, K.S.; Contractor, R.; Haass, N.K.; Kulp, A.N.; Atilla-Gokcumen, G.E.; Williams, D.S.; Bregman, H.; Flaherty, K.T.; Soengas, M.S.; Meggers, E.; Herlyn, M. An organometallic protein kinase inhibitor pharmacologically activates p53 and induces apoptosis in human melanoma cells. Cancer Res. 2007, 67, 209–217. [Google Scholar] [CrossRef]
- Papadopoulos, K.P.; Markman, B.; Tabernero, J.; Patnaik, A.; Heath, E.I.; DeCillis, A.; Laird, D.; Aggarwal, S.K.; Nguyen, L.; LoRusso, P.M. A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of a novel PI3K inhibitor, XL765, administered orally to patients (pts) with advanced solid tumors. J. Clin. Oncol. 2008, 26, Abstr. 3510. [Google Scholar]
- Weber, A.; Kirejczyk, Z.; Potthoff, S.; Ploner, C.; Hacker, G. Endogenous Noxa Determines the Strong Proapoptotic Synergism of the BH3-Mimetic ABT-737 with Chemotherapeutic Agents in Human Melanoma Cells. Transl. Oncol. 2009, 2, 73–83. [Google Scholar]
- Jiang, C.C.; Yang, F.; Thorne, R.F.; Zhu, B.K.; Hersey, P.; Zhang, X.D. Human melanoma cells under endoplasmic reticulum stress acquire resistance to microtubule-targeting drugs through XBP-1-mediated activation of Akt. Neoplasia 2009, 11, 436–447. [Google Scholar]
- Bedikian, A.Y.; Millward, M.; Pehamberger, H.; Conry, R.; Gore, M.; Trefzer, U.; Pavlick, A.C.; DeConti, R.; Hersh, E.M.; Hersey, P.; Kirkwood, J.M.; Haluska, F.G. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J. Clin. Oncol. 2006, 24, 4738–4745. [Google Scholar] [CrossRef]
- Lewis, K.D.; Samlowski, W.; Ward, J.; Catlett, J.; Cranmer, L.; Kirkwood, J.; Lawson, D.; Whitman, E.; Gonzalez, R. A multi-center phase II evaluation of the small molecule survivin suppressor YM155 in patients with unresectable stage III or IV melanoma. Invest. New Drugs 2009. [Google Scholar] [CrossRef]
- Perez, D.G.; Suman, V.J.; Fitch, T.R.; Amatruda, T., 3rd; Morton, R.F.; Jilani, S.Z.; Constantinou, C.L.; Egner, J.R.; Kottschade, L.A.; Markovic, S.N. Phase 2 trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N047A. Cancer 2009, 115, 119–127. [Google Scholar] [CrossRef]
- Schicher, N.; Paulitschke, V.; Swoboda, A.; Kunstfeld, R.; Loewe, R.; Pilarski, P.; Pehamberger, H.; Hoeller, C. Erlotinib and bevacizumab have synergistic activity against melanoma. Clin. Cancer Res. 2009, 15, 3495–3502. [Google Scholar] [CrossRef]
- Kelly, R.J.; Rixe, O. Axitinib (AG-013736). Recent Results Cancer Res. 2010, 184, 33–44. [Google Scholar] [CrossRef]
- Seeger, J.M.; Schmidt, P.; Brinkmann, K.; Hombach, A.A.; Coutelle, O.; Zigrino, P.; Wagner-Stippich, D.; Mauch, C.; Abken, H.; Kronke, M.; Kashkar, H. The proteasome inhibitor bortezomib sensitizes melanoma cells toward adoptive CTL attack. Cancer Res. 2010, 70, 1825–1834. [Google Scholar] [CrossRef]
- Su, Y.; Amiri, K.I.; Horton, L.W.; Yu, Y.; Ayers, G.D.; Koehler, E.; Kelley, M.C.; Puzanov, I.; Richmond, A.; Sosman, J.A. A phase I trial of bortezomib with temozolomide in patients with advanced melanoma: toxicities, antitumor effects, and modulation of therapeutic targets. Clin. Cancer Res. 2010, 16, 348–357. [Google Scholar] [CrossRef]
- O'Day, S.; Gonzalez, R.; Lawson, D.; Weber, R.; Hutchins, L.; Anderson, C.; Haddad, J.; Kong, S.; Williams, A.; Jacobson, E. Phase II, randomized, controlled, double-blinded trial of weekly elesclomol plus paclitaxel versus paclitaxel alone for stage IV metastatic melanoma. J. Clin. Oncol. 2009, 27, 5452–5458. [Google Scholar] [CrossRef]
- Flaherty, K.T. Chemotherapy and targeted therapy combinations in advanced melanoma. Clin. Cancer Res. 2006, 12, 2366–2370. [Google Scholar] [CrossRef]
- Flaherty, K.; Puzanov, I.; Sosman, J.; Kim, K.; Ribas, A.; McArthur, G.; Lee, R. J.; Grippo, J.F.; Nolop, K.; Chapman, P. Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. J. Clin. Oncol. 2009, 27 (Suppl. 15s), Abstr. 9000. [Google Scholar]
- Puzanov, I.; Nathanson, K.L.; Chapman, P.B.; Xu, X.; Sosman, J.A.; McArthur, G.A.; Ribas, A.; Kim, K.B.; Grippo, J.F.; Flaherty, K.T. PLX4032, a highly selective V600EBRAF kinase inhibitor: Clinical correlation of activity with pharmacokinetic and pharmacodynamic parameters in a phase I trial. J. Clin. Oncol. 2009, 27 (Suppl. 15s), Abstr. 9021. [Google Scholar]
- Becker, J.C.; Brocker, E.B.; Schadendorf, D.; Ugurel, S. Imatinib in melanoma: a selective treatment option based on KIT mutation status? J. Clin. Oncol. 2007, 25, e9. [Google Scholar] [CrossRef]
- Carvajal, R.D.; Chapman, P.B.; Wolchok, J.D.; Cane, L.; Teitcher, J.B.; Lutzky, J.; Pavlick, A.C.; Bastian, B.C.; Antonescu, C.R.; Schwartz, G.K. A phase II study of imatinib mesylate (IM) for patients with advanced melanoma harboring somatic alterations of KIT. J. Clin. Oncol. 2009, 27 (suppl. 15s), Abstr. 9001. [Google Scholar]
- Garrido, M.C.; Bastian, B.C. KIT as a therapeutic target in melanoma. J. Invest Dermatol. 2010, 130, 20–27. [Google Scholar] [CrossRef]
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