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Published in final edited form as: Curr Probl Cancer. 2024 Feb 9;49:101065. doi: 10.1016/j.currproblcancer.2024.101065

Targeting MEK in Non-Small Cell Lung Cancer

Matthew S Lara 1, Collin M Blakely 2, Jonathan W Riess 1
PMCID: PMC13200795  NIHMSID: NIHMS2170429  PMID: 38341356

Abstract

The mitogen-activated protein kinase (MAPK or MEK) pathway modulates tumor cell survival and proliferation in non-small cell lung cancer (NSCLC). Unlike RAS or EGFR, activating mutations in MEK are exceedingly rare in NSCLC. Instead, enhanced activation of the MEK pathway is often linked to increased signaling by upstream oncogenic driver mutations. Thus far, MEK inhibitor monotherapy has shown little promise. However, treatment strategies involving MEK inhibition in combination with other targeted therapies in other oncogene-driven NSCLC has proven to be encouraging. For example, MEK inhibition - when combined with BRAF inhibition, - has shown strong anti-tumor activity in BRAF V600 mutated NSCLC. In this review, recent data on MEK inhibitor strategies in NSCLC are summarized. Furthermore, ongoing early phase trials investigating MEK inhibitor combination therapy with immunotherapy, chemotherapy and other oncogene drivers are highlighted. These and other studies could help inform future rational combination strategies of MEK-ERK inhibition in oncogene-driven NSCLC.

Keywords: Non-small cell lung cancer, MEK inhibition, targeted therapy, lung cancer signaling, MEK-ERK pathway

Introduction

Lung cancer is the leading cause of both cancer and cancer-related mortality in the United States. Non-small cell lung cancer (NSCLC) accounts for more than 85% of all lung cancer cases and includes two major types: (1) non-squamous carcinoma (including adenocarcinoma, large-cell carcinoma, other cell types); and (2) squamous cell carcinoma. Adenocarcinoma is the most common histopathologic type accounting for 50% of NSCLC and is also the most frequently occurring type in non-smokers, which make up to 20% of NSCLCs [1]. Although the prognosis for advanced lung adenocarcinoma is often poor, oncogene-directed molecular-targeted therapies can be an effective therapeutic strategy.

One such oncogenic pathway involves mitogen-activated protein kinase (MAPK)/rat sarcoma virus (RAS) which includes a signaling cascade important for tumor cell proliferation and survival. This pathway is composed of Receptor tyrosine kinases (RTKs), which signal to downstream effectors such as RAS, RAF, MEK, and extracellular signal-regulated kinase (ERK); it is also called the MAPK/ERK or MEK kinase pathway (Figure 1) [2].

Figure 1: MEK Signaling Pathway with Potential Resistance Mechanisms.

Figure 1:

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Shown is a simplified representation of the MEK signaling pathway which is activated by upstream RAS/RAF. Resistance is primarily achieved via MEK-mediated reactivation of ERK, which upregulates the pathway through a feedback mechanism. Tumors may also utilize the bypass PI3K/AKT pathway.

While oncogenic mutation in RTKs, RAS, and RAF are common in NSCLCs, activating oncogenic MEK alterations are rarely seen. Marks et al previously reported the presence of gain-of-function MEK1 mutations in only 2 of 207 primary NSCLC tumors [3]. Another retrospective study involving 6,024 lung adenocarcinoma specimens reported that MEK1 alterations are seen in only 0.6%. In this analysis, K57N and Q56P represented the most frequent mutations, at 64% and 19% respectively [4]. Most recently, Cheng et al. reported MEK1 mutations in 0.9% of 75,402 NSCLC tissue specimens. The most common histological subtype among MEK1-mutated tumors was adenocarcinoma at 73% followed by squamous cell carcinoma at 6.4% [5]. Though approved as a combination with BRAF inhibitors for BRAF V600E NSCLC, to-date there have been no formal phase II efficacy studies of single agent MEK inhibitor therapy in MEK-mutated NSCLC that provide sufficient evidence for regulatory approval.

In this review, we describe relevant research on the MEK signaling pathway as well as recent or ongoing investigations on MEK-targeted approaches, specifically those that combine MEK inhibition with other molecularly targeted therapies directed towards oncogenic drivers in NSCLC.

Background

MEK proteins form a dual-specificity protein kinase that phosphorylates serine/threonine and tyrosine residues on ERK1 and ERK2 further down the MAPK pathway. Seven different genes encode for MEK proteins; however, MEK1 and MEK2 are the most relevant. These MEK proteins serve as the sole activators of ERK1 and ERK2 and act as “gatekeeper” kinases that integrate signaling from different upstream kinases. [2]

Various MAP kinase kinases can activate MEK1 and MEK2, including ERK and JNK. These MEK proteins are composed of a core protein kinase domain, an N-terminal domain, and a C-terminal domain. The protein kinase domain contains an ATP site and the primary catalytic region. The other domains help regulate signal transduction and substrate binding. More specifically, the N terminal domain contains docking sites for ERK1 and ERK2 and a nuclear export sequence that determines MEK1/MEK2 cytoplasm localization. The C-terminal domain contains the upstream MAPK kinase docking site. MEK1 and MEK2 activation requires conformational changes of both a specific C-helix within the N-domain and the activation loop in the C-domain. [2]

MEK plays an important role in regulating cell proliferation, differentiation, and apoptosis in tumor cells. In cancer, overactive RAS expression is well known to lead to aberrant activation of the MAPK pathway. Blockade of the MEK pathway was hypothesized to be a potential therapeutic strategy for cancers with RAS-activating alterations. As a result, significant effort has been made to develop clinically viable MEK inhibitors. The first MEK inhibitor was reported in 1995 by Alessi et. Al [6]. Since then, a large body of literature has been published describing preclinical activity of MEK inhibitors in various malignancies. To-date, four MEK inhibitors have been approved by the FDA. These include trametinib, selumetinib, cobimetinib, and binimetinib. Each of these drugs are selective allosteric non-competitive inhibitors of MEK1/2.

Trametinib is FDA approved as a single agent for BRAF-inhibitor treatment-naïve patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. It is also indicated, in combination with dabrafenib, for unresectable or metastatic melanoma with BRAF V600E or V600K mutations and metastatic NSCLC with BRAF V600E mutation, among others. Selumetinib is approved for the “treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas”. Cobimetinib is indicated in combination with vemurafenib for “adult patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation” and “as a single agent for the treatment of adult patients with histiocytic neoplasms”. Binimetinib is used in combination with encorafenib “for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation”. [7]

Several early phase clinical trials have assessed MEK inhibitors as single agents for the treatment of NSCLC. A phase II trial done by Hainsworth et al. showed no significant difference in median progression-free survival (PFS) between NSCLC patients treated with a MEK inhibitor versus pemetrexed in a cohort of 84 patients [8]. Another phase II trial of the MEK inhibitor PD-0325901 led by Haura et al showed no appreciable tumor response in a cohort of 34 patients employing two different administration schedules [9]. In both trials, common side effects included rash, diarrhea, nausea, vomiting, and fatigue. A third randomized phase II trial showed no significant difference in response rate or survival between patients treated with single agent trametinib versus docetaxel (ORR 12% vs. 13%, PFS HR=1.14, OS HR=0.97). [10]. Observed toxicities in this trial included hypertension, rash, diarrhea, and sepsis. One treatment related death of unknown cause occurred but was attributed to trametinib therapy. The overall conclusions from these trials were that MEK inhibitor monotherapy possessed minimal clinical efficacy and may even be more toxic than traditional systemic chemotherapy. As a result, the clinical application of MEK inhibitors transitioned from single agent to combination strategies.

Combined BRAF and MEK inhibition

Mutations in the BRAF gene have long been identified in a variety of cancers. As a part of the MAPK pathway, BRAF is important for cellular proliferation and survival. The most well-characterized mutation in BRAF occurs at position V600 (V600E or V600K), which results in continual activation of BRAF and thus constitutive activation of downstream MEK and ERK. Such BRAF mutations are seen in about 2–8% of NSCLC patients [11].

The addition of MEK inhibition to BRAF inhibition improves clinical outcomes in BRAF V600E NSCLC. The BRAF inhibitor dabrafenib as a single agent in NSCLC had a ORR of 33% (95% CI 22–45%) and a median PFS of 5.5 months (95% CI 3.4–7.3 months) in a phase II trial [12]. A follow up phase II trial performed by Planchard et al. examined the combination of trametinib with the BRAF inhibitor dabrafenib versus dabrafenib monotherapy in NSCLC with BRAF V600E mutations [13]. Enrolled patients were all previously treated. In their 57-patient cohort, the overall response rate was 63.2% and the median PFS was 9.7 months. Median duration of response was 9 months. Observed high grade adverse effects included neutropenia, anemia, and hyponatremia. This same group performed a similar study in patients without any prior treatment [12]. The combination of dabrafenib and trametinib was subsequently evaluated in a cohort of 36 patients. This trial resulted in an ORR of 64%, a median DOR of 10.4 months, and a median PFS of 10.9 months.

In a recent 5-year update of this study clinical activity was similar between pretreated and treatment naïve patients with overall response rate 68.4% (54.8–80.1) and 63.9% (46.2–79.2), median progression-free survival (95% CI) was 10.2 (6.9–16.7) and 10.8 (7.0–14.5) months, and median overall survival (95% CI) was 18.2 (14.3–28.6) and 17.3 (12.3–40.2) months, respectively. The 5-year survival rate was 19% in pretreated patients and 22% in treatment-I patients. (14).

In the NCI MATCH trial, the dabrafenib-trametinib combination was tested in five lung adenocarcinoma patients [15]. One patient was determined to be progression-free at 32.5 months while another patient experienced an 81% reduction in their measured lesions with a PFS of 12.7 months. In a trial performed by Dudnik et al in Israel, BRAF inhibitor (dabrafenib) monotherapy was tested against a BRAF inhibitor in combination with a MEK inhibitor (trametinib) [15]. They subdivided their 58-patient cohort into V600E mutants and wildtype V600E. Within the V600E mutant group, ORR was 40% in the BRAF inhibitor monotherapy arm versus 67% in the combination arm. Likewise, median PFS was 1.2 months for the BRAF inhibitor arm and 5.5 months for the combination.

A recent phase II trial (n = 98) exploring the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib in patients with BRAFV600-mutant metastatic NSCLC showed an ORR of 75% in treatment-naïve patients versus 46% in pretreated patients [16]. The side effect profile of this combination was consistent with prior studies with no new safety signals, diarrhea, nausea and fatigue were the most common TRAEs. One grade 5 intracranial hemorrhage grade 5 AE was reported. The FDA approved encorafenib and binemetinib on October 11th 2023 for metastatic lung cancer with a BRAF V600E mutation.

Co-targeting ALK and MEK

Alterations in the anaplastic lymphoma kinase (ALK) have long been identified as important drivers in the pathogenesis of multiple cancers. ALK rearrangements are the primary oncogenic driver in NSCLC, but somatic mutations and gene amplification may also play a role in the development of ALK-driven oncogenic NSCLC. Monotherapy with ALK inhibitors (such as crizotinib, ceritinib, alectinib, and lorlatinib) are effective in treating NSCLC harboring ALK alterations. [17]. Unfortunately, despite strong initial efficacy, tumors eventually develop drug resistance. One of the main mechanisms of acquired ALK inhibitor resistance is the activation of bypass signaling pathways, including RAS (which includes MEK as part of its downstream cascade) as discussed below. Thus, targeting these pathways could be a viable strategy to abrogate resistance to ALK inhibitors in these cancers.

Hrustanovic et al performed in vitro studies that determined the importance of the MAPK pathway in promoting drug resistance in ALK-positive lung adenocarcinoma. This group showed that constitutive activation of MAPK signaling induced tumor resistance to ALK inhibitor therapy in cancer cell lines that previously responded to crizotinib [18]. This group also found that MAPK dependence was present in most oncogene-driven lung adenocarcinomas; they showed that a specific HELP domain of EML4 in EML4-ALK could activate MAPK directly. Their initial data showed that ALK inhibition was insufficient to fully modulate bypass MAPK signaling. They showed that low dose trametinib was sufficient to sensitize cancer cell lines to ALK inhibitor therapy and that increasing doses of MEK inhibitor induced greater levels of apoptosis. These in vitro results were reinforced when in vivo tumor xenografts showed significant tumor regressions upon treatment with ALKi in combination with trametinib [18]. The combination of ALK inhibitor therapy with sub-maximal trametinib doses also demonstrated no significant toxicity in preclinical models, whereas maximum dose trametinib monotherapy resulted in systemic toxicity. These promising results paved the way for further research into such combination therapy, such as the combination of ceritinib plus trametinib (described in detail in the Discussion section below).

Shrestha et al explored dual MEK/ALK inhibition as a strategy to suppress tumor cell growth. They found that the combination of crizotinib and the MEK inhibitor selumetinib potently inhibited the growth of both crizotinib-naïve and crizotinib resistant ALK+ lung cancer. Specifically, MEK/ALK co-inhibition increased apoptosis and decreased proliferation by suppressing RAS-MAPK cascade signaling. Combination therapy induced a 3-fold increase in Bim (an apoptosis mediator) and p27 when compared to crizotinib monotherapy. [19, 20]

Tanizaki et al evaluated the efficacy of ALK inhibitors in EML4+ NSCLC cell lines, specifically in the context of signal transduction, apoptosis, and cellular proliferation [21]. They found that their experimental ALK inhibitor TAE684 was only effective in inhibiting tumor proliferation and inducing apoptosis when combined with a MEK inhibitor. Mechanistically, TAE684 suppressed STAT3 phosphorylation but not ERK phosphorylation. Adding a MEK inhibitor induced inhibition of ERK pathways and resulted in apoptosis. These results gave unique insight into the mechanism behind MAPK interactions with its upstream and downstream colleagues while reinforcing the rationale behind combination MEK therapy.

Dual MET/MEK inhibition

The MET receptor tyrosine kinase represents another molecular target for cancer therapeutics. The MET receptor, alongside its ligand hepatocyte growth factor (HGF), helps control tissue homeostasis via activation of a variety of cellular pathways, including those involved in motility, proliferation, angiogenesis, and survival. MET has been implicated in a variety of human cancers, often through mutation, overexpression, or amplification. Regarding NSCLC, amplification of the MET pathway often acts as a molecular escape mechanism for tumors treated with epidermal growth factor receptor (EGFR) TKIs, granting such cancers resistance to those therapies [21]. Given the similar effects of MET and MAPK on cancer cells, combination therapy targeting both pathways have been studied in a variety of trials.

Chiba et al were the first group to demonstrate both the importance of the MEK pathway for MET-amplified lung cancer and the synergistic effect of MET inhibitors with MEK inhibitors against MET-amplified NSCLC [22]. They studied the in vitro effectiveness of two MEK inhibitors (trametinib and PD0325901) in different oncogene-driven NSCLC cell lines, including EGFR mutants and MET-amplified tumors. Despite only weak effects in the EGFR lines, MEK inhibition showed significant effects in all MET-amplified cell lines. Interestingly, one cell line that demonstrated EGFR to MET driver gene alteration displayed enhanced sensitivity to MEK inhibitors. The authors believed that such findings suggested that the MEK pathway had biological importance in MET-amplified NSCLC.

Additional preclinical data suggest that co-targeting EGFR and MEK can prevent the emergence of a broad variety of drug resistance mechanisms that coverage on the RAS-RAF-MAPK signaling pathway [23]. RAS-RAF-MAPK alteration have been detected as putative resistance mechanisms to EGFR-TKI, including first line osimertinib that is being co-targeted as a sub-arm of the ORCHARD master protocol [24].

The effectiveness of MET/MEK inhibitor combinations has been further elucidated in other studies. Suzuwa et al focused on a different MET alteration – namely the MET exon14 skipping (METex14) mutation. The METex14 mutation results in an in-frame transcript lacking exon 14, resulting in aberrant MET activation and downstream oncogenesis. Such mutations have been observed in 3–4% of lung adenocarcinomas. This group specifically examined the effects of MET and MEK combination therapy in NSCLC cell lines harboring METex14 with acquired resistance to MET TKI monotherapy [25]. They found that the combination of a MET TKI with trametinib had a synergistic effect and that trametinib-crizotinib combination therapy reduced cell growth in mice tumor xenografts.

Similar MET/MEK combinations have also been used in the preclinical setting outside of the context of NSCLC. In NF1-related malignant peripheral sheath tumors, Peacock et al. showed that capmatinib/trametinib combination therapy was effective in reducing response variability and suppressing tumor growth/downstream pathway signaling [26]. Another trial in metastatic uveal melanoma (an especially lethal subset of cancers) by Cheng et al. showed that MET inhibitor therapy could overcome trametinib resistance induced by exogenous HGF [27]. These trials both provided proof of concept for MET/MEK combination cancer therapy.

Other Combination Strategies

MEK-targeted therapy may have potential applications in other treatment combinations. Elkrief et al demonstrated that combined MDM2/MEK inhibition (milademetan and trametinib) was active in several patient-derived adenocarcinoma models harboring MDM2 amplification with simultaneous oncogenic drivers [28]. Macaya et al used a novel in-vivo and in-vitro drug repurposing approach to show that simultaneous inhibition of MEK (with Trametinib) and PKC (with Midostaurin) is a potentially effective therapeutic strategy for KRAS mutated lung adenocarcinoma [29]. Similarly, Daley et al recently showed that inhibition of the signaling intermediates SOS1 or KSR1 can likewise enhance the efficacy of – and can prevents resistance to – trametinib in KRAS-mutated lung adenocarcinoma cell lines [30]. Given that MEK-ERK signaling is activated downstream of KRAS, the recent successes in targeting KRAS G12C with direct KRAS G12C inhibitors and the acquisition of RAS-MAPK alterations as a mechanism of acquired resistance to these inhibitors [31], co-targeting of KRAS and MEK is an additional therapeutic strategy being explored in clinical trials [32].

Additionally, investigations have likewise focused on MEK inhibition in combination with immunotherapeutic approaches. Studies in melanoma have shown that MEK-ERK signaling upregulates or induces PD-L1 expression [33, 34]. Subsequently, preclinical experiments testing the combination of a MEK inhibitor plus a PDL1/PD1 inhibitor have shown promising results, suggesting that MEK inhibiton can simultaneously potentiate the immune response and modulate PD-L1 expression. Selumetinib treatment in KRAS mt NSCLC resulted in increased PD1 expression in CD8+ T-cells [35], while dual MEK + PD1 or PDL1 inhibition in KRAS/p53-driven lung cancer (syngeneic and transgenic models) yielded an increase in tumor infiltrating CD8+ and CD4+ T cells [36]. Similarly, preclinical models of dual MEK and PDL-1 inhibition also showed synergistic tumor regression [37]. These observations have led to clinical trials of MEK inhibitor plus PD1 or PDL1 antibodies in advanced NSCLC [38; Tables 1, 2].

Table 1:

Selected Ongoing Clinical Trials of MEK-inhibitor-based Combination Strategies in NSCLC (Accessed 12/4/2023)

NCT Number Study Title Conditions/Molecular Alterations Interventions Sponsor
NCT04967079 MEK Inhibitor Combined With Anlotinib in the Treatment of KRAS-mutated Advanced Non-small Cell Lung Cancer Non Small Cell Lung Cancer | MEK+ VEGF Trametinib (MEK) | Anlotinib (VEGF) Shanghai Chest Hospital
NCT04526782 ENCOrafenib With Binimetinib in bRAF NSCLC Non Small Cell Lung Cancer | MEK + BRAF V600E Encorafenib (BRAF) | Binimetinib (MEK) Intergroupe Francophone de Cancerologie Thoracique
NCT03516214 EGF816 and Trametinib in Patients With Non-small Cell Lung Cancer Harboring Activating EGFR Mutations Bronchial Neoplasms | EGFR + MEK EGF816 (EGFR) | =Trametinib (MEK) University of Cologne
NCT03202940 A Phase IB/II Study of Alectinib Combined With Cobimetinib in Advanced ALK-Rearranged (ALK+) NSCLC Non-small Cell Lung Cancer | ALK + MEK Alectinib (ALK) | Cobimetinib (MEK) Massachusetts General Hospital
NCT04620330 A Study of Avutometinib (VS-6766) + Defactinib in Recurrent KRAS G12V, Other KRAS and BRAF Non-Small Cell Lung Cancer Non Small Cell Lung Cancer | RAF/MEK + PTK2/PYK2/MELK Avutometinib (VS-6766) (RAF/MEK) | Avutometinib (VS-6766) and Defactinib (PTK2/PYK2/MELK) Verastem, Inc.
NCT03944772 Phase 2 Platform Study in Patients With Advanced Non-Small Lung Cancer Who Progressed on First-Line Osimertinib Therapy (ORCHARD) Non-Small Cell Lung Cancer | Various molecular phenotypes Osimertinib (EGFR) + other targeted agents including Selumetinib (MEK) AstraZeneca
NCT03600701 Atezolizumab and Cobimetinib in Treating Patients With Metastatic, Recurrent, or Refractory Non-small Cell Lung Cancer Non-Small Cell Lung Cancer | Not molecularly defined Atezolizumab (PDL1) | Cobimetinib (MEK) National Cancer Institute
NCT05358249 Platform Study of JDQ443 in Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation (KontRASt-03) Non-Small Cell Lung Cancer | KRAS G12C JDQ443 (KRAS) | Trametinib (MEK) | Ribociclib (CDK4,6) | Cetuximab (EGFR) Novartis
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Table 2:

Selected Completed Clinical Trials of MEK-inhibitor-based Combination Strategies in NSCLC

Molecular Target Study Phase Therapy Number of Patients Efficacy Reference
KRAS II Docetaxel + Trametinib 60 RR: 34%
mPFS: 4.1 months		 Gadgeel et al. (40)
KRAS III Docetaxel + Selumetinib (Arm 1) vs. Docetaxel + Placebo (Arm 2) 505 Arm 1 – RR: 20%
mPFS: 3.9 months
mOS: 8.7 months
Arm 2- RR: 13.7%
mPFS: 2.8 months
mOS: 7.9 months		 Janne et al. (41)
EGFR Ib Osimertinib + Selumetinib 47 RR: 66.7% *, 22.9% **, 34% overall
mPFS: 15 months*, 2.8 months**, 4 months overall		 Yang et al. (42)
ALK/ROS1 I Ceritinib + Trametinib 9 RR: 22%, DCR: 56%, mPFS: 3 months Lara et al. [39]
BRAF V600E II Dabrafenib + Trametinib 36 RR: 64% (6% with complete response)
RR 63.9% (treatment naïve) 68.4% (previously treated)

mPFS 10.8 months (95% CI 7.0–14.5) (treatment naïve)
10.2 months (95% CI 6.9–16.7),

Overall Survival 17.3 months (95% CI 12.3–40.2) (treatment naïve) and 18.2 months (14.3–28.6) (previously treated)		 Planchard et al. [12]
BRAF V600E II Encorafenib + Binemetinib RR 75% (treatment naïve) 46% previously treated.
mPFS NE (95% CI 15.7 mo to NE) (treatment naïve)
9.3 months (95% CI 6.2 months – NE)		 [43]
KRAS I Pembrolizumab + Trametinib 12 2 partial response, 3 stable disease, 6 progressive disease, 1 non-evaluable Riess et al. [44]
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Abbreviations: RR = Response Rate, mPFS = Median Progression Free Survival, mOS = Median Overall Survival, DCR = Disease Control Rate, NE = not evaluable.

*

first/second generation EGFR TKI pretreated

**

prior T790M EGFR TKI group

Acquired resistance to modulation of MEK signaling pathway

While vertical inhibition of the MEK signaling pathway has shown promising efficacy in solid tumors such as NSCLC, the development of acquired resistance is inevitable. Several resistance mechanisms have been postulated. For example, MEK has been shown to reactivate ERK1/2 (often in the context of concurrent RAS alterations), a process that has been strongly implicated in the development of resistance to BRAF inhibitor monotherapy. MEK1 itself has exhibited increased native kinase activity allowing tumor cell lines to develop resistance to combination MEK and RAF inhibitors in melanoma. Tumor cells could activate or upregulate alternative signaling pathways such as those mediated by PI3K-AKT (Figure 1). Bypass pathway activation allow tumor cells to continue proliferating and surviving even in the presence of MEK inhibitors [39]. Tumor cells can likewise acquire new mutations that alter the target proteins or downstream effectors of the MEK pathway, rendering them less susceptible to MEK inhibition. These mutations may occur in the target (MEK) itself or in other components of the pathway including RAS, BRAF, and ERK. There exist other possible resistance mechanisms not detailed here but are discussed extensively elsewhere [39]. Understanding mechanisms of resistance provides unique insights for the development of more effective combination strategies to overcome or delay the emergence of resistance.

Discussion

Activation of the MEK signaling pathway in NSCLC can promote primary tumor growth and resistance to other therapies through a variety of mechanisms [2]. Although MEK inhibitors have shown minimal activity as monotherapy, they have displayed evidence of preclinical and clinical efficacy when used in combination with other molecularly targeted cancer therapies (Table 2). MEK inhibitor therapy in combination with BRAF inhibitors showed tumor shrinkage and PFS improvement in patients with BRAF V600E NSCLC, leading to the first FDA approved MEK inhibitor-based combination (i.e., trametinib + dabrafenib) for such tumors. The remarkable efficacy of MEK inhibitor-based combination therapy in the BRAF V600E setting has served as proof-of-concept for the evaluation of other MEK inhibitor-containing doublets. As summarized above, combinations of MEK inhibitor therapy with either ALK- or MET-targeted treatments in appropriate NSCLC molecular phenotypes have already shown early evidence of activity.

Our group has sought to contribute to these combination strategies by evaluating MEK inhibitors in the context of either ALK or MET inhibition in early phase clinical trials. For example, we previously reported the results of a Phase Ia dose escalation trial of the ALK inhibitor ceritinib with trametinib in heavily pretreated patients with advanced ALK+ NSCLC [39]. We evaluated the initial safety and efficacy results of the combination in a nine-patient cohort. In this trial, two patients had partial response, three had stable disease, and four experienced disease progression. Preliminary overall response rate was 22% and disease control rate was 56%. Of note, one patient with four prior lines of therapy experienced an 88% reduction in tumor size over the course of the trial. The most common adverse events were rash, diarrhea, and elevated AST/ALT. Only one dose-limiting toxicity (a grade 3 rash) was observed. Thus, we concluded that the combination of trametinib and ceritinib appeared quite tolerable with no unforeseen toxicities. The observed ORR of 22% was thought significant given the heavily pre-treated patient study population. We intend to further evaluate biomarkers of response and resistance in molecularly defined expansion cohorts.

We have also recently initiated a multicenter Phase I/Ib trial examining the combination of the MET inhibitor capmatinib plus trametinib in NSCLC patients with tumors harboring METex14 skipping mutations. As previously discussed, hyperactivation of MAPK signaling promotes resistance to MET TKI therapy; resistance was abrogated by co-treatment with a MET inhibitor and a MEK inhibitor. This current trial seeks to exploit these preclinical findings in the early phase clinical setting. We will employ a dose escalation phase utilizing a standard 3+3 design to determine a recommended phase 2 dose (RP2D) for this treatment combination. Once the RP2D is determined, we will move to a dose expansion phase to further characterize the safety profile of the combination. We anticipate that the results of this trial will further inform the use of combination targeted therapies in this specific oncogene-driven lung cancer subtype.

In summary, recently published literature supports the concept of combination approaches anchored on MEK inhibition in the treatment of molecularly defined phenotypes of NSCLC. Ongoing and planned trials of such combinations are expected to be completed soon. The results of these trials could potentially inform the next generation of therapeutic strategies in NSCLC patients harboring otherwise actionable oncogenic alterations.

Acknowledgments

C.M.B. receives institutional research funding from Novartis, AstraZeneca, Puma, Mirati, Spectrum. Honararia/consulting from BMS, Janssen, Bayer, Gilead.

J.W.R. receives institutional research funding from Novartis, AstraZeneca, ArriVent, Revolution Medicines, Summit, Merck, IO Biotech, Nuvalent. Honararia/consulting from Boehringer Ingelheim, BMS, Turning Point Roche/Genentech, Biodesix, EMD Serono, Daiichi Sankyo, Blueprint, Novartis, SeaGen, Regeneron, Sanofi, Janssen, Jazz Pharmaceuticals, Bayer, Beigene, Merus NV, Amgen, Catalyst.

Footnotes

Conflict of interest disclosures

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