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Targeted therapeutic strategies in malignant melanoma
Drug Discovery Today: Disease Mechanisms
DRUG DISCOVERY
TODAY
Vol. 5, No. 1 2008
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA
DISEASE Skin diseases MECHANISMS
Targeted therapeutic strategies in malignant melanoma Sascha Dietrich, Bernd Kasper* University of Heidelberg, Department of Internal Medicine V, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
Melanoma is one of the most common cancer types among the Caucasian population. Although prognosis is excellent for patients treated by adequate surgery,
Section Editor: Michael Roberts – School of Medicine, University of Queensland, Australia
advanced disease shrinks the overall survival at five years to less than 10%. The appropriate systemic treat-
antigen (CTLA)-4 monoclonal antibody.
tified candidate genes being involved in malignant melanoma, such as WNT5A and B-RAF. Several tumour suppressors and oncogenes have been shown to be involved in melanoma pathogenesis, including CDKN2A, PTEN, TP53, RAS and MYC. Recently, correlations between molecular biology and survival data have been detected. These developments are beginning to produce therapeutic agents that are impacting clinical practice.
Introduction
Status of current treatment strategies
Malignant melanoma is the most aggressive form of skin cancer causing the majority of deaths. During the past few decades, the incidence of cutaneous melanoma has been rising in both sexes in almost all developed countries [1]. The prognosis of malignant melanoma is related to the disease stage: early stage disease is successfully treated with surgery [2,3]. However, the five-year survival of patients with the spread of disease to regional lymph nodes is only 54% [4], for patients with disseminated melanoma the prognosis is extremely poor with a five-year survival of about 6% [5,6]. Advanced disease is generally refractory to conventional chemotherapy. Therefore, there is much interest in the field in novel therapeutics, especially immunotherapy and targeted therapies. The molecular mechanisms and the genetic markers associated with metastatic dissemination are beginning to be defined. High-throughput technologies have iden-
The appropriate systemic treatment for disseminated melanoma is still a matter of discussion and there are no defined and generally accepted standards. Single-agent therapy with dacarbazine has been the reference treatment for melanoma in several randomised trials. However, only temporary clinical responses but no improvement of patients’ overall survival could be achieved [7,8]. Therefore, temozolomide has been studied as first line therapy. However, patients are treated very differently with mono-chemotherapy, poly-chemotherapy or combined therapy with cytokines. Many patients are treated in experimental trials. The palliative treatment of disseminated melanoma has been excellently reviewed [9]. The only FDA-approved immunological approach in this disease in the past 30 years has been high-dose interferon-alpha (IFN-a) and high-dose bolus interleukin-2 (IL-2) in the metastatic treatment setting, but only a minority of patients benefit from this treatment in terms of long-term survival. Moreover, both agents are associated with
ment for disseminated melanoma is controversial. Therefore, we briefly describe current treatment strategies and focus on four emerging developments: antiangiogenic drugs, Bcl-2 antisense therapy, RAF kinase inhibitors and anti-cytotoxic T lymphocyte-associated
*Corresponding author: B. Kasper ([email protected]) 1740-6765/$ ß 2008 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2008.04.008
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Vol. 5, No. 1 2008
high costs and toxicity rates [10]. Recent studies suggest that a combination of temozolomide and IFN-a may be superior to temozolomide alone [11].
Targeted therapeutic strategies As we have shown consistently, there is no defined and generally accepted standard treatment strategy for advanced melanoma and the appropriate systemic treatment for disseminated melanoma is still a matter of discussion. It is obvious that there is a need to develop new and innovative treatment options. The most promising approaches are antiangiogenic and IMiDs, Bcl-2 antisense therapy, B-RAF inhibition and treatment with cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody, which will be reviewed in this paper and are summarised in Table 1 and Fig. 1.
Antiangiogenic and immunomodulatory drugs Thalidomide was one of the first drugs demonstrating antiangiogenic effects. It inhibits the basic fibroblast growth factor (bFGF) as well as the vascular endothelial growth factor (VEGF) [12]. Other immunomodulatory effects are mediated over the inhibition of NF-kB [13], the alterations of CD8+ and CD4+ T cell function, the stimulation of cytokine production of IL-2 and IFN-g as well as the inhibition of other cytokines such as IL-6 and IL-12 [14]. Although there is a confirmed activity of thalidomide in multiple myeloma, its activity in solid tumours is less prominent. Although thalidomide has neglectable efficacy as monotherapy with no objective response in patients with advanced malignant melanoma [15,16], the combination especially with temozolomide has
recently attracted attention. In a phase II trial with 38 patients without brain metastasis combining temozolomide 75 mg/m2 per day with thalidomide 100–400 mg daily an overall response rate of 32% was reported [17]. In another trial in 60 patients including those with brain metastasis a 15% overall response rate could be demonstrated [18]. One deep venous thrombosis was reported in the first trial, no thrombotic events were seen in the second trial. In a third trial, the same group published a phase II study with 26 patients with brain metastasis using the same combination therapy of temozolomide and thalidomide with an overall response rate of 11%. Four patients experienced grade II thrombotic events [19]. Another phase II study was even stopped after the enrolment of 16 patients, because two patients suddenly died of unknown causes, three patients had pulmonary embolism and a fifth patient had a deep venous thrombosis [20]. It was concluded that the high thrombotic risk is prohibitive of further use of temozolomide and thalidomide in melanoma patients with brain metastasis. Lenalidomide (CC-5013, RevlimidTM) is one of the clinically developed compounds among the thalidomide analogues called immunomodulatory drugs (IMiDs) having the advantage of antiangiogenic properties with less severe side effects compared to thalidomide. A phase I dose-escalating study demonstrated safety and tolerability of lenalidomide in 21 metastatic malignant melanoma patients with three partial remissions [21]. Two phase III trials with lenalidomide in metastatic melanoma have recently stopped recruitment with 272 patients per trial; results from these studies are awaited.
Table 1. Targets and related therapeutic strategies in malignant melanoma Therapeutic strategy
Strategic approach to target
Antiangiogenic/ Inhibition of bFGF/VEGF immunomodulatory 1
Expected outcome of intervention at target
Who is working on the target
Therapies in trial
Refs
Reduction of vessel density and tumour shrinkage
Pawlak et al.
Thalidomide alone
[16]
Hwu et al. Bartlett et al. Varker et al.
Thalidomide + temozolomide Lenalidomide Bevacizumab interferon-alpha
[17–20] [21] [23]
Bcl-2 antisense therapy
Inhibition of Bcl-2
Chemotherapy sensitisation Jansen et al. Piro et al.
Dacarbazine oblimersen Dacarbazine oblimersen
[27] [28]
B-RAF inhibition
Inhibition of RAF proteins
Apoptosis and inhibition of proliferation
Flaherty et al.
Sorafenib alone
[39]
Flaherty et al. Molhoek et al. Flaherty et al.
Sorafenib + carboplatin/paclitaxel [40] Sorafenib + mTOR inhibitor [41] Sorafenib + mTOR inhibitor [42]
CTLA-4 inhibition
Inhibition of the co-stimulatory Induction of tumour autoimmunity CTLA-4 receptor inducing T cell activation
Tchekmeddyian et al. Ipilimumab alone
[48]
Hodi et al. Attia et al. Maker et al.
[49] [50] [51]
Ribas et al.
Ipilimumab alone Ipilimumab + vaccination Ipilimumab + vaccination + interleukin-2 Ticilimumab
[53]
bFGF, basic fibroblast growth factor; VEGF, vascular endothelial growth factor; mTOR, mammalian target of rapamycin; CTLA-4, cytotoxic T lymphocyte-associated antigen 4.
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Drug Discovery Today: Disease Mechanisms | Skin diseases
Figure 1. Targeted therapy of signalling pathways which have shown to be important in malignant melanoma.
The humanised antibody bevacizumab (AvastinTM) is another drug candidate investigating the concept of VEGF inhibition showing synergistic anti-tumour activity in combination with cytotoxic chemotherapy in animal models [22]. There are several ongoing phase II trials in malignant melanoma conducted by the National Cancer Institute, most of them in combination with dacarbazine, paclitaxel or IFNa. One randomised phase II trial in 32 patients with metastatic melanoma evaluating bevacizumab with or without daily low-dose IFN-a-2b yielded one partial remission (in the combination arm) and 8 patients (5 in the bevacizumab alone arm, 3 in the combination arm) with disease stabilisation accounting for an overall response rate of 25% [23].
Bcl-2 antisense therapy Bcl-2 is an anti-apoptotic protein, which has been shown to be increased in up to 80% of all human malignant melanoma cases [24]. It is thought that resistance of melanoma cells against chemotherapy is related to overexpression of Bcl-2 [25]. This idea is supported by data that have shown that the inhibition of Bcl-2 or mutations in MITF, a transcriptional regulator of Bcl-2, increases sensitivity of melanoma cells to chemotherapy [26]. One of the candidates acting as a Bcl-2 inhibitor is oblimersen (G3139, GenasenseTM), an 18-base antisense oligonucleotide that mediates cleavage of Bcl-2 mRNA and thereby induces apoptosis. Several preclinical and clinical studies could demonstrate promising results of
this therapeutic approach. Preclinical results from xenograft models of melanoma were especially encouraging, showing tumour responses in combination with the standard treatment dacarbazine. Therefore, the combination of oblimersen and dacarbazine was tested in a phase I/II study in 14 patients with advanced malignant melanoma resulting in 6 objective responses [27]. The results of an international randomised phase III study comprising 771 patients with metastatic melanoma were even more striking. Patients were either treated with dacarbazine alone or in combination with oblimersen. The combination therapy showed an almost doubling of response rate (13% versus 7%, p = 0.006) as well as a significant prolongation in progression-free survival (78 days versus 49 days, p = 0.0003). However, for the primary endpoint, overall survival, a significant benefit was not seen. Although the combination arm was associated with a higher incidence of adverse events such as neutropenia, thrombocytopenia, nausea and anorexia, the treatment-related mortality rate was the same [28–30]. These results suggest that Bcl2 inhibition by oblimersen may have an important clinical impact in melanoma and many other solid tumours [31]. However, longer follow-up data have to be awaited.
B-RAF inhibition The RAS–RAF–MEK–ERK (MAP kinase) pathway (Fig. 1) seems to be of particular clinical relevance for targeted therapy of malignant melanoma. This pathway is known www.drugdiscoverytoday.com
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to promote proliferation and malignant transformation. RAF proteins are a family of serine/threonine-specific protein kinases that are activated downstream the small Gprotein RAS. Activating mutations of the RAS gene can occur in up to 20% of all human melanoma cases resulting in inhibited apoptosis and continuous cell proliferation [32]. In mammals there are three highly conserved RAF genes, ARAF, B-RAF and C-RAF. Of these different isoforms, B-RAF is mutated in a high proportion of melanomas. Detailed information of the role of B-RAF in melanomas has been summarised in an excellent review [33]. Activating mutations in B-RAF have been found in about two-thirds of all melanoma tumours [34]. Interestingly these mutations occur in melanomas, which arise on sun-exposed sites. Primary lesions of tumours that arise on sun-protected sites usually do not harbour these mutations. These mutations appear to be mutually exclusive suggesting that activation at one stage of the pathway is sufficient to predict in vitro sensitivity to inhibition of MEK, which is the downstream effector molecule of all RAF kinases [35]. However, therapeutic implications resulting from these findings are even more fascinating, because better understanding of genetic lesions in malignant melanoma should lead to further developments in targeted therapies [36]. One potential approach targeting B-RAF in malignant melanoma is the use of the orally available compound sorafenib (BAY 43-9006, NexavarTM), a multikinase inhibitor targeting VEGFR, C-RAF and B-RAF [37]. In a phase I trial sorafenib was well tolerated at a dosage of 400 mg bid [38], so that the 400 mg bid dose was recommended for further clinical phase II/III trials. In a phase II randomised trial with 39 metastatic melanoma patients being treated with sorafenib alone no overall responses were documented, but 19% of pre-treated patients demonstrated stable disease suggesting anti-tumour activity [39]. Trials are currently underway of sorafenib in combination with dacarbazine and carboplatin/ paclitaxel. In a phase I/II trial of sorafenib combined with carboplatin and paclitaxel 35 melanoma patients were treated for more than six weeks resulting in 11 partial remissions and 19 stable diseases [40]. For further investigation of combination therapies, a phase III trial has been initiated by the Eastern Cooperative Oncology Group in which 800 patients will be randomised to carboplatin and paclitaxel with either sorafenib or placebo. Another promising approach is to combine B-RAF signalling inhibitors with other targeted agents such as the mTOR inhibitor rapamycin, because single-agent therapy has probably limited success as cancer cells find alternative pathways for survival and proliferation (Fig. 1) [41]. Sorafenib and rapamycin show a synergistic inhibition of melanoma cell proliferation [42]. Following this approach, there is a phase I/II trial of the combination of sorafenib and CCI-779, an mTOR inhibitor, currently ongoing at the M.D. Anderson Cancer Centre. e66
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Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibition The immune system can recognise and respond to a diversity of targets and antigens. Many tumour cells present self-antigens, and therefore tumours are usually not effectively eliminated by the immune system. This tolerance causes major problems in developing therapeutic strategies involving tumour immunity. Suppressor cells called T regulatory cells seem to play an important role in inducing tolerance and down regulation of immune responses to tumour antigens by expressing a receptor called cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD 125) [43]. CTLA-4 actually inhibits T cell responses in an ongoing immune response by suppressing a co-stimulatory signal, which is important for T cell activation [44]. Preclinically, the role of CTLA-4 could be underlined in CTLA-4 knockout mice developing severe signs of autoimmunity and lethal lymphoproliferative disease with infiltration of multiple organs by activated T cells [45]. By contrast, blockade of CTLA-4 by antibody can lead to the enhancement of T cell responses and to tumour rejection of established tumours in mouse models [46]. CTLA-4 blockade in conjunction with tumour vaccine can further enhance anti-tumour activity [47]. On the basis of these findings, different antibodies blocking CTLA-4 have been developed and clinical trails have been initiated. In a phase I trial, 17 patients with metastatic melanoma were treated with a single intravenous dose of 3 mg/kg of the monoclonal antibody ipilimumab (MDX-010). This study showed that the CTLA-4 antibody was well tolerated providing a basis for further studies [48]. Although the administration of a single dose of ipilimumab to nine melanoma and ovarian cancer patients showed no objective clinical responses, significant tumour necrosis could be demonstrated in three of seven melanoma patients [49]. Because of the mode of action of ipilimumab, a major focus was to determine if this agent could increase the effectiveness of a vaccination therapy. In a phase II study including 56 patients with progressive stage IV melanoma, two different dose schedules of anti-CTLA-4 have been evaluated to explore the relationship between autoimmunity and tumour regression. An overall objective response rate of 13% with two complete and five partial remissions was achieved. Tumour regression was seen in lung, liver, brain, lymph nodes and subcutaneous sites. The authors concluded that administration of antiCTLA-4 monoclonal antibody plus peptide vaccination can cause durable objective responses [50]. The same group recently published a phase I/II study combining this approach with IL-2 therapy. An overall objective response rate of 22% could be seen in 36 patients with ongoing responses at 11–19 months [51]. No major side effects were observed. In 19 melanoma patients immunised with melanoma peptides and treated with escalating doses of MDX-010 enterocolitis and/or autoimmune diseases were seen in 11 patients [52].
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Another candidate binding to and blocking CTLA-4 is ticilimumab (CP-675206). In a phase I trial, the human anti-CTLA-4 monoclonal antibody ticilimumab has been used at escalating doses in patients with solid tumours, the majority of them with melanomas [53]. After a single dose of ticilimumab, 2 of 34 melanoma patients showed complete and 2 others showed partial remissions. Toxicities included dermatitis, colitis and hypophysitis. Interestingly, some patients received additional doses, but none of these patients were converted from clinical non-responders to responders. Another trial studying the side effects and optimal dose of ticilimumab administered with autologous dendritic cells pulsed with MART-1 antigen in treating patients with nonoperable stage III or stage IV melanoma is ongoing. A phase II single arm study to evaluate the efficacy, safety, tolerability and pharmacokinetics of ticilimumab in patients with advanced refractory and/or relapsed melanoma aiming to recruit 215 patients is ongoing. Moreover, a phase III, randomised, comparative study of ticilimumab in combination with either dacarbazine or temozolomide in 630 patients with advanced melanoma is planned and will soon start recruiting. However, there is no justification for superiority of any CTLA-4 antibody. Currently, there are more than ten clinical trials including large phase III studies to further explore the safety and efficacy of CTLA-4 inhibition in the treatment of malignant melanoma. Future clinical development of CTLA4 blockade will undoubtedly focus on enhancing clinical efficacy while reducing treatment-related side effects. There may be a narrow window in which CTLA-4 blockade is most effective with less adverse events and the challenge will be to control its toxicity.
Summary The current treatment options for malignant melanoma are not satisfactory for both patients and clinicians. Singleagent chemotherapy with dacarbazine or other agents has low response rates without any survival benefit. This review gives an overview on the exciting and potentially effective compounds that are targeting new pathways in malignant melanoma. Undoubtedly, the most advanced of these agents is sorafenib (BAY 43-9006, NexavarTM), an oral agent acting as an RAF kinase and VEGFR inhibitor with promising activity being extensively tested in large phase II and III trials. Moreover, safety and efficacy of CTLA-4 inhibition in the treatment of malignant melanoma is extensively studied. Progress is being made in our understanding of the molecular characteristics of these tumours. There is a paradigm shift from broad-spectrum cytotoxic chemotherapy to more specific molecular-targeted therapies. The availability of micro-array technologies offers exciting possibilities to gain new information in understanding tumour biology. The data will substantially
Drug Discovery Today: Disease Mechanisms | Skin diseases
improve our ability to predict the biological behaviour of a tumour as well as to determine which tumours are amenable to specific targeted therapies. This information should in the near future translate into molecularly based therapies that can be incorporated into standard treatment strategies that together will be of increasing benefit to all patients with malignant melanoma.
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Varker, K.A. et al. (2007) A randomized phase 2 trial of bevacizumab with or without daily low-dose interferon alfa-2b in metastatic malignant melanoma. Ann. Surg. Oncol. 14, 2367–2376 Korsmeyer, S.J. (1999) BCL-2 gene family and the regulation of programmed cell death. Cancer Res. 59, 1693–1700 Jansen, B. et al. (1998) Bcl-2 antisense therapy chemosensitizes melanoma in SCID mice. Nat. Med. 4, 232–234 Miller, A. et al. (2004) Transcriptional regulation of the melanoma prognostic marker melastatin (TRPM1) by MITF in melanocytes and melanoma. Cancer Res. 64, 509 Jansen, B. et al. (2000) Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet 356, 1728–1733 Piro, L.D. (2004) Apoptosis, Bcl-2 antisense, and cancer therapy. Oncology 18, 5–10 Stein, C.A. et al. (2005) Antisense strategies for oncogene inactivation. Semin. Oncol. 32, 563–572 Danson, S. and Lorigan, P. (2005) Improving outcomes in advanced malignant melanoma: update on systemic therapy. Drugs 65, 733–743 Ugurel, S. and Schadendorf, D. (2003) Systemic treatment in advanced melanoma: innovative perspectives. Onkologie 26, 234–238 Demunter, A. et al. (2001) A novel N-ras mutation in malignant melanoma is associated with excellent prognosis. Cancer Res. 61, 4916–4922 Gray-Schopfer, V.C. et al. (2005) The role of B-RAF in melanoma. Cancer Metast. Rev. 24, 165–183 Davies, H. et al. (2002) Mutations of the BRAF gene in human cancer. Nature 417, 949–954 Solit, D.B. et al. (2006) BRAF mutation predicts sensitivity to MEK inhibition. Nature 439, 358–362 Curtin, J.A. et al. (2005) Distinct sets of genetic alterations in melanoma. N. Engl. J. Med. 353, 2135–2147 Wilhelm, S.M. et al. (2004) BAY43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64, 7099–7109 Strumberg, D. et al. (2005) Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY-43-9006 in patients with advanced refractory solid tumors. J. Clin. Oncol. 23, 695–972 Eisen, T. et al. (2006) Sorafenib in advanced melanoma: a phase II randomised discontinuation trial analysis. Br. J. Cancer 95, 581–586
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DRUG DISCOVERY
TODAY
Vol. 5, No. 1 2008
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA
DISEASE Skin diseases MECHANISMS
Targeted therapeutic strategies in malignant melanoma Sascha Dietrich, Bernd Kasper* University of Heidelberg, Department of Internal Medicine V, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany
Melanoma is one of the most common cancer types among the Caucasian population. Although prognosis is excellent for patients treated by adequate surgery,
Section Editor: Michael Roberts – School of Medicine, University of Queensland, Australia
advanced disease shrinks the overall survival at five years to less than 10%. The appropriate systemic treat-
antigen (CTLA)-4 monoclonal antibody.
tified candidate genes being involved in malignant melanoma, such as WNT5A and B-RAF. Several tumour suppressors and oncogenes have been shown to be involved in melanoma pathogenesis, including CDKN2A, PTEN, TP53, RAS and MYC. Recently, correlations between molecular biology and survival data have been detected. These developments are beginning to produce therapeutic agents that are impacting clinical practice.
Introduction
Status of current treatment strategies
Malignant melanoma is the most aggressive form of skin cancer causing the majority of deaths. During the past few decades, the incidence of cutaneous melanoma has been rising in both sexes in almost all developed countries [1]. The prognosis of malignant melanoma is related to the disease stage: early stage disease is successfully treated with surgery [2,3]. However, the five-year survival of patients with the spread of disease to regional lymph nodes is only 54% [4], for patients with disseminated melanoma the prognosis is extremely poor with a five-year survival of about 6% [5,6]. Advanced disease is generally refractory to conventional chemotherapy. Therefore, there is much interest in the field in novel therapeutics, especially immunotherapy and targeted therapies. The molecular mechanisms and the genetic markers associated with metastatic dissemination are beginning to be defined. High-throughput technologies have iden-
The appropriate systemic treatment for disseminated melanoma is still a matter of discussion and there are no defined and generally accepted standards. Single-agent therapy with dacarbazine has been the reference treatment for melanoma in several randomised trials. However, only temporary clinical responses but no improvement of patients’ overall survival could be achieved [7,8]. Therefore, temozolomide has been studied as first line therapy. However, patients are treated very differently with mono-chemotherapy, poly-chemotherapy or combined therapy with cytokines. Many patients are treated in experimental trials. The palliative treatment of disseminated melanoma has been excellently reviewed [9]. The only FDA-approved immunological approach in this disease in the past 30 years has been high-dose interferon-alpha (IFN-a) and high-dose bolus interleukin-2 (IL-2) in the metastatic treatment setting, but only a minority of patients benefit from this treatment in terms of long-term survival. Moreover, both agents are associated with
ment for disseminated melanoma is controversial. Therefore, we briefly describe current treatment strategies and focus on four emerging developments: antiangiogenic drugs, Bcl-2 antisense therapy, RAF kinase inhibitors and anti-cytotoxic T lymphocyte-associated
*Corresponding author: B. Kasper ([email protected]) 1740-6765/$ ß 2008 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2008.04.008
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Vol. 5, No. 1 2008
high costs and toxicity rates [10]. Recent studies suggest that a combination of temozolomide and IFN-a may be superior to temozolomide alone [11].
Targeted therapeutic strategies As we have shown consistently, there is no defined and generally accepted standard treatment strategy for advanced melanoma and the appropriate systemic treatment for disseminated melanoma is still a matter of discussion. It is obvious that there is a need to develop new and innovative treatment options. The most promising approaches are antiangiogenic and IMiDs, Bcl-2 antisense therapy, B-RAF inhibition and treatment with cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody, which will be reviewed in this paper and are summarised in Table 1 and Fig. 1.
Antiangiogenic and immunomodulatory drugs Thalidomide was one of the first drugs demonstrating antiangiogenic effects. It inhibits the basic fibroblast growth factor (bFGF) as well as the vascular endothelial growth factor (VEGF) [12]. Other immunomodulatory effects are mediated over the inhibition of NF-kB [13], the alterations of CD8+ and CD4+ T cell function, the stimulation of cytokine production of IL-2 and IFN-g as well as the inhibition of other cytokines such as IL-6 and IL-12 [14]. Although there is a confirmed activity of thalidomide in multiple myeloma, its activity in solid tumours is less prominent. Although thalidomide has neglectable efficacy as monotherapy with no objective response in patients with advanced malignant melanoma [15,16], the combination especially with temozolomide has
recently attracted attention. In a phase II trial with 38 patients without brain metastasis combining temozolomide 75 mg/m2 per day with thalidomide 100–400 mg daily an overall response rate of 32% was reported [17]. In another trial in 60 patients including those with brain metastasis a 15% overall response rate could be demonstrated [18]. One deep venous thrombosis was reported in the first trial, no thrombotic events were seen in the second trial. In a third trial, the same group published a phase II study with 26 patients with brain metastasis using the same combination therapy of temozolomide and thalidomide with an overall response rate of 11%. Four patients experienced grade II thrombotic events [19]. Another phase II study was even stopped after the enrolment of 16 patients, because two patients suddenly died of unknown causes, three patients had pulmonary embolism and a fifth patient had a deep venous thrombosis [20]. It was concluded that the high thrombotic risk is prohibitive of further use of temozolomide and thalidomide in melanoma patients with brain metastasis. Lenalidomide (CC-5013, RevlimidTM) is one of the clinically developed compounds among the thalidomide analogues called immunomodulatory drugs (IMiDs) having the advantage of antiangiogenic properties with less severe side effects compared to thalidomide. A phase I dose-escalating study demonstrated safety and tolerability of lenalidomide in 21 metastatic malignant melanoma patients with three partial remissions [21]. Two phase III trials with lenalidomide in metastatic melanoma have recently stopped recruitment with 272 patients per trial; results from these studies are awaited.
Table 1. Targets and related therapeutic strategies in malignant melanoma Therapeutic strategy
Strategic approach to target
Antiangiogenic/ Inhibition of bFGF/VEGF immunomodulatory 1
Expected outcome of intervention at target
Who is working on the target
Therapies in trial
Refs
Reduction of vessel density and tumour shrinkage
Pawlak et al.
Thalidomide alone
[16]
Hwu et al. Bartlett et al. Varker et al.
Thalidomide + temozolomide Lenalidomide Bevacizumab interferon-alpha
[17–20] [21] [23]
Bcl-2 antisense therapy
Inhibition of Bcl-2
Chemotherapy sensitisation Jansen et al. Piro et al.
Dacarbazine oblimersen Dacarbazine oblimersen
[27] [28]
B-RAF inhibition
Inhibition of RAF proteins
Apoptosis and inhibition of proliferation
Flaherty et al.
Sorafenib alone
[39]
Flaherty et al. Molhoek et al. Flaherty et al.
Sorafenib + carboplatin/paclitaxel [40] Sorafenib + mTOR inhibitor [41] Sorafenib + mTOR inhibitor [42]
CTLA-4 inhibition
Inhibition of the co-stimulatory Induction of tumour autoimmunity CTLA-4 receptor inducing T cell activation
Tchekmeddyian et al. Ipilimumab alone
[48]
Hodi et al. Attia et al. Maker et al.
[49] [50] [51]
Ribas et al.
Ipilimumab alone Ipilimumab + vaccination Ipilimumab + vaccination + interleukin-2 Ticilimumab
[53]
bFGF, basic fibroblast growth factor; VEGF, vascular endothelial growth factor; mTOR, mammalian target of rapamycin; CTLA-4, cytotoxic T lymphocyte-associated antigen 4.
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Figure 1. Targeted therapy of signalling pathways which have shown to be important in malignant melanoma.
The humanised antibody bevacizumab (AvastinTM) is another drug candidate investigating the concept of VEGF inhibition showing synergistic anti-tumour activity in combination with cytotoxic chemotherapy in animal models [22]. There are several ongoing phase II trials in malignant melanoma conducted by the National Cancer Institute, most of them in combination with dacarbazine, paclitaxel or IFNa. One randomised phase II trial in 32 patients with metastatic melanoma evaluating bevacizumab with or without daily low-dose IFN-a-2b yielded one partial remission (in the combination arm) and 8 patients (5 in the bevacizumab alone arm, 3 in the combination arm) with disease stabilisation accounting for an overall response rate of 25% [23].
Bcl-2 antisense therapy Bcl-2 is an anti-apoptotic protein, which has been shown to be increased in up to 80% of all human malignant melanoma cases [24]. It is thought that resistance of melanoma cells against chemotherapy is related to overexpression of Bcl-2 [25]. This idea is supported by data that have shown that the inhibition of Bcl-2 or mutations in MITF, a transcriptional regulator of Bcl-2, increases sensitivity of melanoma cells to chemotherapy [26]. One of the candidates acting as a Bcl-2 inhibitor is oblimersen (G3139, GenasenseTM), an 18-base antisense oligonucleotide that mediates cleavage of Bcl-2 mRNA and thereby induces apoptosis. Several preclinical and clinical studies could demonstrate promising results of
this therapeutic approach. Preclinical results from xenograft models of melanoma were especially encouraging, showing tumour responses in combination with the standard treatment dacarbazine. Therefore, the combination of oblimersen and dacarbazine was tested in a phase I/II study in 14 patients with advanced malignant melanoma resulting in 6 objective responses [27]. The results of an international randomised phase III study comprising 771 patients with metastatic melanoma were even more striking. Patients were either treated with dacarbazine alone or in combination with oblimersen. The combination therapy showed an almost doubling of response rate (13% versus 7%, p = 0.006) as well as a significant prolongation in progression-free survival (78 days versus 49 days, p = 0.0003). However, for the primary endpoint, overall survival, a significant benefit was not seen. Although the combination arm was associated with a higher incidence of adverse events such as neutropenia, thrombocytopenia, nausea and anorexia, the treatment-related mortality rate was the same [28–30]. These results suggest that Bcl2 inhibition by oblimersen may have an important clinical impact in melanoma and many other solid tumours [31]. However, longer follow-up data have to be awaited.
B-RAF inhibition The RAS–RAF–MEK–ERK (MAP kinase) pathway (Fig. 1) seems to be of particular clinical relevance for targeted therapy of malignant melanoma. This pathway is known www.drugdiscoverytoday.com
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to promote proliferation and malignant transformation. RAF proteins are a family of serine/threonine-specific protein kinases that are activated downstream the small Gprotein RAS. Activating mutations of the RAS gene can occur in up to 20% of all human melanoma cases resulting in inhibited apoptosis and continuous cell proliferation [32]. In mammals there are three highly conserved RAF genes, ARAF, B-RAF and C-RAF. Of these different isoforms, B-RAF is mutated in a high proportion of melanomas. Detailed information of the role of B-RAF in melanomas has been summarised in an excellent review [33]. Activating mutations in B-RAF have been found in about two-thirds of all melanoma tumours [34]. Interestingly these mutations occur in melanomas, which arise on sun-exposed sites. Primary lesions of tumours that arise on sun-protected sites usually do not harbour these mutations. These mutations appear to be mutually exclusive suggesting that activation at one stage of the pathway is sufficient to predict in vitro sensitivity to inhibition of MEK, which is the downstream effector molecule of all RAF kinases [35]. However, therapeutic implications resulting from these findings are even more fascinating, because better understanding of genetic lesions in malignant melanoma should lead to further developments in targeted therapies [36]. One potential approach targeting B-RAF in malignant melanoma is the use of the orally available compound sorafenib (BAY 43-9006, NexavarTM), a multikinase inhibitor targeting VEGFR, C-RAF and B-RAF [37]. In a phase I trial sorafenib was well tolerated at a dosage of 400 mg bid [38], so that the 400 mg bid dose was recommended for further clinical phase II/III trials. In a phase II randomised trial with 39 metastatic melanoma patients being treated with sorafenib alone no overall responses were documented, but 19% of pre-treated patients demonstrated stable disease suggesting anti-tumour activity [39]. Trials are currently underway of sorafenib in combination with dacarbazine and carboplatin/ paclitaxel. In a phase I/II trial of sorafenib combined with carboplatin and paclitaxel 35 melanoma patients were treated for more than six weeks resulting in 11 partial remissions and 19 stable diseases [40]. For further investigation of combination therapies, a phase III trial has been initiated by the Eastern Cooperative Oncology Group in which 800 patients will be randomised to carboplatin and paclitaxel with either sorafenib or placebo. Another promising approach is to combine B-RAF signalling inhibitors with other targeted agents such as the mTOR inhibitor rapamycin, because single-agent therapy has probably limited success as cancer cells find alternative pathways for survival and proliferation (Fig. 1) [41]. Sorafenib and rapamycin show a synergistic inhibition of melanoma cell proliferation [42]. Following this approach, there is a phase I/II trial of the combination of sorafenib and CCI-779, an mTOR inhibitor, currently ongoing at the M.D. Anderson Cancer Centre. e66
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Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibition The immune system can recognise and respond to a diversity of targets and antigens. Many tumour cells present self-antigens, and therefore tumours are usually not effectively eliminated by the immune system. This tolerance causes major problems in developing therapeutic strategies involving tumour immunity. Suppressor cells called T regulatory cells seem to play an important role in inducing tolerance and down regulation of immune responses to tumour antigens by expressing a receptor called cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, CD 125) [43]. CTLA-4 actually inhibits T cell responses in an ongoing immune response by suppressing a co-stimulatory signal, which is important for T cell activation [44]. Preclinically, the role of CTLA-4 could be underlined in CTLA-4 knockout mice developing severe signs of autoimmunity and lethal lymphoproliferative disease with infiltration of multiple organs by activated T cells [45]. By contrast, blockade of CTLA-4 by antibody can lead to the enhancement of T cell responses and to tumour rejection of established tumours in mouse models [46]. CTLA-4 blockade in conjunction with tumour vaccine can further enhance anti-tumour activity [47]. On the basis of these findings, different antibodies blocking CTLA-4 have been developed and clinical trails have been initiated. In a phase I trial, 17 patients with metastatic melanoma were treated with a single intravenous dose of 3 mg/kg of the monoclonal antibody ipilimumab (MDX-010). This study showed that the CTLA-4 antibody was well tolerated providing a basis for further studies [48]. Although the administration of a single dose of ipilimumab to nine melanoma and ovarian cancer patients showed no objective clinical responses, significant tumour necrosis could be demonstrated in three of seven melanoma patients [49]. Because of the mode of action of ipilimumab, a major focus was to determine if this agent could increase the effectiveness of a vaccination therapy. In a phase II study including 56 patients with progressive stage IV melanoma, two different dose schedules of anti-CTLA-4 have been evaluated to explore the relationship between autoimmunity and tumour regression. An overall objective response rate of 13% with two complete and five partial remissions was achieved. Tumour regression was seen in lung, liver, brain, lymph nodes and subcutaneous sites. The authors concluded that administration of antiCTLA-4 monoclonal antibody plus peptide vaccination can cause durable objective responses [50]. The same group recently published a phase I/II study combining this approach with IL-2 therapy. An overall objective response rate of 22% could be seen in 36 patients with ongoing responses at 11–19 months [51]. No major side effects were observed. In 19 melanoma patients immunised with melanoma peptides and treated with escalating doses of MDX-010 enterocolitis and/or autoimmune diseases were seen in 11 patients [52].
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Another candidate binding to and blocking CTLA-4 is ticilimumab (CP-675206). In a phase I trial, the human anti-CTLA-4 monoclonal antibody ticilimumab has been used at escalating doses in patients with solid tumours, the majority of them with melanomas [53]. After a single dose of ticilimumab, 2 of 34 melanoma patients showed complete and 2 others showed partial remissions. Toxicities included dermatitis, colitis and hypophysitis. Interestingly, some patients received additional doses, but none of these patients were converted from clinical non-responders to responders. Another trial studying the side effects and optimal dose of ticilimumab administered with autologous dendritic cells pulsed with MART-1 antigen in treating patients with nonoperable stage III or stage IV melanoma is ongoing. A phase II single arm study to evaluate the efficacy, safety, tolerability and pharmacokinetics of ticilimumab in patients with advanced refractory and/or relapsed melanoma aiming to recruit 215 patients is ongoing. Moreover, a phase III, randomised, comparative study of ticilimumab in combination with either dacarbazine or temozolomide in 630 patients with advanced melanoma is planned and will soon start recruiting. However, there is no justification for superiority of any CTLA-4 antibody. Currently, there are more than ten clinical trials including large phase III studies to further explore the safety and efficacy of CTLA-4 inhibition in the treatment of malignant melanoma. Future clinical development of CTLA4 blockade will undoubtedly focus on enhancing clinical efficacy while reducing treatment-related side effects. There may be a narrow window in which CTLA-4 blockade is most effective with less adverse events and the challenge will be to control its toxicity.
Summary The current treatment options for malignant melanoma are not satisfactory for both patients and clinicians. Singleagent chemotherapy with dacarbazine or other agents has low response rates without any survival benefit. This review gives an overview on the exciting and potentially effective compounds that are targeting new pathways in malignant melanoma. Undoubtedly, the most advanced of these agents is sorafenib (BAY 43-9006, NexavarTM), an oral agent acting as an RAF kinase and VEGFR inhibitor with promising activity being extensively tested in large phase II and III trials. Moreover, safety and efficacy of CTLA-4 inhibition in the treatment of malignant melanoma is extensively studied. Progress is being made in our understanding of the molecular characteristics of these tumours. There is a paradigm shift from broad-spectrum cytotoxic chemotherapy to more specific molecular-targeted therapies. The availability of micro-array technologies offers exciting possibilities to gain new information in understanding tumour biology. The data will substantially
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improve our ability to predict the biological behaviour of a tumour as well as to determine which tumours are amenable to specific targeted therapies. This information should in the near future translate into molecularly based therapies that can be incorporated into standard treatment strategies that together will be of increasing benefit to all patients with malignant melanoma.
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