Novel Therapeutics for Melanoma

Nagashree Seetharamu; Patrick A Ott; Anna C Pavlick


Expert Rev Anticancer Ther. 2009;9(6):839-849. 

In This Article

Agents Targeting the MAPK and mTOR Pathways

The RAF/MEK/ERK pathway (Figure 1) is an important regulator of growth, survival and migration and it is constitutively activated in many human cancers.[20] Physiologically, this pathway is activated upon binding of extracellular ligands to growth factor receptors with intrinsic tyrosine kinase activity, such as the EGF receptor (EGFR), c-kit, PDGF receptor (PDGFR), VEGF receptor (VEGFR) and FGF receptor (FGFR). Signaling through the RAF/MEK/ERK pathway eventually leads to the transcription of hundreds if not thousands of genes related to cellular proliferation, survival and motility (Figure 1).[21] In melanoma, there has been an increasing interest in the RAF/MEK/ERK pathway since 2002, when Davies et al. first reported that 66% of melanomas harbor activating somatic missense mutations in the BRAF gene (V600E), leading to constitutive activation of this pathway.[22,23,24] Several other tumor-suppressor genes and oncogenes are known to be involved in melanoma pathogenesis, likely leading to functional redundancy of different signaling pathways. Moreover, studies have shown that a high proportion of melanomas carry alterations in the PI3K/AKT pathway (PTEN deletion or AKT amplification) in addition to the BRAFV600E mutation. These findings, in conjunction with preclinical evidence for synergy between MAPK and PI3K inhibition,[25] provide a strong rationale for combination therapy with targeted agents or the use of multi-target inhibitors in the treatment of melanoma.[26,27]

Figure 1.

MAPK and PI3K pathways. Binding of ligands, such as growth factors, to their respective receptors results in receptor dimerization and activation of tyrosine kinases, which in turn triggers a cascade of phosphorylation events (Ras/Raf/MEK/ERK). Alternatively, in melanoma cells the pathway can be constitutively activated. Activated ERK translocates into the nucleus where it phosphorylates specific transcription factors that are involved in the regulation of various key cellular processes. The PI3K/Akt/mTOR pathway is another cascading pathway that can be activated in melanoma, mostly as a result of PTEN deletion (PTEN is a natural inhibitor of the upstream PI3k/Akt). (1) Sorafenib; (2) TKI258; (3) AG-013736; (4) bevacizumab; (5) imatinib; (6) specific blockers of BRAF (PLX4720/PLX 4032/RAF-265); (7) MEK inhibitors (AZD6244/PD-325901); (8) mTOR inhibitor (RAD-001). EGFR: EGF receptor; FGFR: FGF receptor; FLIT-3: FMS-related tyrosine kinase-3; PDGFR: PDGF receptor; PI3 kinase: Phosphatidylinositol-3-kinase; PTEN: Phosphatase and tensin homologue tumor suppressor; RTK: Receptor tyrosine kinase; VEGFR: VEGF receptor.

The drug that is most advanced in clinical trial development in this category is sorafenib (BAY 43-9006), a small-molecule, multi-targeted tyrosine kinase inhibitor that blocks EGFR, c-kit, PDGF and VEGF in addition to BRAF.[28,29] Although sorafenib does not have meaningful activity in melanoma as a single agent,[30] its use in combination with dacarbazine or temozolomide led to superior objective responses and progression-free survival (PFS) compared with historical RRs to these agents.[31] In the first-line setting, a Phase I/II study of sorafenib in combination with carboplatin and paclitaxel reported a RR of 27% and included one complete response (CR), with 73% still demonstrating a response at 6 months.[32] An NCI-sponsored Phase III randomized trial (E2603) comparing carboplatin, paclitaxel and sorafenib versus carboplatin, paclitaxel and placebo in chemotherapy-naive patients recently completed accrual and a futility analysis demonstrated no benefit of the three drug combination compared to the two drug chemotherapy combination, so the trial was terminated early. In the 270 patient, Phase III PRISM study, the addition of sorafenib to the combination of paclitaxel and carboplatin as second-line treatment after chemotherapy with dacarbazine or temozolomide failed to improve PFS, tumor RRs or time-to-disease progression in metastatic melanoma patients.[33] A randomized, 17-center, Phase II study of 101 chemotherapy-naive patients showed a 50% improvement in PFS and a 62% improvement in time-to-progression when sorafenib was added to dacarbazine compared with dacarbazine plus placebo.[34]

TKI258 (Chir-258, Novartis, Switzerland) is an oral multitargeted receptor tyrosine kinase inhibitor with a unique inhibition profile for receptor tyrosine kinases and is currently being tested in a Phase II clinical trial for metastatic melanoma. The Phase I dose-escalating trial in patients with advanced solid tumors defined the maximum tolerated dose as 125 mg daily and showed that the agent has activity in melanoma.[35] Phase II results of axitinib (AG-013736), another potent pan-VEGFR and PDGFR kinase inhibitor were presented at the 2008 American Society of Clinical Oncology (ASCO) meeting. Among 32 enrolled patients, many of whom were previously treated and 75% of whom had stage M1c, there was an objective RR of 19% (six out of 32 patients) with an additional 28% of the patients having SD and 30% being progression-free at 6 months.[36] Sunitinib, which inhibits c-kit in addition to other tyrosine kinases, was studied in patients with heavily pretreated metastatic uveal melanoma (c-kit is hyper-expressed in most of these patients). Of 15 patients treated, one had a PR and ten had SD.[37]

Anti-angiogenic strategies are less well studied in melanoma compared with some other tumor types. VEGF is a fundamental regulator of tumor angiogenesis and its expression is an independent predictive factor of OS in melanoma.[38] Many different mechanisms for the effects of anti-angiogenic therapy have been postulated. Inhibition of new blood vessel growth and vasoconstriction with significant reduction in tumor blood flow, induction of endothelial cell apoptosis and reduced interstitial pressure have been demonstrated. The aforementioned small-molecule tyrosine kinase inhibitors sorafenib, sunitinib, TKI258 and axitinib all inhibit VEGF among a number of other molecules. Antibodies against VEGF, such as bevacizumab, and soluble decoy receptors, such as VEGF-TRAP, specifically target angiogenesis and have been shown to improve OS in colon, lung and breast cancer. In advanced melanoma, bevacizumab was tested in combination with carboplatin and paclitaxel in a two-stage Phase II clinical trial. A PR of 17% (nine out of 53) and SD of 57% at 8 weeks were demonstrated in this study. The combination appeared to be moderately well tolerated and clinically beneficial in patients with metastatic melanoma.[39] SU5416, a preferential inhibitor of the receptor tyrosine kinase Flk-1 (mediator of VEGF activity), was studied in a Phase II trial for metastatic melanoma that enrolled 31 patients.[40] This agent demonstrated modest clinical activity with one PR and one SD; decreased tumor vascularity on dynamic contrast imaging studies was seen in five patients.

Imatinib is a selective tyrosine kinase inhibitor with multiple targets, including c-kit and PDGR receptors, and has shown to be highly efficacious in chronic myelogenous leukemia and GIST tumors.[41] Initial Phase II trials with this agent in melanoma were disappointing with no objective RRs in 41 patients.[42,43] However, gain of function mutations, gene amplifications and overexpression of c-kit, a receptor tyrosine kinase and one of the main targets of imatinib, were recently reported in 30-40% of mucosal, acral and cutaneous melanomas with chronic sun damage.[44] Impressive tumor regression was reported in a patient with mucosal melanoma who carried a mutation in the juxtamembranous domain of c-kit (exon 11) and was treated with single agent imatinib.[45] This observation is substantiated by anecdotal reports of objective response with imatinib in patients with advanced mucosal and acral melanoma. Moreover, preclinical studies showed sensitivity of c-kit mutant mucosal melanoma, providing a rationale for imatinib in this melanoma type, particularly if c-kit is mutated. Two Phase II studies investigating response to imatinib in advanced melanoma patients harboring somatic alterations of c-kit are currently ongoing at several institutions to confirm these observations. Another Phase I/II study to define safety and efficacy of imatinib in combination with temozolomide in patients with unresectable, stage III/IV melanoma is also currently underway. After the data on c-kit alterations became available when the trial was already in progress, patients with mucosal, acral and chronic sun damage melanomas were preferentially enrolled in the Phase II part of the study. Early results of the trial were presented at ASCO 2008.[46] Of the 23 patients treated, 16 had been enrolled in Phase I and seven in Phase II. The combination therapy was well tolerated and demonstrated anti-tumor activity in melanoma. Of the seven patients treated in the Phase II trial, one patient had a CR and six had PRs.[46]

Several other agents targeting the RAF/MEK/ERK pathway are now in various stages of clinical development in advanced melanoma. New compounds with higher selectivity and potency for BRAF blockade, PLX4720 and PLX4032, have recently been discovered and are in preclinical and early clinical development.[47,48] PLX4032 is being studied as single agent in a Phase I trial in metastatic melanoma patients.[96] PLX4720 has a high selectivity for the wild-type BRAF kinase and an even higher selectivity for the BRAFV600E mutated allele (IC50 1/10th compared with wild type), possibly rendering it a true tumor-specific targeted agent in BRAFV600E mutated melanoma. RAF-265 (CHIR-265, Novartis, Switzerland) is another agent that has demonstrated selective and potent BRAF inhibition of wild-type and V600E-mutated BRAF in melanoma cell lines, in addition to blockade of VEGFR-2.[49] This drug is currently being tested in a Phase I trial in metastatic melanoma in the USA.

The serine/threonine tyrosine kinase MEK acts downstream from RAF in the RAF/MEK/ERK pathway; its inhibition is an attractive anticancer strategy as it has the potential to block upregulated signal transduction through this pathway, regardless of the upstream position of the oncogenic aberration. Intriguingly, in preclinical experiments, melanoma cell lines carrying the BRAFV600E mutation were particularly sensitive to MEK inhibition compared with wild-type and NRAS-mutated cell lines. Several MEK inhibitors are in different phases of clinical trials. AZD6244 (ARRY-142886, Array BioPharma, AstraZeneca) is an oral MEK inhibitor that has demonstrated target inhibition at tumor sites at tolerable doses in a Phase I study.[50] This led to a Phase II trial of AZD6244 versus temozolomide in chemotherapy-naive advanced melanoma patients, the results of which were presented at the 2008 ASCO meeting.[51] A total of 200 patients were enrolled with 104 and 96 patients randomized to AZD6244 and temozolomide, respectively; those who progressed on temozolomide could crossover to AZD6244. Tissue samples from study participants were obtained for both BRAFV600E and NRAS mutation analysis. Of 179 patients with non-uveal melanoma, 50% had BRAF mutations; 68% carried mutations of either BRAF or NRAS. There was no difference in the two treatment arms in terms of PFS (hazard ratio [HR]: 1.07) or OS (HR: 1.21). When only patients with BRAF mutations were included in the analysis, the HR for OS favored the AZD6244 group.[51] A Phase I/II trial with another MEK inhibitor, PD-325901, which showed activity in melanoma in a Phase I study, was prematurely terminated due to toxicity concerns.[52]

The PI3K/AKT-mTOR signaling pathway is an alternate pathway that appears to play a role in melanoma development and progression.[53] mTOR, a key modulator of this pathway, is a serine/threonine kinase that effectively regulates the production of VEGF, cell growth and proliferation (Figure 1). The first planned interim analysis results of a Phase II study assessing RAD-001 (everolimus), an oral mTOR inhibitor, in metastatic melanoma patients was presented at the 2007 ASCO meeting. The analysis, carried out on 20 patients with metastatic melanoma, showed no objective responses but 35% had SD.[54] Because of the benign toxicity profile and somewhat encouraging anti-tumor activity, a second cohort of 20 patients was enrolled on a higher dose of RAD-001. However, the interim analysis of this cohort demonstrated significantly more toxicity and no additional clinical efficacy.[55]


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