Prospects for MEK inhibitors for treating cancer.

Review

Prospects for MEK inhibitors for treating cancer

Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Toronto on 03/07/15 For personal use only.

Juan Martin-Liberal, Laura Lagares-Tena & James Larkin† †

The Royal Marsden Hospital, London, UK

1.

Introduction

2.

Alterations of MAPK pathway in cancer

3.

MEK inhibitors

4.

Conclusion

5.

Expert opinion

Introduction: The MAPK pathway is a signaling network that plays a key role in many normal cellular processes and in a large number of human malignancies. One of its effectors, MEK, is essential for the carcinogenesis of different tumors. In recent years, several drugs able to inhibit MEK have been assessed in clinical trials. Trametinib has recently become the first MEK inhibitor licensed for cancer treatment (advanced melanoma). Areas covered: We comprehensively review the safety and clinical efficacy of the family of MEK inhibitors, either alone or in combination with other drugs. We discuss data ranging from the Phase III trial of trametinib in melanoma to the most recent drugs with early signs of antitumor activity. In addition, we explain the reasons for the unsuccessful results of the early trials with MEK inhibitors and provide a view of their role in cancer treatment in forthcoming years. Expert opinion: MEK inhibitors are a potentially safe and active treatment option for the treatment of many human malignancies. The information provided by a large series of studies currently ongoing will be very valuable in order to optimize their use. Adequate selection of patients is crucial for achieving successful results with these compounds. Keywords: MEK, mitogen-activated protein kinase, RAF, trametinib Expert Opin. Drug Saf. (2014) 13(4):483-495

1.

Introduction

The RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway is a complex network that regulates a large number of physiological functions in normal cells [1]. The cascade of phosphorylations and other interactions among the different proteins that form it make possible the transduction of signals from extracellular ligands such as hormones or cytokines. This impacts cell growth, proliferation, and other essential processes [2]. The importance of this pathway in cancer was first reported in the 1980s [3-5]. Since then, many different alterations have been described and their role in the carcinogenesis of some human malignancies is becoming more evident [6]. Thus, melanoma, thyroid cancer, and colon cancer, among many others, have been found to be somehow driven by alterations in the MAPK pathway [7]. Overall, activating point mutations of the RAS family genes (HRAS, KRAS, and NRAS) have been described in up to 30% of all human cancers [6], and the RAF isoform BRAF has been found to be mutated in 20% of all malignancies [7]. The recent development of different drugs able to inhibit some MAPK effectors, such as BRAF has revolutionized a number of tumors, especially melanoma [8]. Thus, the survival of a melanoma patient before the appearance of the new targeted therapies was around 9 months, while with the BRAF inhibitor vemurafenib the overall survival (OS) in the advanced setting is more than 1 year [9]. Successful results with compounds that inhibit other MAPK pathway proteins such as MEK have been reported only recently [10,11]. The data available to date are highly encouraging and one of these drugs, trametinib, has become the first MEK inhibitor licensed for the treatment of cancer [12]. Unfortunately, these new treatments are 10.1517/14740338.2014.892578 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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The MAPK pathway is a complex signaling network that regulates many cellular processes. Abnormalities in some of its components are associated with the development of many human malignancies. The inhibition of MEK is a promising therapeutic strategy for the treatment of tumors in which the MAPK pathway is altered. A number of early Phase II trials with MEK inhibitors failed to reach their efficacy goals. Incorrect selection of patients, without considering the mutational status of their tumors, was responsible for these unsuccessful results. In recent years, new clinical trials with adequate selection of patients have been conducted. Trametinib has become the first MEK inhibitor licensed thanks to the positive results achieved in a Phase III trial in BRAF-mutated melanoma. MEK inhibitors are generally well-tolerated drugs either alone or in combination with other compounds. A large number of clinical trials with MEK inhibitors in a wide range of tumors are currently ongoing.

This box summarizes key points contained in the article.

also associated with new side effects [13]. The increasing use of these compounds makes necessary the correct identification and management of these toxicities to maintain the quality of life of patients. The aim of this article is to extensively review the safety and activity of the MEK inhibitors. Moreover, we also discuss the reasons for the failure of the earliest compounds of this family of drugs. Finally, we provide a perspective of the role of MEK inhibitors in the treatment of cancer in forthcoming years. 2.

Alterations of MAPK pathway in cancer

The first effector of the MAPK pathway, RAS, is generally inactive in normal quiescent cells [14]. When activated by an extracellular stimulus, it binds to RAF and the resulting RAS--RAF complex translocates to the cell membrane where the serine or threonine kinase function of RAF is activated. Subsequently, MEK1 and MEK2 are phosphorylated which activates ERK1 and ERK2, translocating them into the nucleus. There, the kinase activity of ERK1 or ERK2 triggers the phosphorylation of some transcription factors that regulate key genes that eventually control growth, proliferation, and other critical cellular processes [15-18]. Abnormalities in this cascade of phosphorylations have been found to play a decisive role in several human malignancies. Thus, one of the members of the RAS family of genes (KRAS) has been found to be mutated in the majority of cases of pancreatic cancer as well as in colon, lung, and biliary tract tumors [6]. Alterations in other members of this family, such as NRAS and HRAS, are commonly present in melanoma [19] and salivary gland tumors, respectively [20]. Moreover, different histologies of thyroid cancer have different RAS 484

abnormalities, being KRAS mutations common in papillary thyroid carcinoma [21], while NRAS mutations are frequently found in follicular and poorly differentiated thyroid carcinomas [22,23]. Downstream from RAS, the RAF family also plays a crucial role in cancer. One of its members, BRAF, is mutated in 20% of all tumors, including thyroid and colon cancer among others [7]. Nearly 50% of all melanomas and almost every case of hairy cell leukemia harbor an activating mutation in BRAF [8,24,25]. There have been described more than 40 different mutations, the substitution of glutamate for valine at codon 600 of exon 15 (V600E) being the most frequent (around 80% of cases) [7,26]. The importance of this mutation is such that the dramatic results obtained with the BRAF V600E-mutant inhibitor vemurafenib in a Phase III trial have led to its license in both Europe and the US for the treatment of metastatic melanoma [27]. The MEK family, namely MEK1 and MEK2, also plays an important role in carcinogenesis, as extensively reviewed in this manuscript [28]. Finally, alterations in other downstream kinases of the MAPK pathway like ERK1 or ERK2 are also involved in tumors like melanoma, colon, and lung carcinomas, although less commonly (Figure 1) [29,30]. A deeper understanding of some of the alterations in the MAPK pathway has permitted the development of a number of targeted agents. These new inhibitors have a new profile of side effects although they slightly differ depending of the specific point of the pathway inhibited. 3.

MEK inhibitors

3.1

Trametinib (GSK1120212) Toxicity

3.1.1

Trametinib is an orally bioavailable, potent, non-ATP competitive and specific allosteric inhibitor of MEK1/2. It not only inhibits MEK-dependent ERK phosphorylation, but also inhibits MEK1/2 activation by preventing Raf phosphorylation of MEK on S217 [31]. As mentioned earlier, trametinib is the first MEK inhibitor licensed for the treatment of cancer [12]. This license has been gained thanks to the favorable toxicity profile and the positive results of efficacy showed in its clinical development in melanoma. Thus, the dose-finding Phase I trial conducted by Infante et al. was the first to demonstrate that trametinib is a safe drug. In total, 206 patients with advanced solid tumors were enrolled in this study that assessed intermittent and continuous dosing regimens. The dose-limiting toxicities (DLT) reported were grade 3 rash (n = 2), grade 3 diarrhea (n = 1), and grade 2 central serous retinopathy (n = 2). Overall, the most frequent side effects were skin-related toxicities (83%), being rash or dermatitis acneiform mainly on the face, scalp, chest, and back the most common (80%). This skin toxicity was found to be dose-related. Treatment-related ocular toxic effects were recorded in 15% of patients, including three events of central serous retinopathy and one of retinal vein occlusion, which resolved on withdrawal of trametinib. Cardiac toxicity was

Expert Opin. Drug Saf. (2014) 13(4)


Membrane receptor (RTKs, GPCRs, integrins)

MAPK pathway

Plasmatic membrane

BRAF mutations (melanoma, thyroid and colon carcinoma)

SOS

RAF

Cytoplasm

P

SHC

Active RAS-GTP

MEK1/2

Grb2

P


ERK1/2

P

Inactive RAS-GDP

KRAS mutations (pancreatic, colon, lung, biliary tract tumours and papillary thyroid carcinoma) NRAS mutations (melanoma, follicular and poorly differentiated thyroid carcinoma) HRAS mutations (salivary gland tumour)

Gene expression

ERK1/2

Nucleus

P

P Trascription factors (c-Fos, STAT, Ets, etc.)

Growth Survival Proliferation Differentiation

Figure 1. MAPK pathway and most common alterations in different tumor types. c-Fos: Proto-oncogene c-Fos; Ets: E26 transformation-specific; GPCRs: G-protein-coupled receptors; Grb2: Growth factor receptor-bound protein 2; RTKs: Receptor tyrosine kinases; SHC: Src homology 2 domain-containing-transforming protein C; SOS: Son of sevenless homolog; STAT: Signal transducer and activator of transcription.

also seen, with 8% of patients experiencing a drop in left ventricular ejection fraction, mostly grade 2 or lower. Diarrhea, fatigue, and peripheral edema were also commonly found (42, 33 and 29%, respectively), although they were generally mild and easily manageable. One patient had a fatal outcome (sudden death) at the recommended dose (RD) of 2 mg once daily (od) [32]. The subsequent Phase II trial in 97 melanoma patients treated with trametinib 2 mg od in two different cohorts showed a similar toxicity profile. Again, skin rash (75%) and diarrhea (52%) were the most common adverse events reported, together with nausea (30%), peripheral edema (29%), pruritus (27%), and fatigue (26%). Two patients experienced reversible central serous retinopathy and three patients had asymptomatic and reversible grade 3 left ventricular ejection fraction reduction. Only one patient had a grade 4 toxicity (pulmonary embolism) [33]. Adverse events in the registration Phase III trial that compared trametinib 2 mg od with chemotherapy in 322 patients were consistent with those reported previously. Thus, skin rash, diarrhea, peripheral edema, fatigue, and dermatitis acneiform were the most frequent toxicities in the trametinib

arm (57, 43, 26, 26, and 19%, respectively). Cardiac dysfunction was observed in 7% of patients treated with trametinib (grade 3 in two cases), while no cardiac alterations were described in the chemotherapy arm. Once again, ocular events were noticed in 9% of patients (mostly grades 1 -- 2) [10]. Preliminary data of toxicity in studies conducted in other tumors apart from melanoma have been recently reported. Thus, in a randomized Phase II trial that compared trametinib with docetaxel in 134 patients with advanced non-smallcell lung cancer (NSCLC), five fatal adverse events (not specified) related to trametinib were reported and the most frequent toxicities were rash (59%), diarrhea (47%), nausea (34%), and hypertension (34%) [34]. Efficacy Promising efficacy data were first seen in the dose-finding Phase I study, with 10% objective responses noted at all dose levels. Responses were seen in 2 out of 26 patients with pancreatic cancer (one KRAS mutation positive, one KRAS mutation unknown) and in 2 out of 30 patients with NSCLC (both with KRAS mutations) [32]. But the most sensitive population was BRAF-mutant melanoma: of 30 patients that had 3.1.2


485



not received a BRAF inhibitor before, 2 complete responses (CR) and 10 partial responses (PR) were seen. Interestingly, no confirmed PR was reported in any of the six patients who had received previous BRAF inhibition [35]. The Phase II trial conducted in BRAF-mutant melanoma also showed a difference between the BRAF-inhibitor naı¨ve patients and those who had received one of these drugs previously. Thus, patients were enrolled in two different cohorts according to the treatment received before trametinib 2 mg od: BRAF inhibitor (cohort A) or chemotherapy and/or immunotherapy (cohort B). Out of 40 patients in cohort A, 11 (28%) achieved stable disease (SD) and no PR was reported. On the other hand, in cohort B (n = 57) there was 1 CR (2%), 13 PR (23%), and 29 SD (51%). Median progression-free survival (PFS) was 1.8 months (95% confidence interval (CI) 1.8 -- 2.0 months) and 4 months (95% CI 3.6 -- 5.6 months) in cohort A and cohort B, respectively, indicating that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy [33]. These encouraging results were confirmed in the Phase III trial. This study compared the efficacy of trametinib 2 mg od with dacarbazine 1000 mg/m2 or paclitaxel 175 mg/m2 3-weekly in BRAF-mutated melanoma patients in a 2:1 randomization. The response rate (RR), defined as percentage of patients that had CR or PR, was significantly higher in the trametinib arm: 22% (95% CI 17 -- 28) versus 8% (95% CI 4 -- 5) in the chemotherapy group (p = 0.01). Trametinib also showed to be superior in survival. Median PFS was 4.8 months in the trametinib group compared with 1.5 months in the chemotherapy group (hazard ratio [HR] 0.45, 95% CI 0.33 -- 0.63, p < 0.001), and OS at 6 months was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (HR 0.54, 95% CI 0.32 -- 0.92, p = 0.01) [10]. These results have established trametinib as a valid therapeutic option for BRAF-mutated melanoma patients that have not received a BRAF-inhibitor. However, this efficacy of trametinib in monotherapy has not been seen in other malignancies. Thus, the randomized Phase II trial that compared trametinib 2 mg od with docetaxel 75 mg/m2 in patients affected by KRAS-mutant advanced NSCLC previously treated with platinum-based chemotherapy had to be stopped early for futility [34]. Combination regimens Following the success achieved by trametinib as a single agent in melanoma, several studies have assessed the feasibility of its combination with other drugs. The most promising study is a Phase I--II trial of trametinib plus the BRAF inhibitor dabrafenib conducted in melanoma patients with either V600E or V600K mutations in BRAF. First, pharmacokinetic (PK) activity and safety of oral dabrafenib (75 or 150 mg twice daily [b.i.d.]) and trametinib (1, 1.5 or 2 mg daily) were evaluated. Then, patients were randomly assigned to receive combination therapy with dabrafenib plus trametinib or single-agent dabrafenib. Among the 85 patients enrolled in the dose-finding part, only one 3.1.3

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DLT was observed (recurrent neutrophilic panniculitis). The maximum tolerated dose (MTD) was not reached and the RD for the Phase II allowed full doses of both agents: trametinib 2 mg od plus dabrafenib 150 mg b.i.d. The most common side effects reported at the RD were pyrexia (71%), chills (58%), fatigue (53%), and nausea (44%). Interestingly, the incidence of cutaneous squamous-cell carcinoma was 19% with dabrafenib in monotherapy and 7% with the combination at the RD, although the difference was not statistically significant (p = 0.09). The second part of the study assessed the efficacy of trametinib 2 mg od plus dabrafenib 150 mg b.i.d. compared to single-agent dabrafenib in 162 patients that had not previously received any RAF or MEK inhibitor. The rate of CR or PR with the combination therapy was 76%, as compared with 54% with monotherapy (p = 0.03) and median PFS in the combination group was 9.4 months, whereas in the monotherapy group it was 5.8 months (HR 0.39, 95% CI 0.25 -- 0.62, p < 0.001) [11]. These results strongly suggest the superiority of the concomitant inhibition of RAF and MEK compared to RAF inhibition alone in melanoma. Indeed, the combination of trametinib and dabrafenib has recently been approved by the FDA for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation [36]. Also, this treatment has preliminarily showed to be tolerable and active in BRAFV600-mutant colorectal cancer [37]. Another combination trial has been recently published. In this study, the safety and preliminary clinical activity of trametinib plus gemcitabine were evaluated. In general, the combination was well tolerated in the 31 patients enrolled, being grade 3 and grade 4 febrile neutropenia, grade 3 transaminase increase and grade 2 uveitis the DLTs reported. The RD was trametinib 2 mg od plus gemcitabine 1000 mg/m2 on days 1, 8 and 15 of 28-days cycle. At this dose, grades 3 -- 4 toxicities observed included neutropenia (38%), thrombocytopenia (19%), and transaminase elevation (14%). The combination of trametinib and gemcitabine also showed encouraging signs of efficacy. Thus, of 10 patients with pancreatic cancer, three PR were documented and two additional patients achieved objective responses: one CR in breast cancer and one PR in salivary gland cancer [38]. These promising results led to a randomized, double-blind trial with gemcitabine versus gemcitabine plus trametinib in patients affected by pancreatic cancer. Unfortunately, the combination treatment failed to achieve an improvement in OS, PFS, or RR independently of KRAS mutation. In addition, an increased incidence of skin, gastrointestinal and hematologic toxicities were reported with trametinib compared to placebo [39]. Other combination regimens including trametinib are currently under evaluation. Preliminary positive toxicity and efficacy results with trametinib plus pemetrexed and docetaxel have been reported in KRAS-mutant and wild-type NSCLC [40,41]. Very early results of trametinib plus other drugs such as erlotinib or nab-paclitaxel have been reported although the data are still immature [42].



Selumetinib (AZD6244) 3.2.1 Toxicity


3.2

Selumetinib is an oral, non-ATP competitive, highly selective MEK1/2 inhibitor. It has been proposed to lock MEK1/2 into an inactive conformation that enables binding of ATP and substrate but disrupts both the molecular interactions required for catalysis and the proper access to the ERK activation loop [43]. The good tolerance to selumetinib was demonstrated in a Phase I trial published in 2008. Fifty-seven patients were enrolled in this dose-escalation study that also assessed clinical activity. The most frequently reported toxicities were rash, diarrhea, nausea and fatigue (43, 33, 25 and 22 cases, respectively), being recorded as grades 1 -- 2 in the majority of cases. Rash, diarrhea, hypoxia, and T-wave inversion were the observed DLTs and the incidence of reversible blurred vision was 12%. In general, selumetinib was well tolerated and the RD was 100 mg b.i.d. [44]. A number of subsequent Phase II trials in a wide range of malignancies were conducted. Thus, the efficacy of selumetinib 100 mg b.i.d. in monotherapy was assessed in colorectal, pancreatic, lung, papillary thyroid, liver cancers, and melanoma [45-50]. These trials, although negative, provided valuable information in terms of toxicity. The most frequent adverse events consistently reported in these trials were skin rash, fatigue, diarrhea, nausea, and peripheral edema. Overall, the tolerance to selumetinib was good, with the majority of toxicities being grades 1 -- 2 even in cirrhotic patients [49]. Two pulmonary deaths occurred in the papillary thyroid study but they were judged unlikely to be related to the drug [48]. More recently, some Phase II studies with positive results using selumetinib as single agent have been published. These studies, performed in ovarian and thyroid cancer, used different doses of selumetinib (50 and 75 mg b.i.d., respectively) [51,52]. In spite of this, the toxicity profile in both studies was similar to the 100 mg b.i.d. dose being skin rash, fatigue, and gastrointestinal disorders again the most common toxicities reported. Interestingly, grades 3 -- 4 cardiac events were seen in 3 out of 52 patients with ovarian cancer [51]. On the other hand, no grade 3 or higher toxicities were reported in the thyroid cancer study [52]. Efficacy The history of the efficacy of selumetinib has been hindered by the poor selection of the patients in trials. In the initial Phase I study, 33% of patients achieved SD, with prolonged stabilization for at least 5 months in 16% of cases. One patient with medullary thyroid cancer experienced SD for 19 cycles, whereas one patient with both uveal melanoma and renal cell carcinoma had SD for 22 cycles [44]. Patients with mutated RAS or RAF remained longer in the study with higher RR but analysis of statistical significance could not be performed due to small number of patients [28]. The series of failed Phase II studies in several tumors conducted afterward enrolled patients irrespective of their 3.2.2

RAS or RAF mutational status. Thus, a randomized study that compared selumetinib 100 mg b.i.d. with capecitabine 1,250 mg/m2 b.i.d. for 2 weeks in 3-weekly cycles showed similar efficacy in both arms [45]; another randomized study that assessed the same regimens but in pancreatic cancer also failed to find differences between the two treatments [46]; selumetinib 100 mg b.i.d. showed no advantages over standard treatment with pemetrexed 500 mg/m2 every 3 weeks in NSCLC [47]; a single-arm trial of selumetinib 100 mg b.i.d. in papillary thyroid carcinoma did not meet the primary end point of RR [48]; another comparative study of selumetinib 100 mg b.i.d. versus temozolomide 200 mg/m2 for 5 days in 28-day cycles in melanoma found no significant differences in PFS [50], and no responses were seen in hepatocellular carcinoma patients treated with selumetinib 100 mg b.i.d. [49]. However, in these trials patients with RAS or RAF mutations achieved higher response rates, which indicates that careful patient selection depending on their mutational status is mandatory for future trial designs. Nevertheless, two studies without selection based on RAS or RAF mutations achieved successful results. One of them was a single-arm Phase II trial that assessed the efficacy of selumetinib 50 mg b.i.d. in recurrent low-grade serous carcinoma of the ovary. Out of 52 patients enrolled, 8 (15%) responded to selumetinib (one CR, seven PR) and 34 patients (65%) achieved SD [51]. In the other study, performed in 20 patients with metastatic thyroid cancer refractory to radioiodine, selumetinib increased the uptake of iodine-124 in 12 cases. Interestingly, the authors suggested that the efficacy may be greater in patients with RAS-mutant disease [52]. Provisional efficacy data in two more tumors have been recently reported. Selumetinib 75 mg b.i.d. demonstrated to be superior to temozolomide 150 mg/m2 daily for 5 days in 28-day cycles in patients with gnaq/Gna11 mutant uveal melanoma [53]. On the contrary, selumetinib 100 mg b.i.d. only showed modest activity in advanced acute myeloid leukemia [54]. Combination regimens New studies with selumetinib-containing regimens in patients harboring mutations in RAS or RAF have achieved encouraging results. However, in some cases the toxicity observed was significantly higher than with selumetinib in monotherapy. For instance, a randomized, placebo-controlled, Phase II study that evaluated the efficacy of selumetinib 75 mg b.i.d. plus docetaxel 75 mg/m2 compared to single-agent docetaxel in KRAS-mutant advanced NSCLC found the combination arm to be more toxic. Thus, adverse events of grade 3 or higher occurred in 36 out of 44 patients (82%) in the combination group and in 28 out of 43 patients (67%) in the docetaxel group. The most common grades 3 -- 4 toxicities reported were neutropenia, febrile neutropenia, dyspnoea, and asthenia (67, 18, 2 and 9% in the combination cohort, respectively, and 55, 0, 12 and 0% in the monotherapy cohort, respectively). However, median PFS was significantly prolonged in the 3.2.3


487



combination arm (5.3 months) compared to the docetaxel arm (2.1 months) (HR 0.58, 80% CI 0.42 -- 0.79, p = 0.014) [55]. On the other hand, another positive combination study did not show increased toxicity when selumetinib was combined with a cytotoxic agent. Selumetinib 75 mg b.i.d. plus dacarbazine 1000 mg/m2 on day 1 of a 21-days cycle were compared to dacarbazine alone in 91 patients in a Phase II double-blind randomized study in BRAF-mutant metastatic melanoma. The tolerability of this combination was generally consistent with the safety profiles of each drug alone and no unexpected adverse events were recorded. Moreover, PFS was significantly improved in the selumetinib plus dacarbazine group compared to the placebo plus dacarbazine group (HR 0.63, 80% CI 0.47 -- 0.84, p = 0.021), with a median of 5.6 months versus 3.0 months, respectively [56]. A large number of clinical trials with combinations of selumetinib plus other drugs are currently ongoing thanks to the encouraging results achieved with the strategy of selecting RAS/RAF mutated patients. The efficacy and safety profile of selumetinib combined with both cytotoxic drugs (such as docetaxel, irinotecan, or dacarbazine) and targeted therapies (such as erlotinib, cetuximab, or MK2206) are being assessed in a range of malignancies [57-65]. Some provisional results have been reported and, although still not definitive, they suggest that some regimens are safe [60,62,65]. Also, preliminary signs of efficacy have been seen [60,62]. The new patient selection strategy warrants further investigation with this drug either alone or in combination with other compounds. Pimasertib (AST03026) Pimasertib is a highly selective, potent, oral, ATP noncompetitive allosteric generation inhibitor of MEK1/2. It binds to MEK1/2 in an allosteric site that is distinct from, yet in close proximity to, the ATP binding site [66,67]. Its preclinical antitumor activity has been demonstrated in vitro and in vivo, mainly in myeloma, colorectal, and lung cancers [66-68], but no clinical trials have been fully published to date. However, there are some preliminary results available. A Phase I/II study of pimasertib plus folinic acid, fluorouracil, and irinotecan (FOLFIRI) in KRAS-mutant advanced colorectal cancer has been conducted. In the dose-escalation part, 16 patients were enrolled. At the dose of pimasertib 60 mg od, two out of five patients experienced grade 3 mucositis and the most common treatment-related side effects reported were asthenia, diarrhea, mucositis, ocular events, nausea, rash, and vomiting [69]. Another dose-finding trial of pimasertib and standard dose gemcitabine in patients affected by metastatic pancreatic cancer found two DLTs: grade 3 confusion with ataxia and disorientation at 60 mg b.i.d. and grade 4 suicidal ideation at 75 mg b.i.d. In total, 53 patients were treated and the most common adverse events were asthenia (70%), ocular events (68%), skin rash (62%), nausea (58%), diarrhea (58%), peripheral edema (51%), thrombocytopenia (49%), vomiting (45%), mucositis (43%), neutropenia (38%), 3.3

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decreased appetite (36%), and anemia (34%). The main ocular event was serous retinal detachment (58%) and manageable retinal vein occlusion occurred in five cases. The RD for future Phase II studies was 60 mg b.i.d. Early signs of activity were seen, with PR noted in 10 patients and SD for at least 3 months in 13 cases [70]. The remaining trial with pimasertib in which provisional results are available is a Phase Ib dose-escalation trial with the combination of pimasertib plus SAR245409, a phosphatidyl inositol 3¢-kinase/mammalian target of rapamycin (PI3K/ mTOR) inhibitor. The reported DLTs were grade 3 nausea or vomiting, grade 3 skin rash, and grade 3 asthenia, and the most frequent toxicities were rash (62%), diarrhea (56%), fatigue (51%), nausea (49%), vomiting (45%), peripheral edema and pyrexia (34% each), and visual impairment with underlying serous retinal detachment (21%). The RD was pimasertib 60 mg od plus SAR245409 70 mg od. Concerning efficacy, four patients achieved PR: one KRAS-mutant colorectal cancer and three low-grade ovarian cancer (one KRAS-mutant and two wild-type) [71]. Refametinib (RDEA119) Refametinib is an orally available, potent, non-ATP competitive compound that selectively binds directly to an allosteric pocket in the MEK1/2 enzymes [72]. It has showed preclinical signs of antitumor activity in thyroid and pancreatic cancer models when combined with mTOR inhibitors and erlotinib [73-75]. Subsequently, its safety and clinical efficacy are currently being evaluated. Some data are already available: a dose-escalation Phase I trial that assessed its safety reported that refametinib was generally well tolerated at doses £ 100 mg daily, with rash being the most common treatmentrelated toxicity [76]. Partial results of two combination trials have also been reported. The first one found that the combination of refametinib 30 mg b.i.d. with gemcitabine 1000 mg/m2 had a manageable safety profile, with acneiform rash as the clinically most relevant toxicity. In addition, the treatment showed signs of activity, with PR seen in 5 out of 13 patients affected by advanced pancreatic cancer [77]. A trial that evaluated refametinib plus sorafenib in 70 patients reported four fatal events: hepatic failure, sepsis or hepatic encephalopathy, tumor lysis syndrome, and unknown cause. Moreover, dose modifications due to adverse events were necessary in almost all cases [78]. 3.4

Cobimetinib (GDC-0973) Cobimetinib is an ATP-uncompetitive, allosteric, oral inhibitor of MEK1. It is 100-fold selective for MEK1 versus MEK2 [79-81]. A first-in-human Phase Ib study tested its safety in combination with the PI3K inhibitor GDC-0941. The most common toxicity was grades 1 -- 2 diarrhea (90%) and the DLTs found were grade 3 lipase and grade 4 creatine kinase (CK) elevation. Early signs of efficacy were found, with 3 out of 46 evaluable patients achieving PR (one BRAF-mutated melanoma, one BRAF-mutated pancreatic cancer, and one KRASmutated endometrioid carcinoma). Moreover, 26 patients had 3.5




metabolic response by fludeoxyglucose-positron emission tomography [82,83]. Further partial results with cobimetinib have been recently reported. A Phase Ib study conducted in BRAFV600-mutated melanoma patients with the combination of cobimetinib and the BRAF inhibitor vemurafenib showed very encouraging results. The combination proved to be safe, with the most common treatment-related adverse events being nonacneiform rash (58%), diarrhea (52%), fatigue (37%), liver laboratory test abnormality (37%), and photosensitivity/ sunburn (37%). DLTs were found in only 4 patients of the 115 treated and the RD was cobimetinib 60 mg od 21 days on/7 days off plus vemurafenib 960 mg b.i.d. Interestingly, BRAF-inhibitor naı¨ve patients achieved a RR of 73%, while the RR was just 14% in patients that had progressed on a BRAF inhibitor [84]. These results are similar to those observed in the Phase II study of trametinib [33], suggesting that inhibition of MEK is not able to improve the outcome of patients after progression to BRAF inhibitors. MEK162 MEK162 is a potent, selective, oral, non-ATP competitive allosteric second generation inhibitor of MEK1 and MEK2 [28]. It demonstrated to have an acceptable safety profile and antitumor activity in biliary tract cancer at 60 mg b.i.d. [85]. Its efficacy has been confirmed in a recently published study by Ascierto et al. In this Phase II trial, 71 patients with advanced melanoma harboring NRAS or V600BRAF mutations were enrolled. The most frequent adverse events found were acneiform dermatitis (in 60% of patients with NRAS-mutated melanoma and in 37% of patients with mutations in BRAF), rash (20 and 39%), peripheral edema (33 and 34%), facial edema (30 and 17%), diarrhea (27 and 37%), and CK increase (37 and 22%). Regarding efficacy, 20% of 30 patients with NRASmutated melanoma had a PR as well as 20% of 41 patients with BRAF-mutated melanoma [86]. This is the first time that MEK inhibition has showed to be an active treatment in NRAS-mutated melanoma, which warrants further investigation. 3.6

RO5126766 RO5126766 is a first-in-class dual MEK/RAF inhibitor that binds directly to MEK and prevents its phosphorylation by RAF through the formation of a stable RAF--MEK complex. Consequently, RO5126766 inhibits both the phosphorylation of MEK by RAF and the activation of ERK by MEK [87]. Two Phase I trials with RO5126766 have been published to date. The DLTs found in the first study were elevated CK and blurred vision and in the second study, conducted in Japanese population, no DLTs were reported although the dose levels assessed were lower. Skin rash and CK raise were the most commonly observed side effects in both studies, followed by diarrhea and ocular disorders, respectively. RD for Phase II studies were 2.7 mg od 4 days on/3 days off in the first trial 3.7

and 2.25 mg od continuously in the Japanese study. Responses were reported in both studies, mainly in BRAF or NRASmutant melanoma patients [87,88]. RO4987655 RO4987655 is a potent, novel, oral, allosteric non-ATP competitive MEK1/2 inhibitor. Its unique 3-oxo-oxazinane ring structure confers high metabolic stability. In addition, RO4987655 shows slow dissociation from MEK with remarkable antitumor efficacy [89]. The only clinical data published to date with this compound is a Phase I study that reported blurred vision and elevated CK as DLTs. Skin rash toxicity (91.8%) and gastrointestinal disorders (69.4%) were the most frequent adverse events. The drug was considered well tolerated and the RD for future trials was 8.5 mg b.i.d. [90]. 3.8

AZD8330 AZD8330 is a potent, selective, oral, allosteric non-ATP competitive MEK1/2 inhibitor [28]. Its safety profile has been evaluated in a Phase I study that included 82 patients with advanced malignancies. The most frequent AZD8330-related adverse events were acneiform dermatitis (16%), fatigue (13%), diarrhea (13%), and vomiting (11%). DLTs were found in four patients: mental status changes in three cases and rash in one case. The disease control rate was reported as 40%, although mutation analyses of RAS or RAF were not performed. The final RD for further clinical trials was 20 mg b.i.d. [91]. 3.9

PD-0325901 PD-0325901 is a second-generation, small-molecule, oral, allosteric non-ATP competitive inhibitor with specific activity against MEK1/2 [92]. A Phase I study of its analogue CI-1040 suggested 800 mg b.i.d., administered with high-fat food for increasing the drug exposure, as the RD [93]. However, a Phase II study conducted in NSCLC patients did not meet the primary efficacy end point of objective response, which halted its clinical development [94]. 3.10

4.

Conclusion

MEK inhibitors are a safe and active option for the treatment of cancer. Trametinib has recently been approved for patients affected by advanced melanoma with BRAF V600E or V600K mutations, becoming the first of these compounds ever licensed. Many other MEK inhibitors are currently being assessed in clinical trials, which results will hopefully provide the necessary information to establish the role of MEK inhibition in cancer. However, adequate selection of patients is crucial for the success of this family of drugs. 5.

Expert opinion

MEK inhibitors have proved to be safe either alone or in combination. Their most common side effects are skin rash,


489



Table 1. Clinical trials with MEK inhibitors currently ongoing. Drugs

Phase

MEK162 + gemcitabine + cisplatin MEK162 + AEB071 MEK162 + erlotinib MEK162 + panitumumab MEK162 versus physician’s choice chemotherapy MEK162 Trametinib + GSK2141795 Trametinib + GSK2141795 Trametinib +/- GSK2141795 Trametinib + GSK2141795 Trametinib + pazopanib

I/II Ib/II I Ib/II III II II II II II I

Trametinib + dabrafenib versus placebo Selumetinib Selumetinib MSC1936369B +/- gemcitabine

III II I/II I/II

Tumor

Biliary tract carcinoma Uveal melanoma Non-small-cell lung cancer Colorectal cancer Low-grade serous ovarian, fallopian tube or peritoneal cancer Solid tumors Acute myeloid leukemia Multiple myeloma Endometrial cancer Cervical cancer Solid tumors (thyroid cancer, soft-tissue sarcoma, cholangiocarcinoma) Melanoma Diffuse large B-cell lymphoma Kaposi’s sarcoma Pancreatic cancer

diarrhea, peripheral edema, and fatigue. Other frequent adverse events include hypertension. Thus, in the trametinib registration trial the incidence of hypertension grades 2 -- 3 was 15% in the trametinib arm while in the chemotherapy arm it was 7% [10]. Nevertheless, MEK inhibitor toxicity is in general mild and easily manageable in the majority of cases. The safety profile of MEK inhibitors differs from another successful family of drugs that also targets the MAPK pathway: BRAF inhibitors. Thus, although rash is a common side effect of both families, the rash observed with MEK inhibitors is papulo-pustular [10], while the rash associated to RAF inhibitors is generally maculo-papular [27]. Photosensitivity is much more frequent with BRAF inhibitors [27], while it is rare with MEK inhibitors. However, central serous retinopathy and retinal-vein occlusion have been reported with trametinib, indicating that ocular toxicity is less frequent with MEK inhibitors but clinically more important [32]. Another relevant issue is the high incidence of cutaneous squamous-cell carcinomas observed with RAF inhibitors [27] and its absence with MEK inhibitors [10]. This intriguing observation may be explained by the fact that BRAF inhibitors may paradoxically activate the MAPK pathway in other tissues leading to the development of secondary malignancies [95-97]. It has been recently described in preclinical models that the blocking of the MAPK pathway by the addition of a MEK inhibitor prevents this [98]. However, in the only study published to date with a combination of drugs belonging to these two families (dabrafenib plus trametinib) the rate of proliferative skin lesions was nonsignificantly reduced [11]. Similar data have been reported with vemurafenib plus cobimetinib [84]. Besides these considerations and with the exception of a few regimens [39,55], the tolerance of MEK 490

Setting

ClinicalTrials.gov Identifier

Advanced Advanced Advanced Advanced Advanced

NCT01828034 NCT01801358 NCT01859026 NCT01927341 NCT01849874

Advanced Refractory Refractory Advanced Advanced Advanced

NCT01885195 NCT01907815 NCT01989598 NCT01935973 NCT01958112 NCT01438554

Adjuvant Refractory Advanced Advanced

NCT01682083 NCT01278615 NCT01752569 NCT01016483

inhibitors is acceptable. Moreover, their favorable toxicity profile may allow their concomitant administration with other drugs at full doses in combination treatments, which might positively impact efficacy. Further investigation with novel schedules and regimens is therefore warranted. Apart from their safety, MEK inhibitors have also achieved successful results in terms of efficacy in recent years. This was not the case in the early stages of the development of these drugs. The results of the first Phase II trials were disappointing, with a large number of failed studies in a broad spectrum of tumors [45-50]. The main reason for such poor results was the inadequate selection of patients. Thus, in neither of these trials the enrolled patients were required to harbor activating mutations of the MAPK pathway. The strategy of selecting patients with tumors RAS or RAF-mutated led to a dramatic improvement in the efficacy results and, finally, to the license of the first MEK inhibitor (trametinib) in a tumor in which RAF and RAS mutations play a crucial role: melanoma [10]. However, not all mutations in RAS or RAF are sensitive to MEK inhibitors. Thus, two trials that enrolled patients with KRAS-mutated NSCLC and pancreatic cancer failed to reach their efficacy end points [34,39]. On the other hand, another study reported preliminary positive results in wild-type and KRAS-mutated NSCLC cancer patients [40]. Also, successful results have been achieved in patients affected by NRASmutant melanoma [86]. This might be explained by the existence of different mutations intrinsically sensitive or resistant to MEK inhibitors even within the same tumor type. The mutations that predict a good response to the inhibition of MEK, like BRAFV600, have not been fully described yet. Therefore, the identification of these mutations is essential for the success of future clinical trials.




In addition, the different mechanisms of action of the MEK inhibitors might also be relevant for the efficacy of these drugs. Since the mechanism of activation of MEK is distinct in KRAS and BRAF-driven tumors, different therapeutic approaches in each genotype are necessary. MEK inhibitors with superior efficacy in KRAS-driven tumors, such as the novel compounds GDC-0623 and G-573, form a strong hydrogen-bond interaction with MEK that is critical for blocking MEK feedback phosphorylation by wild-type RAF. On the other hand, potent inhibition of active, phosphorylated MEK (the mechanism of action of cobimetinib) is required for the inhibition of the MAPK pathway in BRAF-mutant tumors. Therefore, development of inhibitors that target distinct activation states of MEK is required for reaching optimal antitumor activity in each genotype [99]. Nevertheless, the success of MEK inhibitors has its limitations. The activation of the PI3K/AKT/mTOR pathway as a result of the treatment with MEK inhibitors may diminish their efficacy since MEK inhibition abolishes the MEK/ERK negative-feedback loop on AKT phosphorylation [100]. The combined suppression of both MAPK and PI3K/AKT/ mTOR is therefore a sensible approach. This strategy is currently under investigation and might result in improved efficacy compared with inhibition of either pathway alone [101,102]. On the other hand, the advantages of the use of MEK inhibitors over RAF inhibitors are not clear since RRs observed with MEK inhibition are generally lower that those reported with RAF inhibition [10,27]. Moreover, in at least two clinical trials, MEK inhibitors did not achieve significant benefit in patients previously treated with BRAF inhibitors, neither administered sequentially nor concomitantly [33,84]. It has been postulated that resistance to BRAF inhibitors is associated with reactivation of MEK and ERK [103,104], so the mechanisms for the limited activity of MEK inhibitors in patients that have progressed to RAF inhibitors are still not well understood. The administration of these compounds in an inverse sequential fashion, that is, RAF inhibitors after progression to MEK inhibitors, has not been prospectively evaluated yet. Recent evidences suggest that the concurrent inhibition of RAF and MEK is superior to RAF or MEK inhibition alone in terms of efficacy without a

significant increase in toxicity [11]. Several Phase III trials that address this question are currently ongoing (NCT01689519, NCT01584648, NCT01597908), but the FDA has already granted accelerated approval to the combination of trametinib and dabrafenib in BRAF-mutated advanced melanoma [36]. In summary, the future of MEK inhibitors is highly promising due to their well-proved safety and efficacy. Their activity in early clinical studies and in preclinical models of many different malignancies such as melanoma, NSCLC, thyroid, colorectal, or pancreatic cancer among others, has been sufficiently demonstrated, which warrants further investigation. Thus, a large number of clinical trials are currently ongoing in a broad spectrum of tumors: biliary tract carcinoma (NCT01 828034), uveal melanoma (NCT01801358), NSCLC (NCT0 1859026), colorectal cancer (NCT01927341), ovarian cancer (NCT01849874), pancreatic cancer (NCT01016483), acute myeloid leukemia (NCT01907815), multiple myeloma (NCT01951495), diffuse large B-cell lymphoma (NCT0127 8615), Kaposi’s sarcoma (NCT01752569), endometrial cancer (NCT01935973), cervical cancer (NCT01958112), thyroid cancer, soft-tissue sarcoma and cholangiocarcinoma (NCT014 38554), advanced solid tumors (NCT01885195), or combined with a BRAF inhibitor in melanoma in the adjuvant setting (NCT01682083). The most relevant studies with MEK inhibitors that are currently being conducted are summarized in Table 1. The outcome of these studies will help to optimize the use of MEK inhibitors in cancer and therefore to meet the essential goal of improving the survival of patients.

Acknowledgement Figure was elaborated using Servier Medical Art.

Declaration of interest No funding or sponsorship was received for the preparation of this manuscript. J Larkin has received research funding from Pfizer and Novartis. He has also been a consultant for GlaxoSmithKline, Bristol-Myers Squib, Pfizer, and Novartis.


491


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Affiliation Juan Martin-Liberal1, Laura Lagares-Tena2 & James Larkin†1 † Author for correspondence 1 The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK Tel: +44 20 7811 8576; Fax: +44 20 7811 8103; E-mail: [email protected] 2 Institut d’Investigacio´ Biome`dica de Bellvitge (IDIBELL), Hospital Duran i Reynals 3ª plantaGran Via de l’Hospitalet, Laboratori d’Oncologıá Molecular, 199. L’Hospitalet de Llobregat, 08908 Barcelona, Spain

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Prospects for the Use of ATR Inhibitors to Treat Cancer.

Combined PKC and MEK inhibition for treating metastatic uveal melanoma.

Assessing options for treating haemophilia with inhibitors.

Mutant HRAS as novel target for MEK and mTOR inhibitors.

MEK inhibitors against MET-amplified non-small cell lung cancer.

Immunotherapy for lung cancer: advances and prospects.

Buprenorphine for treating cancer pain.

Prospects for cancer control in the 1990s.

Mechanisms of Acquired Resistance to ALK Inhibitors and the Rationale for Treating ALK-positive Lung Cancer.

Next-Generation EGFR Tyrosine Kinase Inhibitors for Treating EGFR-Mutant Lung Cancer beyond First Line.

Inhibitors of hydroxymethylglutaryl coenzyme A reductase for treating hypercholesterolaemia.

Injury site-specific targeting of complement inhibitors for treating stroke.

Rituximab for treating inhibitors in people with inherited severe hemophilia.

The clinical development of MEK inhibitors.

Treating cancer: the potential role of stem cell inhibitors.

In Vivo Assessment of Stem Cells for Treating Neurodegenerative Disease: Current Approaches and Future Prospects.

Soluble RAGEs - Prospects for treating & tracking metabolic and inflammatory disease.

Molecular pathways: the basis for rational combination using MEK inhibitors in KRAS-mutant cancers.

Helicase-primase inhibitors for herpes simplex virus: looking to the future of non-nucleoside inhibitors for treating herpes virus infections.

Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy.

PARP Inhibitors for Cancer Therapy.

miRNA in Prostate Cancer: New Prospects for Old Challenges.

Selective anti-gene therapy for cancer: principles and prospects.

Tumor suppressor genes: new prospects for cancer research.