Selumetinib

Treating non-small cell lung cancer with selumetinib: an up-to-date drug evaluation

Evgeny N. Imyanitov , Evgeny V. Levchenko , Ekatherina S. Kuligina & Sergey
V. Orlov

To cite this article: Evgeny N. Imyanitov , Evgeny V. Levchenko , Ekatherina S. Kuligina & Sergey V. Orlov (2020): Treating non-small cell lung cancer with selumetinib: an up-to-date drug evaluation, Expert Opinion on Pharmacotherapy, DOI: 10.1080/14656566.2020.1798930
To link to this article: https://doi.org/10.1080/14656566.2020.1798930

1. Introduction

The RAS-RAF-MEK-ERK pathway is apparently the best-studied signal transduction module, especially in the context of cancer development (Figure 1). Many cellular processes, including proliferation, differentiation, survival, apoptosis, etc., can be influenced by external stimuli. A number of growth factors, hormones and cytokines interact with membrane receptors. Binding of the ligands to corresponding membrane tyrosine kinases usually induces homo- or heterodimerization of involved receptors, which results in cross-phosphorylation of the members of these dimers. Activation of the receptors triggers the conformational change of RAS proteins (KRAS, NRAS, and HRAS), which in turn activates RAF kinases (ARAF, BRAF, and CRAF). Activated RAF proteins phosphorylate MEK1 and MEK2 kinases, which transmit the signal further to ERK1 and ERK2 kinases. Upon stimulation, ERK kinases translocate to the nucleus and phosphorylate their nuclear protein sub- strates. Thus, RAS-RAF-MEK-ERK pathway translates various external signals into appropriate transcriptional reprogram- ming and corresponding phenotypic effects [1–4].

There are multiple bypasses of this ‘classical’ signaling cas- cade involving other mitogen-activated protein kinases (MAPKs). In particular, some stimuli lead to activation of MEKK4, MLK2/3, TAK1, and ASK1/2, which phosphorylate MEK3 and MEK6 kinases and transduce the signal to p38 proteins. Another ‘non-classical’ MAPK pathway consists of MEKK2/3, MEK5, and ERK5/BMK1 kinases. The third ‘non- classical’ MAPK core includes MEKK1/2/4, DLK, MLL2/3, and TAK1 kinases, which activate MEK4/7 and result in phosphor- ylation of JNK1/2/3 and p38 proteins. Furthermore, even within the RAS-RAF-MEK-ERK pathway there are some alter- native regulators. For example, MEK1 and MEK2 can be phos- phorylated not only by RAF proteins but also by MAP3K1 and MAPK3K8 kinases. In addition, other cascades, e.g. PI3K/AKT/ mTOR pathway, may significantly interact with RAS-RAF-MEK- ERK signaling. The existence of multiple interchangeable cas- cades underlies enormous plasticity of mitogen signaling [1,4–6].

RAS-RAF-MEK-ERK pathway is activated in the majority of human tumors [2]. Several receptor tyrosine kinases are over- expressed, amplified, or mutated in a variety of cancers; the examples include EGFR overexpression in gastrointestinal tumors, EGFR, ALK, ROS, RET, BRAF, MET, HER2, and NTRK mutation-driven activation in lung cancers, HER2 amplifica- tion in breast carcinomas, etc [7]. KRAS mutations are char- acteristic for colorectal and pancreatic cancers, while NRAS mutations are relevant to melanomas, colorectal malignan- cies, some types of leukemia, etc [8]. BRAF mutations affect over half of cutaneous melanomas and are also observed in several other cancer types [9]. Many components of RAS-RAF- MEK-ERK signaling cascades are druggable. For example, develop additional drugs, which are able to control RAS- RAF-MEK-ERK signal transduction.

Activation of membrane receptors, or RAS proteins, or BRAF kinase are usually reciprocal events, with significant diversity among tumors. For example, melanomas may contain either KIT, or NRAS, or BRAF mutation. Similarly, the development of lung adenocarcinomas may involve activation of EGFR, ALK, ROS1, RET, MET, NTRK, or HER2 receptor tyrosine kinases, mutations in KRAS or NRAS oncogenes, or alterations in BRAF kinase encoding gene [7]. Irrespective of which compo- nent of the cascade is affected by mutation, all these events result in the up-regulation of MEK kinases [1,3,4]. Accordingly, MEK kinases may serve as a ‘universal’ cancer target, as they are activated in the majority of human tumors.

Several therapeutic compounds act as MEK inhibitors (MEKi), e.g., trametinib (GSK1120212), cobimetinib (GDC-0973, XL-518), selumetinib (AZD6244, ARRY-142886) and binimetinib (ARRY- 162, MEK162). There are several already approved indications for MEKi, and a significant number of clinical studies are currently underway. Combinations of trametinib, cobimetinib, and bini- metinib with BRAF inhibitors are utilized for the treatment of BRAF-mutated melanoma. Dabrafenib plus trametinib doublet is also recommended for the therapy of NSCLCs carrying BRAF V600E or V600K substitutions. Selumetinib has recently received FDA approval for the treatment of pediatric patients with neuro- fibromatosis type 1 who have symptomatic inoperable plexiform neurofibromas. In addition, MEKi have the potential of targeting otherwise non-druggable cancers, e.g., RAS-mutated carcinomas [3,14,15]. This review is focused on potential clinical applications for selumetinib with the emphasis on NSCLC studies.

2. An overview of the drug
2.1. Overview on the market

Lung cancer incidence exceeds 2 million cases per year world- wide, with almost 1.8 million patients dying from this disease. It accounts for 11.6% and 18.4% of global cancer incidence and mortality, respectively [16]. Lung adenocarcinoma is the prevailing histological type of non-small cell lung cancer (NSCLC) in the Western world and in Asian countries.

Approximately 20% of NSCLC in whites and more than half of lung cancers in Asians are related to EGFR mutations and can be targeted by EGFR inhibitors. Another 15–20% of NSCLCs is attributed to ALK, ROS1, RET, and NTRK transloca- tions as well as to MET, HER2, and BRAF activating mutations; these tumors are also well druggable by corresponding kinase inhibitors. This statistic significantly differs between smokers and nonsmokers, with the former group demonstrating approximately threefold lower frequency of the kinase gene mutations as compared to the latter one. The discovery of drug-sensitizing mutations in NSCLC made a tremendous impact on the management of this disease, as the majority of NSCLCs harboring ‘actionable’ genetic events demonstrate a very rapid and pronounced response to appropriately tar- geted drugs. Clinical ivestigations on ALK-rearranged NSCLCs are the most spectacular examples of success of oncogene- directed therapy: for example, an unprecedented progression- free survival (PFS) of 34.8 months was achieved in a recent therapeutic antibodies can target HER2 and EGFR receptor tyrosine kinases. Recent years were characterized by the invention of a number of mutation-specific drugs, which inhibit activated cancer-specific isoforms of EGFR, ALK, ROS1, MET, BRAF, NTRK, etc., proteins [7]. On the other hand, targeting some members of RAS-RAF-MEK-ERK path- way turned out to be complicated. For example, while the discovery of KRAS, NRAS, and HRAS mutations heralded the emergence of molecular oncology many years ago, the attempts to develop specific antagonists for mutated RAS proteins faced critical obstacles [8,10–12]. Furthermore, even inhibition of well-druggable targets results only in tem- porary therapeutic responses; this is mainly due to the ability of tumors to restore the affected signaling cascade or utilize collateral pathways [13].

Figure 1. RAS-RAF-MEK-ERK signaling pathway.

Many signaling cascades are initiated by the interactions between ligands and their receptors. Homo- and heterodimerization of receptor tyrosine kinases results in their cross- phosphorylation. Phosphorylated tyrosines interact with adaptor molecules and transduce the signal to RAS GTP-ases. Activation of RAS is negatively controlled by NF1 protein. RAF kinases, being the downstream targets of activated RAS, upregulate MEK kinases. MEK subsequently phosphorylate ERK kinases, which translocate to the nucleus and mediate transcription reprogramming. RAS-RAF-MEK-ERK signaling cascade is involved in various cellular processes, particularly in the stimulation of cell proliferation and maintenance of cell survival. Activating mutations in receptor tyrosine kinases, RAS proteins or RAF serine-threonine kinases as well as the loss of negative regulators of this pathway (e.g., genetic inactivation of the NF1) facilitate tumor progression.

In contrast to above lesions, KRAS mutations are more characteristic for smokers than for nonsmokers. However, when one considers the share of KRAS lesions in NSCLC patients, who are negative for druggable (EGFR, ALK, ROS1, etc.) mutations, the proportion of KRAS-driven cancers will be roughly the same in smokers and nonsmokers, with approxi- mately one third of tumors carrying KRAS gene activation. It is also essential to acknowledge that the types of KRAS substitu- tions may differ between smoking-induced and smoking- unrelated NSCLC. KRAS G12C substitutions are somewhat more relevant to NSCLC arising in smokers, while tumors from nonsmokers are often characterized by elevated occur- rence of KRAS G12D mutation [19,20]. This difference may be of some clinical relevance, as specific KRAS G12C inhibitors have been recently developed and are currently undergoing seemingly successful clinical trials [21,22].

While NSCLC mutation testing became a mandatory part of treatment decision schemes, many therapies are given irre- spectively of the mutation status of the tumor. In particular, virtually all metastatic NSCLC patients, who do not have life- threatening contraindications, experience administration of cytotoxic agents [23]. Chemotherapy is usually considered for ‘non-oncogene addicted’ tumors, e.g. for NSCLCs which do not carry activating mutations in the kinase encoding genes. First- line chemotherapy regimens are normally given as doublets containing a platinum compound and some other cytotoxic drug. The subsequent therapies mainly rely on a single-agent drug administration. Almost all mutation-driven NSCLCs, which were subjected to a targeted therapy, eventually develop drug resistance, i.e. they lose oncogene addiction during the treatment course and therefore require other ther- apeutic options [24]. Recent invention of immune checkpoint inhibitors (ICIs), which are able to abrogate peritumoural immune suppression and to restore the pathways of natural anticancer defense, resulted in unprecedented breakthrough in NSCLC management. ICIs may be given in combination with cytotoxic therapy as a first-line treatment or as single agents after the failure of other therapeutic regimens. Some ICIs are approved for the upfront use without chemotherapy; how- ever, only NSCLCs expressing significant amount of PD-L1 are eligible for this scheme. ICI-containing therapies increased up to 15–25% the proportion of NSCLC patients, who achieve 3-years survival threshold after being diagnosed with meta- static NSCLC [25]. ICIs are particularly important for ‘non- oncogene addicted’ NSCLCs, given that only a few other treat- ment options are available for the management of tumors without actionable mutations [24].

Despite all advances in the development of cytotoxic, tar- geted and immune therapies, metastatic NSCLC remains a largely incurable disease. Many NSCLC patients do not respond to standard therapeutic regimens [23,25]. Furthermore, even responding tumors inevitably develop drug resistance during the course of treatment [13]. Therefore, the development of new treatment modalities of NSCLC is of utmost medical importance.

2.2. Introduction to the compound

Selumetinib (6-(4-Bromo-2-chloro-phenylamino)-7-fluoro- 3-methyl-3 H-benzoimidazole-5-carboxylic acid (2-hydroxy- ethoxy)-amide; C17H15BrClFN4O3) was initially developed by Array Biopharma and then acquired by AstraZeneca. It is an oral selective inhibitor of MEK1 and MEK2 kinases, with similar activity toward both these enzymes (Box 1). It acts through allosteric mechanisms: it does not compete with ATP and does not affect ATP-binding site; however, it changes the conforma- tion of MEK1/2 and prevents MEK interaction with the sub- strate molecules, ERK1 and ERK2 [26,27].

2.3. Pharmacodynamics

Preclinical experiments demonstrated selective activity of selu- metinib toward MEK1 and MEK2 enzymes, which was not accompanied by off-target effects against the spectrum of various protein kinases including other members of the MEK family. Selumetinib inhibited the growth of cancer cell lines and xenografts, with evidently stronger effects toward RAS- and RAF-mutated tumors [26]. Inhibition of MEK1/2 enzymes prevents phosphorylation of their only known targets, ERK1 and ERK2 kinases; therefore, ERK1/2 phosphorylation status is considered to be a proper pharmacodynamic marker for MEK inhibitors [26,28–30]. Interestingly, experiments in mice showed that selumetinib may exert somewhat distinct biolo- gical effects toward different cancer cells. In particular, while some xenografts demonstrated activation of apoptosis in response to selumetinib treatment, other tumors showed inhi- bition of cell proliferation. Biological mechanisms underlying these differences are not entirely clear [31].

2.4. Pharmacokinetics and drug metabolism

Based on dose-finding studies, selumetinib is usually adminis- tered in hydrogen sulfate capsules 75 mg twice a day. The peak plasma concentration of the drug is observed approxi- mately in 1.5 hours after drug ingestion. The mean selumetinib half-life approaches approximately 5 hours. Accordingly, continuous treatment with therapeutic doses of selumetinib does not result in its accumulation in the tissues [29]. Preceding food uptake may significantly decrease the absorption of the drug; therefore, it is recommended for patients to take selumetinib capsules on an empty stomach [32,33]. Concurrent use of cytochrome inducers or inhibitors is likely to affect plasma concentration of selumetinib [34]. White and Asian subjects have significant differences in the pharma- cokinetics of this drug, which result in higher selumetinib concentrations in Asians; this remains valid even after adjust- ment for body weight [35]. The most common adverse events associated with selumetinib treatment include fatigue, derma- tological toxicities (especially acneiform dermatitis), gastroin- testinal complications (diarrhea, nausea, vomiting), excessive fluid accumulation (peripheral edema) and blurred vision. Most of these toxicities have a mild to moderate manifesta- tion, and are reversible upon drug interruption or dose reduc- tion [29,30]. Combinations of selumetinib with other therapeutic compounds may require the same or reduced dosing of the drug [36–44]. Some preclinical studies indicate that the schedule is essential when selumetinib is combined with other agents, given that MEK inhibition may halt cell cycling and induce various molecular changes in the targeted cells [45,46]. Pediatric patients require reduced dosing of selu- metinib [47].

2.5. Lung cancer studies

Selumetinib was initially evaluated as a monotherapy in che- motherapy-pretreated unselected NSCLC patients (Table 1). Hainsworth et al. [48] utilized an early formulation of free- base selumetinib oral suspension, which was administered at a dose of 100 mg twice daily. In the comparator arm peme- trexed was given intravenously 500 mg/m2 once every 3 weeks. Objective responses were documented in 2 out of 40 patients receiving selumetinib and 2 out of 44 subjects treated with pemetrexed. There was no difference in median PFS [36]. KRAS mutation status was not considered in this study.

Lopez-Chavez et al. [49] administered single-agent selume- tinib to lung cancer patients with RAS/RAF mutations within a basket trial. This study included patients with a non-specified number of previous therapies and registered objective response to selumetinib in 1 (11%) out of 9 evaluable cases.

Carter et al. [28] examined the clinical activity of selumeti- nib alone and in combination with the EGFR inhibitor erlotinib in second- and third-line NSCLC treatment. The study involved both KRAS-mutated and KRAS wild-type NSCLCs. Treatment regimens differed depending on KRAS status. Selumetinib served as a backbone therapy for patients with KRAS muta- tions: they received either single agent selumetinib 75 mg twice a day (n = 11) or a combination of selumetinib 150 mg once a day plus erlotinib 100 mg once a day (n = 30). In contrast to patients with KRAS mutations, erlotinib served as a core therapy for KRAS wild-type NSCLC; the patients were randomized to receive either erlotinib alone 150 mg once a day (n = 19) or erlotinib 100 mg once a day in the morning Statistically higher response rates in selumetinib plus regular dose of docetaxel group (33% vs. 18% vs. 14%, p = 0.02), but similar PFS (4.2 months vs. 3.0 months vs. 4.3 months), respectively.

Acceptable tolerability of combination of selumetinib with pemetrexed and platinum therapy, but poor tolerability of gemcitabine-containing regimens. The estimated response rate was 20/55 (36%), including 11 (20%) confirmed and 9 (16%) unconfirmed partial responses
Acceptable tolerability of both drug combinations. Objective responses in 7/23 (30%) and 6/16 (38%); PFS = 5.0 months and 5.4 months, respectively.

Preclinical data indicate that selumetinib may potentiate the action of several cytotoxic drugs, e.g., docetaxel [45]. Jänne et al. [50] reported the results of a phase II study, which offered second-line treatment to patients with KRAS- mutated NSCLC. Given that the backbone treatment of this study was docetaxel therapy (75 mg/m2, every 3 weeks), patients who received this drug during first-line treatment were excluded from consideration. The patients were rando- mized to receive either selumetinib hydrogen sulfate capsules 75 mg twice a day (n = 44) or placebo (n = 43). Four patients were excluded from further analysis due to failure of centra- lized confirmation of KRAS mutated status. There was a striking increase in the rate of objective responses in the selumetinib arm (16/43 (37%) vs. 0/40 (0%), p < 0.0001). Median PFS was 5.3 months in the docetaxel plus selumetinib group vs. 2.1 months in the docetaxel plus placebo group (p = 0.014). The investigators observed numerically longer overall survival (OS) in the experimental vs. control arm, although the difference was far beyond the threshold for statistical significance (9.4 months vs. 5.2 months, p = 0.21). The results of this trial looked as an advance in the man- agement of KRAS-mutated NSCLC and led to the launch of an appropriate phase III trial. It involved 505 patients, 251 of whom received docetaxel plus selumetinib and 254 were taking docetaxel plus placebo. Selection criteria and treatment regimens were the same as in the phase II trial. However, in contrast to the prior phase II study, the administration of granulocyte colony-stimulating factor (G-CSF) was mandatory for all patients. This phase III trial produced numerically better outcomes in selumetinib vs. control arm, nevertheless the differences were small and failed to reach statistical signifi- cance (median PFS: 3.9 months vs. 2.8 months, p = 0.44; OS: 8.7 months vs. 7.9 months, p = 0.64; objective response rate: 20.1% vs. 13.7%, p = 0.05) [51]. In retrospect, one could ques- tion whether the results of the phase II trial [50] indeed provided sufficient grounds to initiate the aforementioned phase III study [51]. Unfortunately, a failure of large-scale phase III investigations after a seemingly successful phase II trials is a common practice in clinical oncology. Many cancer experts call for critical evaluation of existing regulatory pipe- lines for drug approval in order to ensure rapid adoption of truly breakthrough medicines but discourage clinical develop- ment of compounds with borderline or unclear efficacy [52–54]. Soria et al. [55] considered published data on the sensitivity of KRAS wild-type tumors to selumetinib and included in the randomized phase II second-line trial NSCLC patients with both mutated and normal KRAS status. In addition to the regimens and arms described above, a subset of patients in the selumetinib arm received a reduced dose of docetaxel (60 mg/m2, every 3 weeks). The study included 212 patients; 69% subjects had wild-type KRAS. Median PFS was 3.0 months in docetaxel 60 mg/m2 plus selumetinib 75 mg b.i.d. arm, 4.2 months in docetaxel 75 mg/m2 plus selumetinib 75 mg b.i.d. group and 4.3 months in patients receiving docetaxel 75 mg/m2 plus placebo. Subjects treated by docetaxel 75 mg/ m2 plus selumetinib 75 mg b.i.d. had a higher response rate compared to controls (33% vs. 14%, p = 0.020). Disease out- comes in KRAS wild-type patients were similar to the ones observed in the overall population. The subgroup analysis for KRAS-mutated NSCLCs was not performed due to small num- ber of cases. Lung cancer patients undergoing second-line chemother- apy after the failure of the first cytotoxic drug usually have a low life expectancy and compromised health status. Second- line treatment rarely results in pronounced responses in NSCLC patients, unless mutation-specific targeted agents are utilized [56]. Preclinical animal experiments, which evaluate the potential for drug combinations, usually utilize chemona- ive tumors. This is an essential difference between animal experiments and early-phase clinical trials, which may underlie failures to translate laboratory findings into clinical advances. Multiple evidences support the feasibility of combining selu- metinib with other drugs [45]. These assumptions led to NSCLC clinical trials, which involved first-line administration of selumetinib in combination with conventional chemotherapy. Greystoke et al. [30] carried out a phase I study, which evaluated the tolerability of combination of conventional pla- tinum-based doublets with selumetinib in first-line NSCLC treatment. Standard 21-day cycles of pemetrexed (500 mg/ m2)/carboplatin (AUC = 5) or pemetrexed (500 mg/m2)/cispla- tin (75 mg/m2) were compatible with selumetinib given in capsules 75 mg twice a day. However, conventional 3-week cycles of gemcitabine (1250 mg/m2)/carboplatin (AUC = 5) or gemcitabine (1250 mg/m2)/cisplatin (75 mg/m2) regimens were not sufficiently safe when selumetinib was added in its standard or reduced (50 mg twice a day) dose. Goffin et al. [44] confirmed the data on good tolerability of the aforemen- tioned combination of pemetrexed, cisplatin, and selumetinib when applied as the first-line treatment for NSCLC. Goffin et al. [44] also evaluated the addition of selumetinib (75 mg twice a day) to 21-day cycles of paclitaxel (200 mg/m2) plus carbo- platin (AUC = 6) and concluded that this combination is toler- able as well. Melosky et al., 2019 [57] examined the value of adding selumetinib to the combination of platinum and pemetrexed in the first-line NSCLC therapy. The study included patients with non-squamous tumor histology, who had wild-type or unknown KRAS status. Based on preclinical data of Holt et al. [45], which suggested that MEK inhibition may rescue tumor cells from chemotherapy, this study considered an intermit- tent schedule, where patients had a selumetinib holiday within 2 days preceding chemotherapy infusion. In addition to this, this study included patients receiving continuous selu- metinib combined with standard platinum/pemetrexed cycles and the control chemotherapy-only arm. The dose of peme- trexed was 500 mg/m2. Platinum agents were either cisplatin (75 mg/m2) or carboplatin (AUC = 6). Twenty patients received intermittent selumetinib plus platinum/pemetrexed 21-day cycles, 21 subjects were treated by continuous selumetinib plus standard chemotherapy and 21 NSCLC cases were allo- cated to the control group. Median PFS was 7.5, 6.7, and 4.0 months, and the tumor responses were seen in 35%, 67%, and 24% of patients, respectively. The authors acknowl- edged some promising tendencies revealed by this study, in particular, higher response rates upon addition of selumetinib. The report of Melosky et al. [57] stated that the study stopped accrual due to a high number of competing trials and an emerging trend for incorporating immune checkpoint inhibi- tors in the NSCLC first-line treatment. Oxnard et al. [58] investigated patients with EGFR-mutated NSCLC, who progressed on any therapy involving EGFR tyro- sine kinase inhibitors. They analyzed whether the addition of various drugs to the third-generation EGFR inhibitor, osimerti- nib, was safe and tolerable. Patients (n = 36) received 80 mg of osimertinib once a day, while selumetinib was given at doses 25–75 mg as continuous or intermittent treatment. Intermittent selumetinib administration was associated with fewer adverse events and therefore was recommended for subsequent phase II trials. Twenty-eight patients carried an EGFR T790M mutation in the tumor tissue at the trial start, while eight patients received osimertinib plus selumetinib while being EGFR T790M mutation-negative. The response rate was 15/36 (42%). Objective tumor responses, as assessed by the RECIST criteria, were seen not only in osimertinib-naïve EGFR T790M mutated patients (13/23, 57%), but also in some subjects who were either EGFR T790M mutation-negative (1/7, 14%) or received prior third-generation EGFR inhibitor therapy (1/6, 17%). There are several ongoing NSCLC studies, which aim to assess efficacy of selumetinib. These trials mainly consider [60]. Ho et al. [61] evaluated clinical activity of selumetinib toward RAI-refractory thyroid carcinomas. RAI uptake was increased in 5 out of 5 patients with NRAS mutations, 4 of 9 subjects with BRAF mutations and 3 out of 6 BRAF/NRAS muta- tion-negative patients. Eight of 12 patients with increased RAI uptake reached the dosimetry threshold and therefore were subjected to RAI therapy. All these patients experienced the disease control (three partial responses and five instances of disease stabilization). BRAF-mutated patients fared seemingly worse when compared with NRAS-mutated subjects; this could be explained by the fact that BRAF-mutated but not NRAS- mutated tumors are able to develop feedback collateral signal- ing when treated with selumetinib [62]. Rothenberg et al. [63] and Brose et al. [64] evaluated BRAF V600E inhibition by dab- rafenib or vemurafenib in patients with BRAF-mutated thyroid RAI-refractory cancer and observed significant rates of clinical benefit. It is of notice that BRAF-mutated tumors tend to have a significantly more pronounced and durable response when treated by a combination of BRAF V600E and MEK inhibitors, as shown in melanoma and lung cancer. There are some relevant studies confirming feasibility of this doublet in BRAF-mutated thyroid cancers [65–68]. Activation of receptor tyrosine kinases or mutations affect- ing RAS or BRAF oncogenes are the most known causes of the up-regulation of RAS-RAF-MEK-ERK pathway. Similar stimula- tion of RAS-RAF-MEK-ERK cascade can be achieved by inacti- vation of NF1 gene, which serves as a negative regulator of RAS activity (Figure 1). Expectedly, MEK inhibition suppresses the growth of NF1-deficient tumors in preclinical experiments [69]. Dombi et al. [70] conducted a phase I trial in children with a hereditary cancer syndrome, neurofibromatosis type 1, who developed inoperable plexiform neurofibromas. This study confirmed data of Banerjee et al. [47] in establishing combinations of selumetinib with other drugs, although some biomarker-driven investigations still evaluate selumetinib monotherapy in specific subgroups of patients. Ongoing selu- metinib clinical studies are summarized in Table 2. 2.6. Other relevant studies Uptake of iodine by thyroid cells is a crucial component in the synthesis of triiodothyronine (T3) and thyroxine (T4). Thyroid cancers of follicular cell origin (papillary and follicular thyroid carcinomas) often retain the ability to consume iodine. This property led to the development of targeted therapy: when radioiodine (RAI) is given to a patient, it is absorbed only by cells of thyroid origin but not by other tissues. This warrants tissue-specific action of radioactivity and selective elimination of thyroid cells [59]. Most thyroid cancers are characterized by upregulation of MAPK pathway, which is achieved by mutation-driven activa- tion of BRAF, NRAS, or some receptor tyrosine kinases. Preclinical experiments demonstrate that activation of RAS- RAF-MEK-ERK signaling cascade inhibits sodium-iodide sympor- ter and compromises RAI uptake. Accordingly, down-regulation of this pathway restores sensitivity of thyroid cancer cells to RAI a pediatric dose for selumetinib (25 mg per square meter twice daily). Partial tumor responses were observed in 17/24 (71%) patients [70]. A virtually identical response rate (35/50, 70%) was observed in a subsequent phase II study involving children with inoperable plexiform neurofibromas [71]. Fangusaro et al. [72] reported results of evaluation of selume- tinib (25 mg per square meter twice a day) in 25 patients with recurrent, refractory, or progressive low-grade gliomas. Ten (40%) patients achieved a sustained partial response; only 1 (4%) out of 25 had progressive disease. The study of Fangusaro et al. [72] also included children with BRAF-driven low-grade gliomas. BRAF mutations were represented by KIAA1549–BRAF fusions or BRAF V600E sub- stitutions. Tumor responses were observed in 9 (36%) patients. In addition, 9 (36%) patients experienced stable disease. It has to be commented that tumors harboring BRAF V600E muta- tion, including brain tumors, are often considered for com- bined BRAF and MEK inhibition [73–76]. 3. Conclusion Selumetinib demonstrated promising activity in KRAS-mutated non-small cell lung cancer in phase II clinical trials; however, it failed to achieve pre-specified end-points in a subsequent phase III clinical investigation. A subset of NSCLC patients benefit from this drug; however, markers of selumetinib sensitivity or resistance have not been established yet. Preclinical evidence suggests that MEK inhibition may significantly improve the effi- cacy of chemotherapy; however this trend remains to be vali- dated in the clinical setting. There are several highly successful non-NSCLC selumetinib studies in oncological patients. In parti- cular, selumetinib demonstrated the ability to restore radioio- dine uptake in radioiodine-refractory thyroid cancers, that resulted in some tumor responses. Selumetinib showed high efficacy in neurofibromatosis type 1 associated tumors. In addi- tion, selumetinib exerted clinical activity in low-grade pediatric gliomas harboring activated BRAF oncogene. 4. Expert opinion Selumetinib demonstrates promising signals of activity in tumors with evidence of activation of the RAS-RAF-MEK-ERK pathway. The detection and interpretation of BRAF, KRAS, and NRAS mutations is relatively straightforward, given that these mutations are usually located in ‘hot’ codons and their func- tional significance is well established. Of notice, treatment of BRAF V600E mutated tumors is likely to require BRAF V600E inhibitors as a therapy backbone, with supplementation by MEK inhibitors to prolong the depth and duration of the effect [15]. Similarly, treatment of cancers with KRAS G12C mutation will likely require KRAS G12C inhibitors if the latter will succeed in clinical trials [21,22]. There are other indicators of RAS- RAF-MEK-ERK pathway activation, whose clinical detection is not yet well established. For example, inactivation of the NF1 gene may serve as a marker of upregulation of RAS signaling and call for the use of MEK inhibitors [69–72,77]. There are occasional reports on mutations in kinases belonging to the MEK-ERK module of the MAPK cascade, which are associated with a pronounced response to selumetinib [78]. ERK1/2 tyr- osine phosphorylation may be used as a marker of RAS-RAF- MEK-ERK pathway activity [26,28], although it has not been utilized in selumetinib clinical trials. There are also some potential predictive markers located outside the RAS-RAF- MEK-ERK signaling cascade [79–83]. There are several MEK inhibitors available for routine medical use or clinical trials, with trametinib and cobimetinib being the most studied. It is unclear, to what extent they are inter- changeable with selumetinib. Early clinical trials suggested that selumetinib exerts activity in BRAF-mutated melanomas similar to the one observed for trametinib and cobimetinib [81,84,85]. We are not aware of selumetinib trials in BRAF V600E mutated lung cancer; these cancers are currently man- aged by a combination of dabrafenib and trametinib [86]. Some MEK inhibitors may have an advantage compared to selumetinib, as they have a different mode of interaction with the target and do not allow the development of collateral signaling cascade [62]. The emergence of immune checkpoint inhibitors, which normalize antitumor immunity, is often regarded as the most sig- nificant advance in clinical oncology in recent years. Multiple evidences suggest that MAPK pathway activation not only ren- ders an increased cell proliferation but also supports tumor escape from immune surveillance [87]. Consequently, combining MEK inhibitors with immune therapy is viewed as promising avenue for clinical research [88–90]. Acknowledgments We thank Dr A Whitehead of The University of Illinois College of Medicine for the critical reading of this manuscript. Funding This work has been supported by the Russian Science Foundation [grant 17-75-30027]. Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Reviewer disclosures One referee declares having participated in the phase 3 trial of selumeti- nib + docetaxel as well as in ongoing trials with trametinib. Peer reviewers on this manuscript have no other relevant financial relationships or other- wise to disclose. References Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers. 1. Akinleye A, Furqan M, Mukhi N, et al. MEK and the inhibitors: from bench to bedside. J Hematol Oncol. 2013;6:27. 2. 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