Selumetinib in the treatment of NSCLC

Reyes Bernabé1,2, Ana Patrao1, Louise Carter1, Fiona Blackhall3,1, Emma Dean3,1

Affiliations:1 The Christie NHS Foundation Trust, Manchester, UK2 Hospital Valme, Seville, Spain3 The University of Manchester, Manchester, UK

Conflicts of InterestDr. Emma Dean has been Chief Investigator on commercial trials of selumetinib.

INTRODUCTION

Lung cancer is the commonest cancer worldwide with an estimated 1.8 million new cases

per year and high mortality rates representing 1 in 5 deaths from cancer [1]. NSCLC (non-

small cell lung cancer) accounts for approximately 85% of all cases of lung cancer and about

70% present with locally advanced or metastatic disease at diagnosis [2]. Chemotherapy is

the backbone of treatment for many patients, but increased knowledge about cancer biology

garnered interest in the development of targeted therapies against molecular drivers within

the tumour. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase

(ALK) inhibitors have proven efficacy with response rates of around 45-65%, and are

standard treatment strategies in patients with EGFR mutant and ALK mutant disease,

respectively [3, 4].

The RAS-RAF-MEK-ERK pathway has been extensively researched in the past 25 years

and it is estimated that one third of human cancers contain mutations in this pathway [5].

KRAS mutations are the most common mutations seen in NSCLC with a prevalence of

approximately 30% in patients with adenocarcinoma and about 6% in squamous histology

[6]. RAS proteins are anchored to the cytoplasmic side of the plasma membrane and are

responsible for the communication of external cellular signals to the nucleus [7]. In normal

cells, when RAS signalling is activated, it interacts with RAF (A-RAF, B-RAF, C-RAF and

RAF-1), a serine/threonine kinase, leading to its activation. The activated RAF

phosphorylates and activates MEK 1 and MEK 2 kinases, leading to downstream

phosphorylation and activation of extracellular signal-regulated kinases, ERK 1 and 2. This

activation triggers downstream activation of nuclear and cytoplasmic targets associated with

transcription, cell proliferation, differentiation and metabolism, [6,7], Figure 1.

Mutations in the KRAS pathway lead to constitutive activation of the RAF-MEK-ERK

pathway. Originally, KRAS mutations were considered to have similar clinical and biological

activity but recent data suggests that different KRAS mutations might produce different

downstream signalling effects. KRAS G12D, the dominant mutation found in the tumours of

non-smokers seems to transduce signals via the PI3K-AKT, INK, p38 and FAK pathways

[8]. There is also some evidence that MEK signalling can be activated independent of RAS

signal by MAP3k1 and MAP3k8 which are mutated in some tumour types [6].

OVERVIEW OF RAS-RAF-MEK-ERK TARGETED THERAPIES

Recognition of the RAS-RAF-MEK-ERK pathway as an oncogenic driver in tumours has led

to the development of targeted agents that can inhibit its activity. Efforts to inhibit mutant

RAS or its membrane association using farnesyl transferase inhibitors failed to show clinical

benefit [9]. Two BRAF inhibitors are currently approved for the treatment of BRAF mutated

malignant melanoma, vemurafenib and dabrafenib. Although impressive initial responses are

observed, unfortunately the majority of patients relapse in less than one year. Second

generation B-RAF inhibitors are being developed [5]. The most advanced in development is

encorafenib (LGX-818, Novartis, Array), that is currently being tested in the phase III trial

COLUMBUS versus vemurafenib either alone and in combination with a MEK-inhibitor [10].

MEK is a central component of the signalling cascade. MEK 1/2 inhibitors have their greatest

anti-tumour effects in patients harbouring RAS or BRAF mutations but there are examples of

activity in non-mutant patients. MEK1/2 inhibitors have also been implicated in modifying the

response to cytotoxic chemotherapy and other targeted agents [11]. MEK inhibitors have

been shown to induce apoptosis by reducing cyclin D1 levels and inducing p27KIP1

expression, as well as the dephosphorylation of Retinoblastoma protein (Rb) causing the

arrest of cells in G1 phase. Furthermore, MEK inhibitors alter the balance between

proapoptotic / prosurvival proteins from the Bcl2 family in favour of apoptosis [7].

Even though MEK seemed a promising target, the first generation MEK inhibitors, PD098059

and U0126, did not have in vivo activity [12,13]. CI-1040 and subsequently PD0325901 were

the first to be tested in clinical trials but research was suspended due to lack of clinical

activity and toxicity profile [14,15]. Second generation MEK inhibitors, believed to be more

potent and less toxic, have shown more promise pre-clinically and have demonstrated

efficacy in clinical trials. The only approved MEK inhibitor to date is trametinib, which is used

in combination with dabrafenib for the treatment of malignant melanoma patients, but several

others are in development [5]. In NSCLC, the MEK inhibitor selumetinib has shown the most

promising results to date. Table 1 summarizes the MEK inhibitors that are currently in clinical

trial or have been tested in NSCLC patients. Several other MEK inhibitors such as

Pimasertinib, Refametinib, E06201 and cobimetinib are in development in other cancer

disease types [5].

ERK is the only substrate to MEK kinase and has been considered a druggable target

although most efforts have focussed on upstream blockade. Several ERK inhibitors have

been studied in phase I trials; Ulixertinib (BVD-523), GDC-0994 (RG-7842), CC-90003 and

SCH900353. The results of the Phase I trial of Ulixertinib were presented at ASCO 2015

where it was reported that the toxicity profile was manageable and the maximum tolerated

dose was 600 mg twice a day. Other ERK inhibitor trials are still ongoing [16].

SELUMETINIB

Selumetinib (AZD6244: ARRY-142866) is an orally available, potent, selective inhibitor of

MEK 1 and 2 [6]. This drug has been extensively researched in several tumour types with

mixed results, Table 2. In this review we will analyse its pharmacokinetic and

pharmacodynamic properties as well as discuss trials results considering its clinical efficacy,

toxicity and potential developments in the future in NSCLC.

Chemistry

Selumetinib, (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-

methylbenzimidazole-5-carboxamide) has the molecular formula C17H15BrClFN4O3 and the

molecular weight of 457.681403 g/mol. It is a second generation, orally active small

molecule that acts as a selective and ATP-uncompetitive inhibitor of MEK 1 and 2, binding to

the allosteric binding site.

Pharmacodynamics

The activity of selumetinib has been investigated in a number of preclinical studies.

Selumetinib inhibits the enzymatic activity of purified constitutively active MEK 1 with a half

maximal inhibitory concentration (IC50) of 14 nmol/L. It is highly selective for MEK 1 and 2

compared to 40 other serine/threonine and tyrosine kinases at concentrations of up to 10

µmol/L [17]. Selumetinib causes inhibition of growth in a range of cell lines including NSCLC,

melanoma, pancreatic and colorectal cell lines. Analysis of the IC50 in cell lines showed a

tendency for cell lines with BRAF and RAS mutations to be more sensitive to selumetinib

than those that were wild type for the genes, though this trend was not absolute, particularly

amongst KRAS mutated cell lines [18]. Selumetinib had little effect on the growth of Malme-

3, the control cell line to the melanoma cell line Malme-3M, suggesting its effects are not due

to general cytotoxicity [17].

Analysis of a range of cell lines showed that selumetinib effectively inhibits the

phosphorylation of ERK 1 and 2, which are substrates of MEK 1 and 2 in the MAP kinase

pathway [17,18]. The inhibition of ERK phosphorylation by selumetinib has also been

confirmed in clinical trials through the analysis of both circulating lymphocytes and tumour

samples before and after dosing. In circulating lymphocytes up to 100% inhibition of ERK

phosphorylation was seen 1 hour after the first dose of selumetinib and with continued

dosing up to 90% inhibition was seen in trough samples at day 15 and 22, confirming target

inhibition [19]. In the analysis of paired tumour biopsies, inhibition of ERK phosphorylation by

on average 79% was also demonstrated by IHC, though Ki67 was not as consistently

reduced in these samples [19].

Preclinical animal studies have confirmed that selumetinib causes tumour growth inhibition in

mouse models bearing xenografts containing both KRAS and BRAF wild type and mutated

genes [17,18]. Analysis of the effect of chronic twice daily dosing of 25mg/kg of selumetinib

showed stasis in Colo-205 tumours, moderate inhibition of growth in SW-620 tumours

(colon) and strong inhibition of growth in Calu-6 tumours (head and neck), suggesting that in

vitro sensitivity generally predicts for in vivo sensitivity [18]. Inhibition of ERK

phosphorylation was also demonstrated, with an inverse correlation between the plasma

drug concentration and the levels of phosphorylated ERK seen in Calu-6 xenografts [18].

Increased markers of apoptosis such as cleaved caspase 3 and decreased cell proliferation

were seen in response to treatment with selumetinib in the xenograft models [18].

Selumetinib has been shown in preclinical studies to be effective when combined with both

standard cytotoxics such as docetaxel and irinotecan, and targeted agents such as mTOR

inhibitors and AKT inhibitors [11,18,20,21,22,23,24]. The combination of docetaxel and

selumetinib has been shown to be synergistic in studies utilising SW-620 xenograft mouse

models [18]. The response of genetically engineered KRAS NSCLC mouse models to

docetaxel was reduced if there was concomitant loss of p53 or Lkb1 [25]. However, the

addition of selumetinib to docetaxel showed significant augmentation of the response to

docetaxel in the KRAS mutant models and the KRAS/p53 mutant mouse models. The

KRAS/Lkb1 mutant mouse models were resistant to docetaxel and selumetinib. This

suggests that response to selumetinib may be influenced by a combination of mutations

rather than driven by a single mutation.

Pharmacokinetics and Metabolism

Selumetinib was originally formulated as a free-base suspension which was also referred to

as selumetinib “mix and drink” formulation. After a single dose, the free-base suspension

had a median half-life (t1/2) of 8.3 hours in a study of 57 patients [19]. The mean area under

the plasma concentration-time curve (AUC) after both single doses and at steady state

increased with increasing doses but in a less than dose-proportional manner. A capsule

formulation incorporating a hydrogen sulfate salt (Hyd-Sulfate) was latterly formulated for

ease of dosing. A phase I trial looking at the Hyd-Sulfate capsule showed it was rapidly

absorbed with a median time to maximum plasma concentration (tmax) of 1 to 1.6 hours and

median t1/2 of 5 to 8 hours [26]. The total body clearance (CL/F) and volume of distribution in

the steady state (Vss/F) were consistent across the dose range studied, with mean values of

12 to 23L/h and 87 to 126 L respectively.

Comparison of the pharmacokinetics of the two selumetinib formulations was undertaken in

a phase I trial in which single doses of each formula at maximum tolerated dose (MTD) were

given sequentially to patients with a wash-out between the two formulations [26]. Analysis of

results from 27 patients showed similar tmax and mean t1/2 obtained for both formulations as

were CL/F and Vss/F. However, both the maximum serum concentration and AUC over 24

hours (AUC0-24) were higher at the MTD dose for the Hyd-Sulfate formulation than the free

base solution at 1,316 ng/ml and 4,545 ng x h/ml respectively in contrast to the 523

ng/mland 2,260 ng x h/ml. The estimated oral bioavailability, calculated using the AUC0-24 of

the Hyd-Sulfate formulation relative to the free-base suspension was 263% (90% CI 241-

322%).

A randomised phase I study was performed to assess the effect of food on the absorption of

selumetinib Hyd-Sulfate capsules [27]. It demonstrated that both the Cmax and AUC of

selumetinib were decreased by 62% and 19% respectively in the fed versus the fasted state.

The rate of absorption of selumetinib was delayed by approximately 2.5 hours in the

presence of food. These results have led to the recommendation that selumetinib should be

taken on an empty stomach (no food or drink for two hours prior and one hour after dosing).

Selumetinib is metabolised in the liver by the cytochrome P450 enzymes 1A2, 2C19 and

3A4 with CYP1A2 being responsible for the metabolism of Selumetinib to the active

metabolite N-desmethyl-selumetinib [27]. In comparison to selumetinib, N-desmethyl-

selumetinib showed 3 to 5 fold greater potency for the inhibition of MEK 1 but lower

exposure (AUC) was noted. [26] Elimination of selumetinib is likely to be predominantly

through glucuronidation as the majority of selumetinib metabolites are detected as

glucuronide conjugates [27]. The selumetinib metabolites are then excreted in faeces.

Trametinib and selumetinib have similar tmax values of approximately 1.5 hours but the t1/2 of

trametinib is much longer than selumetinib at 4 days in contrast to less than 8 hours,

highlighting one of the differences of Selumetinib compared to other MEK inhibitors [8].

CLINICAL TRIALS

PHASE I TRIALS

Initial phase I trials of selumetinib in patients with solid tumours established the MTD of the

two formulations: free-base suspension and capsule. Subsequent phase I trials were

performed to assess novel combinations of selumetinib with chemotherapies or targeted

treatments.

Adjei et al. reported [19] that AZD6244 formulated as free based suspension, is well

tolerated up to 100 mg bid. The maximum tolerated dose (MTD) was 200 mg bid, but due to

a dose dependent increase in the frequency and severity of rash, a lower dose level (100

mg) was the recommended dose for phase II trials. Among the 57 patients analyzed, the

most frequent toxicity was rash occurring in 74% of all patients. Nine of the 43 episodes of

rash were grade 3 or 4 (20%). Other grade 3 or 4 toxicities reported were fatigue, oedema

and ALT elevation. The best overall response was stable disease (SD) in 17 patients with

solid tumours.

Barneji et al. reported the MTD of the hydrogen sulfate oral capsule formulation of

selumetinib at 75 mg bid [26]. The overall evaluation of the safety and tolerability of Hyd-

sulfate capsules showed a toxicity profile similar to that observed with the free-base

suspension formulation. The most frequent grade 3/4 toxicity was fatigue (17%). Other grade

3/4 toxicities were acneiform dermatitis (5.7%), vomiting (5.7%), peripheral edema (2.9%),

and exertional dyspnea (2.9%). Out of 55 patients with solid tumours evaluable for response,

the best overall response seen was a complete response in one patient and a further 26

patients had SD.

SELUMETINIB AND CHEMOTHERAPY TRIALS

The combination of docetaxel and selumetinib has been shown to be synergistic in vivo [18].

Two schedules were compared: a single dose of docetaxel (15 mg/kg) followed 24 hours

later by selumetinib (25 mg/kg bid) for 7 days or selumetinib administered for 7 days

followed 24 hours later by docetaxel. The tumor growth inhibition was 110% when docetaxel

was administered before selumetinib compared with 61% when docetaxel was administered

after selumetinib. These results suggested that the best sequence of treatment in order to

enhance the efficacy was docetaxel followed by selumetinib [11].

Subsequently, the docetaxel/selumetinib combination was tested in a Phase I trial

investigating different combinations of selumetinib and chemotherapy in advanced solid

tumors to establish the safety and pharmacokinetics profile of 75 mg b.i.d continuous

selumetinib dosing in combination with docetaxel 75 mg/ m2 intravenously every 21 days

[28]. In a heavily pretreated population the most common adverse events were peripheral

oedema (71%), diarrhea (69%) and fatigue (63%). The commonest grade 3-4 toxicities were

hematological events (51%) and infections (26%). Other toxicities noted were nausea (49%),

vomiting (46%) and dermatitis acneiform (40%). A phase I trial investigating the safety and

tolerability of selumetinib alone or in combination with docetaxel in Japanese patient with

advanced solid tumours or NSCLC has been completed with results awaited (NCT

01605916) [10].

Two phase I trials in an unselected population of patients with NSCLC have explored the

optimal dose of selumetinib in combination with standard first line chemotherapy regimens

used in NSCLC. SELECT-3 is assessing Selumetinib in combination with cisplatin or

carboplatin combined with either gemcitabine or pemetrexed. The primary objective is to

investigate the safety, tolerability and recommended dose of selumetinib in combination with

first line chemotherapy. The secondary objectives are the pharmacokinetic analysis and

preliminary assessment of efficacy based on objective response rate (ORR). Preliminary

results were presented at ESMO 2014, selumetinib 75mg bid was tolerated in combination

with carboplatin and pemetrexed and selumetinib 50 mg bid was tolerated in combination

with cisplatin and gemcitabine. Selumetinib 50mg bid was not tolerated in combination with

carboplatin and gemcitabine due to grade 4 thrombocytopenia. Serious AEs were reported in

13 patients, 7 of them were considered related to selumetinib. The preliminary activity

observed was four partial response and 13 patients with stable disease > 6 weeks. [29]. In

the NCT 01783197 trial, 39 patients with NSCLC were recruited in to three cohorts. The

patients were randomized to receive selumetinib combined with carboplatin and paclitaxel

(cohort 1), cisplatin and pemetrexed (cohort 2) or pemetrexed alone (cohort 3). The primary

objective was to determine the MTD of selumetinib in combination with chemotherapy and

secondary aims included the determination of the pharmacokinetic profile of selumetinib,

study KRAS codon subtypes that may influence response and preliminary assessment of

efficacy. Toxicity results of cohort 1 and cohort 2 patients were reported at ASCO 2015 [30]. Among 11 evaluable patients who received carboplatin, paclitaxel and selumetinib, 4 had ≥

grade 3 adverse events including a fatal lung infection, 1 patient with a fatal stroke, 2

patients with G3 neutropenia and 1 patient had G4 thrombocytopenia. For the

cisplatin/pemetrexed/selumetinib cohort, 16 patients were evaluated: 4 patients had G3

adverse events (AEs) (retinal vascular disorder, thromboembolism and gastrointestinal (GI)

toxicity). One patient had a G3 CPK increase. Patients continue to be enrolled into the

recommended phase II dose expansion cohorts at a dose of 75 mg bid d1-21.

SELUMETINIB AND TARGETED THERAPY TRIALS

The combination of selumetinib with novel agents targeting other molecular pathways has

also been explored to ascertain whether greater efficacy can be obtained with parallel

pathway blockade. Selumetinib in combination with vandetanib, a dual EGFR and VEGFR

inhibitor, has been investigated in a Phase I trial (NCT01586624). The first part of the study

included patients with any solid tumor whilst the expansion cohort was restricted to patients

with NSCLC. The main objectives were to determinate the safety and toxicity profile of the

combination and establish the MTD. The secondary objectives included the plasma PK

profile of both drugs, assessment of tumour metabolism using FDG-PET, progression free

survival (PFS) at 12 weeks by RECIST criteria and 1-year survival rates. Preliminary data

has shown that amongst the 41 patients enrolled (23 with NSCLC), the most prevalent

toxicities were GI (88% patients) and skin (95% patients). 16 related eye disorders were

seen including 2 retinopathies (G2 and G3). Both toxicities, skin and eye, were found to be

dose-dependent and a higher incidence of reversible eye events was observed with the

combination of vandetanib and selumetinib when compared to that of the single agent. The

PK data for the combination were similar to those reported for either drug alone. The

selumetinib dose recommended in combination with vandetanib is 100mg once daily or 50

mg twice daily. SD was confirmed in 4 NSCLC patients and the expansion cohort is currently

recruiting [31].

A Phase Ib combination trial of selumetinib and gefitinib in EGFR-mutant NSCLC patients

who progressed on first line of tyrosine kinase inhibitor (TKI) treatment is currently recruiting

(NCT02025114). Its primary objective is to determine the MTD of selumetinib in combination

with gefitinib whilst the expansion phase will evaluate the efficacy, safety and tolerability of

the combination. Twenty patients will be required for the expansion phase, 10 patients with

and 10 patients without T790M mutations. TATTON (NCT02143466) is a multi-arm phase Ib

trial studying AZ9291 in combination with the anti-PD-L1 monoclonal antibody (mAb)

MEDI4736, the MET inhibitor (AZD6094) or selumetinib. The target patient population

includes patients with advanced EGFR-mutant lung cancer who have progressed on any

prior EGFR-TKI. AZD9291 was dosed at 80 mg daily and dose of the 2nd agent was

escalated. Forty-two patients were enrolled (21 in selumetinib arm). The initial results from

20 patients across all the arms have been reported [32]. Mild/moderate AEs were observed

in 16 patients and severe AEs in 4 patients (1 skin, 1 laboratory, 1 GI and 1 metabolism). In

the selumetinib arm, one dose limiting toxicity of transaminase elevation has been reported

and two partial responses have been observed.

One possible resistance mechanism to selumetinib in NSCLC patients is activation of the

PI3K pathway [33]. A high level of AKT activation is associated with resistance to MEK

inhibitor whilst dual inhibition of the AKT and ERK pathways increased the antitumor activity

of selumetinib. The combination of selumetinib and the PI3Kα inhibitor BYL719 can induce

synergistic inhibition of tumour growth both in vitro and in vivo [34]. Tolcher et al. conducted

a dose/schedule-finding study evaluating MK-2206 (AKT inhibitor) and selumetinib in

patients with advanced treatment-refractory solid tumours [35]. In this phase I trial, initial

cohorts of 3-6 patients with advanced, treatment-refractory solid tumours were recruited and

given combinations of MK-2206 and selumetinib. Additional patients were enrolled to

evaluate tolerability. A dose-expansion cohort at the MTD recruited an additional 11 patients

with KRAS-mutant non–small-cell lung cancer (NSCLC); the most frequent adverse event

was rash and other DLTs include diarrhoea and stomatitis which appeared to be dose-

related. No haematological toxicities were observed and a dose limiting detachment of

retinal pigment epithelium was observed in 2 patients. Pharmacokinetics suggested no

meaningful drug-drug interaction between MK-2206 and selumetinib. Among the 29 patients

with KRAS-mutant disease treated in this study, 3 partial responses were observed among

NSCLC cancer patients (23%) and a one partial response in a patient with ovarian cancer.

The combination of afatinib and selumetinib is also being investigated in PI3KCA wild-type

and KRAS mutant colorectal, lung cancer and pancreatic cancer (NCT02450656). NCT

02583542 trial is exploring the combination of selumetinib and an mTOR inhibitor (AZD2014)

inpatient with squamous lung cancer, non-squamous lung cancer (with and without mutant

KRAS) and triple negative breast cancer.

SELUMETINIB AND RADIOTHERAPY

The effect of combining selumetinib with fractionated radiotherapy in human tumour models

(Calu/6 lung and HCT116 colon tumor xenografts) has been reported, showing a significant

increase in antitumor effects compared with single therapy treatment. The underlying

mechanisms may be a direct radiosensitization of tumour cells by AZD6244, modifications in

tumor hypoxia or in tumor vasculature that could sensitize to radiation damage [36]. A phase

I trial of selumetinib in combination with thoracic radiotherapy in stage III or stage IV NSCLC

in patients with dominant chest symptoms (NCT01146756) is currently enrolling. The

objectives are to determine the recommended phase II dose and safety profile of the

combination.

PHASE II TRIALS

Selumetinib has been evaluated in a Phase II trial compared with pemetrexed in the second

or third line treatment of patients with advanced NSCLC [37]. 84 patients were randomized

in a 1:1 ratio to receive selumetinib 100mg oral free-based suspension bid continuously or

pemetrexed 500 mg/m2 every 21 days. There was no selection based on BRAF or KRAS

status and patients with adenocarcinomas made up less than 50% of each arm. The primary

objective was to evaluate the efficacy through assessment of disease progression events.

There was no statistical difference between the two arms of treatment in progression-free

survival. The most common adverse events in the selumetinib group were dermatitis

acneiform and diarrhea. Severe adverse events included one patient with a respiratory

failure in the selumetinib arm. Currently, a further randomized phase II trial is ongoing in

KRAS wildtype or unknown non-squamous NSCLC patients. The trial is comparing two

different regimens of selumetinib plus cisplatin/pemetrexed or cisplatin/pemetrexed alone.

The primary objective is response rate, (NCT 02337530).

The potential synergy between selumetinib and docetaxel was assessed in a phase II trial of

previously treated patients with advanced KRAS-mutated NSCLC. The prospective,

randomized, double-blind trial enrolled 87patients. The primary objective was overall survival

(OS). The patients were randomized to receive docetaxel 75 m/m2 iv every 21 days plus oral

selumetinib Hyd-sufate capsule 75mg bid (n=44) or matched placebo (n=43) until disease

progression or unacceptable toxicity. Median follow-up was 7.2 months. Median OS was 9.4

months (CI 6.8-13.6) in the selumetinib arm and 5.2 months (95% CI 3∙8–non-calculable) in

the placebo arm. Median PFS was 5.1 months (95% CI 4∙6–6∙4) in the selumetinib group vs.

2.1 months (CI 1.4-3.7) in the placebo group. Sixteen patients in the selumetinib group

achieved a PR and 19 patients (37%) had SD>6 weeks. No patients in the placebo group

had an objective response and SD was observed in 20 patients. The proportion of any grade

adverse events was higher in the selumetinib group and the most frequent grade 3-4

toxicities were neutropenia, febrile neutropenia and asthenia. Selumetinib seemed to

increase the severity of neutropenia associated with docetaxel and the use of granulocyte-

colony stimulating factor (GCSF) was higher in the selumetinib group. Consistent with

preclinical data, the combination of the two drugs, selumetinib and docetaxel, seems to have

a synergistic effect compared with docetaxel alone. SELECT-2 (NCT01750281) is a double-

blind randomized three arm phase II trial that is exploring two different doses for docetaxel in

combination with selumetinib (75 mg/m2 or 60 mg/m2). The control arm is docetaxel

monotherapy. Recruitment is complete but final data is awaited.

Retrospective analysis of this study has recently reported the impact of different KRAS

codon mutations or combinations of codon mutations on the efficacy of treatment [38]. Two

groups of patients were assessed: the MG1 group who harboured KRAS G12C or G12V

mutations and the MG2 group with all KRAS mutations other than G12C or G12V. The most

common KRAS mutations were G12C (46%), G12D (22%) and G12V (11%). For the

patients who harboured G12C or G12V (MG1 group) the median OS for the

selumetinib/docetaxel arm was 9.6 months and 8.6 months in placebo arm. However, in the

MG2 group, the OS for selumetinib/docetaxel was 4.4 months versus 7.1 months in the

placebo arm. The weak trend towards longer survival in the group MG1 compared to MG2

seems to be largely driven by patients with KRAS G12C mutations (HR0.59, 80% CI:0.35-

1.00). The ORR was higher in the MG1 group compared to the MG2 group in the

selumetinib/docetaxel arm. The trends to differences between both groups, MG1 and MG2,

in OS and PFS were not statistically significant. However, the initial study design was not

powered to detect differences in survival among the different KRAS mutations subtypes but

the authors hypothesized that different KRAS mutations may vary in the degree to

dependence produced upon RAS/RAF/MEK/ERK signaling.

The combination of selumetinib and erlotinib in patients with NSCLC has been investigated

in two parallel phase II trials (NCT01229150) [10]. 89 patients were included across both

trials. Participants were divided into two groups based on the status of KRAS in their tumour.

Fifty percent of the patients recruited had wild type KRAS and 50% had mutated KRAS, with

half the patients receiving selumetinib and erlotinib and the remaining patients erlotinib

alone. The main objective was ORR for the KRAS mutant group and PFS for the KRAS wild

type group. In the mutant KRAS patient group, the ORR was higher in the combination arm

but the PFS was similar in the two arms. In the wild type KRAS group no difference was

identified in either ORR or PFS between the two treatment arms.

PHASE III

Several phase III trials are currently ongoing. SELECT-1 (NCT01933932) is a phase III,

doubled-blind trial designed to assess the efficacy of docetaxel with selumetinib compared

with docetaxel alone as a second line treatment in KRAS mutant advanced NSCLC patients.

The primary end-point is PFS and the secondary end-points are OS, ORR, duration of

response, symptoms improvement rate and time to symptom progression, safety and

toxicity. The patients were randomized to receive docetaxel 75mg/m2 every 3 weeks with

selumetinib 75mg capsules orally twice a day or placebo. The trial is ongoing though

recruitment is completed [10].

BASKET TRIALS

Selumetinib has also been investigated using the novel basket design. The goal of this

design is to investigate the effects of targeted agents against specific molecular aberrations

across multiple tumour and histological subtypes at the same time. The CUSTOM TRIAL

(NCT01306045) evaluated the efficacy of multiple therapies in specific molecular subsets of

patients with NSCLC, small cell lung cancer and thymic malignancies. Patients were

screened for a range of mutations to determine the treatment arm they were allocated to:

KRAS, HRAS, NRAS or BRAF mutations (selumetinib), EGFR mutations (erlotinib), PI3KCA,

PTEN or AKT1 mutation or PI3KCA amplification (an AKT inhibitor MK2206), ErbB2

mutation or amplification (lapatinib), KIT or PDGFRA (sunitinib). Patients without these

mutations received standard treatment. 647 patients were enrolled into the trial. Of the 110

patients with RAS/RAF mutations, 11 patients had lung cancer (10 with NSCLC and 1 with

SCLC) and were treated with selumetinib. In 9 evaluable patients with NSCLC, only one PR

was observed, and a median PFS time of 2.3 months and median OS time of 6.5 months

were seen. [39] The trial was powered to identify an ORR of 40% in patients whose

treatment was selected based on molecular alterations. Selumetinib monotherapy failed to

achieve the primary endpoint of the trial with an ORR for patients treated with selumetinib of

just 11%. One possible explanation of these data could be that KRAS mutant tumors not

only depend on MAP kinase signaling but another additional genetic aberration, such as the

loss of key tumor suppressors that might be involved in the response of the selumetinib

treatment [40]. BATTLE-2 trial is a bayesian 2-stage biomarker-based adaptive randomized

trial for advanced NSCLC patients designed to test the efficacy of the targeted agents and

their combinations and identify corresponding prognostic and predictive markers [41]. The

primary objective is 8 week disease control rate and four treatment arms are erlotinib,

sorafenib, MK-2206 (AKT inhibitor) plus erlotinib and MK-2206 and selumetinib. The

recruitment is still on going and the first data on 480 patients are expected to be available in

July 2017.

SAFETY, TOLERABILITY AND QUALITY OF LIFE

The most prevalent toxicities of selumetinib are skin and gastrointestinal (GI) toxicities, Table

3. Skin toxicity was identified in phase I trials as a dose-limiting toxicity [19]. Selumetinib skin

toxicity is a dose-dependent toxicity and normally results in an erythematous maculopapular

rash that predominantly affects the upper torso of patients. The majority of the cases are

mild to moderate in severity, and interruption of the drug or dose reduction results in

resolution of symptoms. For the management of patients with grade 1 rash mild or moderate

strength topical steroids are recommended with in some cases topical antibiotics required in

addition. For grade 2 toxicity, oral antibiotics can be considered. For 3-4 grade toxicity

selumetinib interruption and treatment with topical steroid and oral antibiotic are required.

Broad spectrum antibiotics cover is indicated if infection is suspected. Other skin toxicities

reported include acute paronychia, xerosis cutis, pruritus, fissures, telangiectasias,

hyperpigmentation, increased alopecia and angular cheilitis [42].

GI toxicities, which were commonly reported in the phase I trials, included diarrhea, nausea

and vomiting. Mild to moderate diarrhea was the principal toxicity (56%) and one third of

patients required concomitant loperamide treatment. Most diarrhea adverse events started in

the first two weeks of selumetinib treatment. Nausea and vomiting were effectively managed

with antiemetic treatment [26]. Other reported toxicities in selumetinib phase I trials were

grade 1-2 peripheral edema and visual events.

The toxicity from the combination of selumetinib and chemotherapy has also been evaluated

in phase I and phase II trials. The addition of selumetinib to docetaxel results in higher

incidence of ≥ grade 3 adverse events compare to that docetaxel monotherapy [43]. The

most frequent serious adverse events of the combination treatment were febrile neutropenia

(14%), pneumonia (9%) and neutropenia (7%). An increased in the use of GCSF was

reported and treatment discontinuation due to toxicity occurred more frequently in the

combination arm. Higher rates of non-hematologic adverse events were also seen, mostly

grade 1-2, including diarrhea, vomiting, stomatitis and dry skin. Haematologic adverse

events have also been commonly reported in the trial combination of selumetinib and

cisplatin/pemetrexed, selumetinib and carboplatin/paclitaxel and selumetinib and

pemetrexed [37].

Special mention is required for the combination of selumetinib and other targeted therapies

which normally have overlapping toxicities. Vandetanib and selumetinib (Van-Sel1 trial)

reported higher eye disorder events including two retinopathies (G2 and G3). GI toxicities

were reported in 88% of patients and skin toxicities in 95%.

Quality of life data has been evaluated in a post hoc analysis of disease-related symptoms

based on Lung Cancer Subscale (LCS) in the docetaxel+ /-selumetinib in patients with

previously treated advanced KRAS-mutated NSCLC [43]. The results showed that

significantly more patients treated with the combination of selumetinib and docetaxel

experienced improvements in quality of life compared with those who received docetaxel

plus placebo (LCS improvement rates: 44% versus 25% OR 2.5,80% CI1.34 to 4.77) and the

time to worsening of quality of life also favoured the combination treatment.

CONCLUSIONS AND FUTURE PERSPECTIVES

The management of NSCLC continues to pose significant challenges. Molecularly targeted

therapies have been a valuable weapon to prolong survival in some subsets of patients. The

RAS-MEK-ERK pathway has been shown to have an important role in the oncogenic

process. Results available to date on the use of MEK inhibitors, in particular selumetinib,

provide proof of concept that this pathway is a valid target in NSCLC. Nevertheless, the

complexity of this pathway, its interaction with other pathways and the early development of

resistance mechanisms present barriers to the successful development of novel targeted

drugs. The first unanswered question is the role of molecular testing to predict response to

MEK inhibitors. At the present moment, KRAS testing is not standard of care in lung cancer

given its role was predominantly to indicate poor prognosis. The recent and ongoing trials

with selumetinib and other MEK inhibitors, including the findings that different KRAS

mutations effect downstream signaling in other signaling pathways raises the question

whether this should be considered in the future. The evidence of primary resistance to MEK

inhibitors suggests that molecular analysis beyond KRAS testing alone may be required for

patient selection. The development of a predictive biomarker for MEK inhibitors will certainly

be crucial to further development and clinical utility.

Resistance, primary and secondary, is another critical issue in the development of these

drugs. Amplification of mutant BRAF, STAT3 upregulation, mutation in the allosteric pocket

of MEK blocking inhibitor binding or leading to constitutive MEK activity, biochemical

feedback loops and crosstalk with other pathways (mainly PIK2-AKT-mTOR) are some of

the mechanisms responsible for resistance. Suggestions to overcome resistance, such as

ERK inhibition or treatment with HGF/c-met, have been proposed, but the emergence of

resistance phenotypes are still not completely known and can be a limiting step to the

development of these drugs. Pre-clinical evidence suggests that parallel blockade,

combining MEK and AKT inhibitors, might be beneficial in KRAS mutant patients. The initial

phase I trial has shown some activity of this combination and further clinical trials are

awaited to better understand its clinical impact. The dual blockade of RAS-MEK-ERK

cascade has proven successful using the combination of trametinib (MEK inhibitor) and

dabrafenib (BRAF), recently approved by the FDA for the treatment of BRAF mutant

metastatic melanoma. This rationale may be applicable to NSCLC, potentially providingone

mechanism to prolong clinical benefit and overcome resistance.

Considering the rather modest benefit seen in the use of MEK inhibitors as single agents,

the recent focus has been the combination of MEK inhibitors either with novel agents or with

standard of care options such as chemotherapy and tyrosine kinase inhibitors. The

combination of selumetinib and docetaxel has shown promising results and the phase III trial

conclusions are awaited to confirm the clinical validity of this regimen.

Selumetinib has shown tolerability, with a manageable toxicity profile associated with some

clinical efficacy. It is not clear if the results obtained will be practice changing and most

expectations rely on the combination trials. A vast numbers of trials have also been

conducted in other tumour types with mixed results.The most promising data has been

observed in uveal melanoma and billiary tract cancer. With theemergence of other MEK

inhibitors in lung cancer, it isunclear whether selumetinib will be the MEK inhibitor of choice

for this particular target. In summary, there is a strong rationale and promising initial clinical

data, but the future will depend on optimizing the efficacy of selumetinib or other agents by

an enhanced biological understanding of the complex signaling pathways inherent in cancer

and an understanding on how best to exploit their relationships to achieve the maximal

clinical benefit.

Executive summary

RAS-MEK-ERK pathway aberrations are commonly observed in NSCLC

MEK is a central component of this cascade. MEK inhibitors as selumetinib, trametinib, PD-0325901, binimetinib and RO4987655 are being tested as part of clinical trials in NSCLC patients.

Pharmacokinetics and pharmacodynamics

Selumetinib is an orally available, potent, selective inhibitor of MEK 1 and 2

The Hyd-sulfate capsules replaced the initial free base suspension with improved bioavailablity

There is interaction with food, so the recommendation in to take on an empty stomach

Selumetinib is metabolized in the liver cytochrome P450 system, and its elimination is predominantly through glucuronidation

Clinical efficacy and safety

MTD was 75 mg b.i.d

Disease control rate in the phase I trials with selumetinib monotherapy were less than 20%.

Selumetinib has shown synergistic activity with docetaxel (75mg/m2 every 21 days). Median OS was 9.4 months (95% CI 6.8-13.6) in the docetaxel+ selumetinib arm and 5.2 months (95% CI 3∙8–non-calculable) in the docetaxel+placebo arm

Combining with erlotinib did not show benefit in a phase II trial. Combinations with other TKIs are currently being tested in phase I trials.

Combinations with AKT and mTOR inhibitors are currently being trialed to explore potential mechanism to overcome acquired resistance to MEK inhibitors. Interactions with radiotherapy are being tested

Acneiform rash, gastro-intestinal toxicity and peripheral oedema are common toxicities;.other toxicities include eye problems such as retinopathy and elevation in transaminases.

Final disclosure/Acknowledgements

Dra R. Bernabé was funded by Spanish Society of Medical Oncology (SEOM) translational research fellowship grant

Figure 1: The phosphorylation of RAS (GDP to GTP) activates the RAF family of molecules (A-RAF, B-RAF, C-RAF and RAF-1). This activation results in phosphorylation of MEK1/2 that subsequently activates ERK 1 and 2. Activated ERK leads to a number of cytoplasmic and nuclear phenomena that

result in survival, proliferation, cell cycle progression and alteration metabolic regulation. Targeted treatments are being developed for the different components of this pathway. Currently, the only approved targeted agents in this pathway (highlighted in bold) are indicated for the treatment of BRAF mutant melanoma. Several other MEK inhibitors are being developed. ERK inhibitors are in an early stage of clinical development.

Drug Relevant published results in NSCLC

Ongoing trials in NSCLC*

Trametinib

(GSK 1120212, Mekinist®)

Randomized phase II trial [44]Population: NSCLC KRAS mutantArms: Trametinib vs DocetaxelOutcome: similar PFS to Docetaxel (12 vs 11 weeks)

Phase I/Ib trial[45]Population: NSCLC patients stratified by KRAS mutationSingle arm trametinib + pemetrexedOutcome: overall DCR 65%

Phase I trialsNCT01912625Population: NSCLC stage III not suitable for surgeryDrugs: Trametinib + Chemoradiotherapy (Carboplatin/Paclitaxel) followed by consolidation chemotherapy (2 cycles Carboplatin/Paclitaxel)NCT02258607Population: NSCLC KRAS-mutated who failed platinum based chemotherapyDrugs: Trametinib in combination with Momelotinib (JAK 1 and 2 inhibitor)

Phase I/II trialsNCT02580708Population: advanced or metastatic NSCLC EGFR positiveDrugs: Rociletinib + TrametinibNCT02230553

Population: NSCLC, colorectal and pancreaticDrugs: Lapatinib + Trametinib

Phase II trialsNCT01336634Population: advanced NSCLC BRAF-mutantDrugs: Dabrafenib vs Dabrafenib + Trametinib

PD-0325901 (Pfizer)

Open-label phase II trial[46]Population: NSCLC after standard treatmentDrug: PD-0325901 aloneOutcome: no objective responses found

Phase I/II trials

NCT02022982Population: NSCLC and other tumoursDrugs: PD-0325901 + palbociclib

NCT02039336Population: KRAS mutant NSCLC, CRC and pancreaticDrugs:PD-0325901 + dacomitinib

Binimetinib (MEK-162)

-

Phase I trials

Not yet open to recruitment:

NCT02451865Population: pre-treated stage IV NSCLCDrugs:binimetinib + Docetaxel

NCT02185690Population: NSCLCDrugs: MEK 162 + Carboplatin/pemetrexed

RO4987655 Phase I [47] -

(CH4987655) Population: expansion cohort in NSCLC KRAS mt – 24 patients, 18 evaluableOutcome: ORR 11%, SD 44%

Table 1: Summary of MEK inhibitors (other than selumetinib) in clinical development that have been or are currently being tested in lung cancer patients. All the drugs mentioned are in early stages of its development in this group of patients and there are no ongoing phase III trials.

Tumour type Relevant published trial results and ongoing Clinical trials*

Results

Acute Myeloid leukaemia

Jain et al: Phase II trial, open-label, single arm in patients with advanced disease [48]

Modest activity

Billiary tract Bekaii-Saab et al: Phase II, open-label, patients with metastatic biliary cancer [49]

Phase III trial cisplatin/gemcitabine with selumetinib/placebo [10]

RR about 12%, PFS 3.7 months

Ongoing

Breast Zaman K, et al: Phase II, randomized trial in ER-positive breast cancer with fulvestrant +/- selumetinib[50]

No clinical activity (may have deteriorated activity of fulvestrant)

Colorectal Do K, et al: Phase II, biomarker-driven study, single-arm with selumetinib in combination with MK-220690 (AKT inhibitor) [51]

Hotcher, et al: Phase II, single-arm, with selumetinib in combination with irinotecan in KRAS mutant patients [52]

Bennouna et al: Phase II, open-label, randomized trial with selumetinib vs capecitabine in metastatic patients that failed one or two regimens previously [53]

No clinical activity

Some activity (9.7% had a PR)

No differences

Endometrial cancer Coleman, et al: Phase II, open-label, single-arm, in recurrent or persistent disease [54]

No clinical activity

Hepatocelular carcinoma (HCC)

O’Neil et al: Phase II, open-label trial, in advanced or metastatic HCC patients without previous systemic treatment [55]

Phase I/II in combination with sorafenib10

Minimal activity (PFS 8 weeks)

Awaiting results

Low grade glioma Phase I/II and re-treatment study in the pediatric population10

Ongoing

Melanoma Gupta, et al: DOC-MEK, Phase II trial, double-blind randomized in wt BRAF advanced melanoma with Docetaxel +/- selumetinib [56]

Robert et al: Phase II trial, double-blind, randomized in

No activity

Improvement in PFS (5.6 vs 3 m), no

advanced or metastatic patients with darcabazine +/- selumetinib [57]

Kirkwood, et al: Phase II trial, open-label, randomized with selumetinib +/- temozolomide in advanced melanoma [58]

impact in OS

No clinical activity

Multiple Myeloma Hew K, et al: Phase II trial, single arm, in relapsed patients [59]

Minimal activity

Ovary Farley et al: Phase II trial, open-label, single arm in low grade serous carcinoma of the ovary or peritoneum [60]

Modest activity 15.4% ORR

Pancreatic Adenocarcinoma

Ko AH, et al: Phase II, open-label, single arm selumetinib in combination with EGFR inhibitor [61] Bodoky et al: Phase II, open-label, selumetinib vs capecitabine in patients with advanced or metastatic disease who failed first-line gemcitabine [62]

Phase II in metastatic pancreatic cancer after prior chemotherapy with selumetinib+MK2206 (AKT inhibitor) vs mFOLFOX [10]

Minimal activity

No difference in OS

Ongoing

Soft tissue sarcomas Eroglu, et al: Phase II trial, randomized with selumetinib vs selumetinib + temsirolimus [63]

No activity (some benefit in leiomyosarcoma cohort in combination arm)

Thyroid Hayes, et al: Phase II, open-label trial in papillary thyroid cancer iodine-refractary [64]

ASTRA trial: Phase III, randomized, double-blind selumetinib/placebo in patients with differentiated thyroid cancer [10]

No activity

Ongoing

Uveal melanoma Carvajal, et al: Phase II, randomized trial, selumetinib vs temozolamide [65]

Phase III, double blind, placebo-controlled trial (SUMIT) in first-line treatment comparing dacarbazine + selumetinib/placebo [10]

Modest improvement in PFS and RR, no impact in OS

Ongoing

Table 2: Summary of most relevant results published with selumetinib in tumour types other than NSCLC. *Source: clinicaltrials.gov

Summary of Toxicity in Monotherapy trials

Toxicity Description Reported Prevalence /G3-4 prevalence

Treatment

Rash Dose-dependent

Maculopapular

Truncal

Resolution typically with dose reduction or dose interruption

43-74% [19,26]

G3-4: 5.7-20%

Topical steroid

Oral antibiotics

G3-4: dose interruption + oral antibiotics+ topical steroid

Diarrhoea Started within first 2 weeks 30-56%

Mainly G1-2

Anti-motility agents ( required in 30% patients); dose interruption or discontinuation

Nausea and vomiting

Generally starting

slightly later after the onset of the treatment

N: 18-39%;

V:14 -18%

G3-4:N:0; V:7.1%

Standard antiemetic therapy

Peripheral oedema Onset commonly after several weeks into treatment.

Other forms: eyelid edema, face edema and periorbital edema

39.6%-45.7%

G3-4: 2.9%-3.6%

Cardiac surveillance of LVEF

Ocular Central Serous Retinopathy

Blurred vision (transient and reversible)

12-28% Self-limiting on dose interruption

Fatigue Dose –dependent 13-48% [26,37]

G3-4: 17.1%

Self-limiting on dose interruption

Table 3: Summary of most relevant toxicity published with selumetinib in monotherapy trials.

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