Targeting MEK for the Treatment of Non Small-Cell Lung Cancer

Inhibition of the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway has been the focus of drug development for many years. The pathway is dysregulated in a significant percentage of solid tumors, including approximately 20% to 35% of non–small-cell lung cancers (NSCLC).¹ Nevertheless, successful targeting of this pathway has been difficult to achieve.² Inhibitors of RAS, the most commonly mutated gene in this pathway, have not generated successful results in clinical trials. Therefore, inhibition at other points along the pathway has been evaluated.

MEK1 and MEK2 are threonine/tyrosine protein kinases that are phosphorylated by activated RAF and in turn, phosphorylate ERK1 and ERK2, leading to proliferation and migration. Mutations in RAS or RAF lead to a sustained oncogenic signal and predict response to MEK inhibition in laboratory models.^3,4 Three MEK inhibitors and an Akt inhibitor were presented in this session at the 12th Annual Targeted Therapies of the Treatment of Lung Cancer and will be reviewed here.

SUMMARY OF PRESENTATIONS

Selumetinib (AZD6244 or ARRY-142886) is an oral, 14 nM for uncompetitive, potent inhibitor of MEK 1/2 (IC₅₀ MEK1). Selumetinib has high specificity for MEK1/2, with little activity against a panel of more than 40 other kinases. Although a gene-expression profile associated with response to selumetinib among cell lines has been demonstrated,⁵ the strongest association was arguably the association with RAS mutations.⁴ When evaluating a large panel of human NSCLC cell lines, a significant association was found between sensitivity to the compound and RAS mutational status. Preclinical combinations have been an active area of investigation and studies have been reported with concomitant VEGF or mTOR inhibition.

Clinical development of selumetinib began with a phase I trial demonstrating tolerability and preliminary efficacy of selumetinib at 100 mg twice daily.⁶ An acneiform rash was the most frequently reported and dose-limiting toxicity. In a randomized, open-label, phase II trial of selumetinib versus pemetrexed in pretreated NSCLC, selumetinib showed no advantage in an unselected population.⁷ On the basis of the preclinical data discussed above, further study specifically in RAS or RAF mutated tumors was suggested.

A randomized trial of selumetinib with docetaxel versus docetaxel alone in patients with RAS-mutated NSCLC has completed accrual. At the time of this meeting, data regarding this trial had not been formally presented, and the only data with respect to the outcome of the trial came from a press release. The press release described that the study was powered for a benefit in overall survival, and although survival was numerically superior, the result did not reach statistical significance. However, a statistically significant improvement in response rate and progression-free survival with the combination of docetaxel and selumetinib was seen in this small phase II trial, generating some enthusiasm.

Several selumetinib trials are currently enrolling patients, including a phase II study (NCT01229150) in previously treated NSCLC stratified by KRAS status; mutated KRAS patients are randomized to receive selumetinib and erlotinib or selumetinib alone, and wild-type KRAS patients are randomized to receive selumetinib and erlotinib or erlotinib alone. In addition, the drug is being evaluated with thoracic radiation in one trial (NCT01146756) and in two multiarm trials (NCT01306045 and NCT01248247) that assign treatment by molecular tumor characteristics. Other combinations in various tumor types are also under study.

Trametinib (GSK 1120212 or JTP-74057) is a reversible, allosteric MEK1/MEK2 inhibitor with an IC₅₀ of 0.7 nM for MEK1, and a high specificity as demonstrated by limited activity against a panel of 180 other kinases.⁸ In vitro and in vivo models reveal significant activity against tumors harboring mutant RAF or RAS. A phase I trial using trametinib demonstrated acneiform rash, diarrhea, and rare left ventricular cardiac dysfunction as the primary toxicities.⁹ A reversible serous retinopathy was observed at higher doses and seemed to be a potential class effect of MEK inhibitors. The recommended phase II dose was 2 mg daily. The half-life was 4.5 days and sustained target inhibition was seen in pharmacodynamic studies. Preliminary evidence of activity was demonstrated in melanoma and pancreatic cancer.

Combination treatment with trametinib is under study with agents including gemcitabine, everolimus, pazopanib, the BRAF inhibitor GSK 2118436, the Akt inhibitor GSK 2141795, and the PI3K inhibitors GSK 2126458 and BKM120. A multiarm phase I/Ib trial (NCT01192165) is assessing many treatment combinations—docetaxel, erlotinib, pemetrexed, carboplatin, cisplatin, and nab-paclitaxel—specifically with a goal of identifying appropriate regimens for lung and pancreatic cancer treatment. An open-label, randomized phase II trial (NCT01362296) in second-line NSCLC that harbors a mutation in KRAS, NRAS, BRAF, or MEK1 is currently recruiting patients.

PD-0325901 is a derivative of the first-generation MEK inhibitor CI-1040. A maximum tolerated dose of 15 mg twice daily was identified in a phase I trial, but late adverse events included retinal vein occlusion and neurotoxicity.¹⁰ The same schedule in a single-arm phase II trial in previously treated NSCLC demonstrated significant toxicities whereas an intermittent dosing schedule revealed insufficient anticancer activity to warrant future single-agent study in an unselected population.¹¹

MK-2206 is an oral pan-Akt inhibitor. The PI3K/Akt pathway is frequently activated in cancer. In NSCLC and small-cell lung cancer, activity of this pathway has been seen with PIK3CA mutations and amplification, AKT mutations, and loss of the PTEN tumor-suppressor as well as in tumors that do not demonstrate these genetic alterations. MK-2206 binds Akt in its inactive configuration. Preclinical activity has been seen in a panel of NSCLC lines, with the greatest activity in a PIK3CA-mutated model.¹² Synergy is seen with docetaxel, carboplatin, gemcitabine, and erlotinib. Of note, combination therapy with selumetinib demonstrated synergy and is being evaluated clinically (NCT01021748).¹³ A phase I trial of MK-2206 revealed good tolerance with common adverse events of rash, nausea, fatigue, and hyperglycemia. The maximum tolerated dose is 75 mg every other day and weekly doses up to 300 mg are being evaluated.

In addition to concurrent treatment with selumetinib, other MK-2206 combinations are being clinically evaluated. MET (also known as HGF) up-regulation has been shown to mediate resistance to EGFR inhibition, and preclinical studies reported at the meeting reveal that this resistance to EGFR inhibition is overcome with the addition of MK-2206. A phase II trial (NCT01294306) of MK-2206 with erlotinib in patients who benefited from and then progressed on erlotinib is currently accruing subjects. In relapsed small-cell lung cancer patients, a trial of topotecan versus topotecan with MK-2206 is under development.

FUTURE DIRECTIONS

The RAS/RAF/MEK/Erk pathway underlies carcinogenesis in multiple tumor types but has been a difficult target for drug therapy. Successful MEK-directed treatment of lung cancer potentially depends on two factors: identification of biomarkers to predict sensitivity and the selection of optimally beneficial drug combinations. At this time, RAS mutation may be the most reliable predictor of a cancer cell’s dependence on this pathway but other techniques have been evaluated to refine selection further. Concurrent treatment with cytotoxic agents has shown early promise in phase II trials. Dual targeting of MEK with inhibition of other kinases in the same pathway (such as EGFR) or with inhibition of a parallel pathway (such as the PI3K/Akt pathway) are also promising directions for ongoing trials.