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Advances in Targeted Therapy for Melanoma: a Focus on MEK Inhibition

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Advances in Targeted Therapy for Melanoma: a Focus on MEK Inhibition Review: Clinical Trial Outcomes Salama & Kim Advances in targeted therapy for melanoma: a focus on MEK inhibition 6 Review: Clinical Trial Outcomes Advances in targeted therapy for melanoma: a focus on MEK inhibition Clin. Investig. (Lond.) Increased knowledge of the role that dysregulated MAPK signaling plays in melanoma April KS Salama*,1 & Kevin B has opened the door for novel therapeutic strategies, among them MEK-targeted Kim2 approaches. With the recent approval of the selective MEK inhibitor trametinib, both 1Division of Medical Oncology, Duke University Medical Center, DUMC 3198, as a single agent and in combination with dabrafenib for patients with BRAF-mutant Durham, NC 27710, USA metastatic melanoma, MEK-based therapy now has a place as a standard of care 2Department of Melanoma Medical option for the treatment of this disease. Early data suggest a benefit of MEK inhibition Oncology, The University of Texas MD in other melanoma subtypes as well, including NRAS-mutant and uveal melanoma. Anderson Cancer Center, 1515 Holcombe This review summarizes the clinical development and the currently available data Blvd, Houston, TX 77030, USA *Author for correspondence: regarding the role of MEK inhibitor therapy in the treatment of advanced melanoma. Tel.: +1 919 681 6932 Fax: +1 919 684 5163 Keywords: BRAF • MAPK pathway • MEK • melanoma • NRAS • targeted therapy • uveal [email protected] melanoma While there have been numerous advances growth and proliferation, and represents an in systemic therapy for the treatment of attractive target for therapeutic intervention metastatic melanoma in recent years, for [7]. First identified in a screen of cell lines and most patients it remains an incurable dis- melanoma specimens in 2002, the majority ease [1] . Notably, since 2011, there have of BRAF mutations in melanoma result from 10.4155/CLI.14.76 been US FDA approvals for four new agents the substitution of a glutamic acid for a valine used to treat metastatic disease, three of (V600E), though other variants exist [2]. It is which – vemurafenib (PLX4032; RG7204), now known that this change results in a con- dabrafenib (GSK2118436) and trametinib stitutively active kinase with resultant per- (GSK1120212) – target aberrant MAPK sistent downstream activation of the MAPK pathway signaling. The identification of pathway [8]. The subsequent development of 19 mutated BRAF as a major driver of oncogen- the selective BRAF inhibitors vemurafenib esis in approximately half of all melanomas, and dabrafenib represented a landmark break- and the resultant successful clinical devel- through in the treatment of metastatic mela- opment of selective BRAF inhibitors has noma [3,4]. Vemurafenib, the first molecular 2014 opened the door for novel agents that target targeted agent to receive regulatory approval this pathway [2–4]. Among these are MEK in 2011, has demonstrated an overall survival targeted therapies, and while MEK inhibi- advantage in a Phase III study when com- tors have been in development for some time, pared with chemotherapy in patients with V600E recent evidence of early clinical activity in BRAF melanoma [3,9]. Dabrafenib has many tumor types, including thyroid and also been shown to improve progression-free ovarian cancer, as well as specific subsets of survival (PFS) when compared with dacarba- melanoma has provided a platform for the zine in a randomized Phase III trial [4]. High continued expansion of possible treatment response rates coupled with the potential for options [5,6]. a relatively rapid response make these agents The RAS-RAF-MEK signaling cascade particularly useful for patients with symp- is an integral component in regulating cell tomatic or rapidly progressive disease. How- part of 10.4155/CLI.14.76 © 2014 Future Science Ltd Clin. Investig. (Lond.) (2014) 6(19), 903–913 ISSN 2041-6792 903 Review: Clinical Trial Outcomes Salama & Kim ever, like many systemic agents for the treatment of Figures 1 & 2 highlight some of the potential media- advanced cancer, limitations exist due to the emergence tors involved in this process. Additionally, treatment of resistance as well as toxicity. On average, responses with these agents is uniquely associated with the devel- with BRAF inhibitor monotherapy last 6–7 months, opment of hyperproliferative skin lesions, including and most patients relapse within a year of starting treat- squamous cell carcinomas (SCCs), largely attributed ment [4,9–11] . The development of resistance is a multi- to persistent MAPK signaling through RAS mediated factorial process, though MAPK reactivation through paradoxical activation of other RAF isoforms [22]. different mechanisms appears to play a key role [12–21] . The hypothesis that MEK inhibition in melanoma has the potential to have a meaningful clinical benefit Receptor tyrosine has now come full circle. In 2013, the MEK inhibitor kinase trametinib was approved as monotherapy for the treat- ment of patients with metastatic BRAFV600 melanoma, and the approval of its use in combination with dab- rafenib in this same population came in early 2014. Subsequent studies have continued to build upon the understanding of the molecular pathogenesis of mela- Cell membrane NRASmut RAS noma. In addition to having a role in BRAF-mutated melanoma, it is also becoming apparent that other dis- Dabrafenib tinct subsets, including NRAS mutated and uveal mela- CRAF Vemurafenib LGX818 noma may also be susceptible to targeting this pathway. This review aims to summarize the history of MEK COT MEK inhibitor development in melanoma, the current role in clinical practice as well as future therapeutic strategies. MEKmut ERK Early MEK inhibitor development As the MAPK pathway plays an integral role in reg- ulating cell growth and proliferation, there has long Sustained proliferation and been an interest in targeting this pathway for thera- suppression of apoptosis peutic benefit. One of the first MEK inhibitors to enter Figure 1. Potential mechanisms of resistance to clinical testing included the non-ATP-competitive selective BRAF inhibition that are dependent on MAPK MEK 1/2 inhibitor CI-1040. CI-1040 is highly selec- pathway activation/MEK signaling. tive for MEK, and acts to form a bond at a hydropho- Receptor tyrosine bic binding pocket on MEK 1/2. This induces a con- kinase formational change in unphosphorylated MEK, and essentially locks the protein in its inactive state [23] An initial dose escalation study that included patients with a variety of solid tumors, including melanoma, estab- lished that CI-1040 could be safely administered, but subsequent studies failed to demonstrate clinical effi- Cell membrane NRASmut RAS cacy [23,24]. PD-0325901 is a second-generation MEK inhibitor that had a more favorable pharmacokinetic Dabrafenib profile than CI-1040, and demonstrated promising CRAF Vemurafenib preclinical activity [25,26]. In early phase testing, there LGX818 was some signal of potential clinical activity with a Selumetinib CI-1040 COT few partial responses (PRs) and stable disease seen in Trametinib PD-0325901 Cobimetinib MEK162 some of the melanoma patients that were treated [27,28]. Pimasertib However, there were a number of concerning toxicities MEKmut ERK noted, including neurologic effects as well as retinal vein occlusion. With this concern, development of this agent was subsequently suspended. Growth inhibition Selumetinib Figure 2. MEK targeted strategies provide a mechanism Selumetinib (ARRY-142886; AZD-6244) is a second- to overcome selected mediators of resistance. generation, highly selective MEK 1/2 inhibitor that 904 Clin. Investig. (Lond.) (2014) 6(19) future science group Advances in targeted therapy for melanoma: a focus on MEK inhibition Review: Clinical Trial Outcomes has recently shown some promising results in later generation MEK inhibitors, but it is unique in that it phase clinical trials for patients with metastatic mel- has a favorable mean peak:trough ratio, making once anoma, particularly with a newer formulation of the daily dosing feasible [34,35]. Initial clinical trials with drug. Initial preclinical work and molecular model- trametinib yielded promising results, and established ing data showed that selumetinib was able to bind the 2 mg daily as the recommended dose to move forward allosteric inhibitor site on MEK 1/2, rendering it cata- in subsequent studies on the basis of pharmacokinetic, lytically inactive. Early phase testing of the free base pharmacodymic, long-term safety and preliminary formulation of selumetinib established 100 mg b.i.d. efficacy data although the MTD administered was 3 as the dose to pursue in subsequent studies, largely due mg daily [35]. Multiple tumor types were treated in this to cutaneous toxicity seen at higher doses [29]. How- Phase I study, with an overall response rate of approxi- ever, in a Phase II study using the initial formulation mately 10%, however, BRAF mutant melanoma of the drug in which patients with advanced melanoma appeared to be a particularly sensitive subset. A total of were randomized to receive either selumetinib or temo- 97 patients with melanoma were enrolled, 36 of which zolomide, response rates were similar and there was no had BRAF mutant tumors [36]. In a separate analysis of improvement in PFS in the selumetinib arm [30]. In the cohort of melanoma patients, the 30 patients with this study, median progression free survival (PFS) was BRAF mutant disease that had never received BRAF only 78 days and the response rate was 5.8% for those inhibitor therapy had an overall unconfirmed response who received selumetinib treatment, and even among rate (complete response (CR) + PR) of 40%, with a patients with BRAF mutant melanoma, the response median PFS of 5.7 months [36]. Additionally, of the six rate was 11%. Subsequent studies using a hydrogen sul- patients with BRAF mutant melanoma that had previ- fate formulation, which appears to have a more favor- ously received a BRAF inhibitor, one had a PR and able pharmacokinetic profile, have demonstrated more four had stable disease. Overall, trametinib appeared promising results [31] . Phase I studies have established to be well tolerated, with the most common adverse 75 mg b.i.d.
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