clinical topic updates

MEK Inhibition and Targeted Combinations for Advanced Lung Cancer

by Roy S. Herbst, MD, PhD

Overview

The identification of mutations in signaling pathways that are oncogenic has allowed the development of targeted therapies in the treatment of non–small cell lung cancer (NSCLC). Overcoming redundancy in tumorigenic pathways and the rapid development of resistance is an important ongoing goal, and different strategies are being pursued toward that end.

Expert Commentary

Roy S. Herbst, MD, PhD

Ensign Professor of Medicine (Medical Oncology) and Professor of Pharmacology
Chief of Medical Oncology
Director, Thoracic Oncology Research Program
Associate Director for Translational Research
Yale Cancer Center
Yale School of Medicine
Smilow Cancer Hospital
New Haven, CT

“Because of the redundancy in tumorigenic pathways and the rapid development of resistance, we usually use MEK inhibitors in combination with RAF inhibitors.” 

Roy S. Herbst, MD, PhD

The RAS/RAF/MEK/ERK (MAPK) signaling pathway has a well-defined role in tumorigenesis, including in NSCLC. Point mutations in members of this cascade are drivers of tumor formation and/or indicators of poor prognosis. RAS mutations, particularly in KRAS, are common in most cancer types, including NSCLC, while MEK is seen less commonly. BRAF is mutated in approximately 2% to 4% of NSCLC, and the BRAF V600E mutation leads to activation of the RAF family of kinases, and downstream from them are the MEK kinases. So, activation through the mutation of the BRAF gene also leads to activation of MEK. MEK mutations are common enough that they should be included in the routine testing of patients with NSCLC, along with RAS and BRAF mutations.

There are 2 MEK inhibitors (trametinib and cobimetinib) that have been approved by the US Food and Drug Administration for the treatment of tumors with a BRAF V600E mutation. Because of the redundancy in tumorigenic pathways and the rapid development of resistance, we usually use MEK inhibitors in combination with RAF inhibitors. For example, combination dual inhibition of the MAPK pathway with an MEK inhibitor (trametinib) plus a BRAF inhibitor (dabrafenib) has been shown to have robust activity in patients with BRAF V600E–mutant metastatic NSCLC.

One of the most exciting developments in the management of NSCLC is the introduction of novel therapies that target KRAS mutations. KRAS is the most commonly mutated oncogene in cancer, and these mutations are often present in NSCLC. However, until recently, there was no effective targeted therapy for these mutations. KRAS has been considered “undruggable” because the binding pocket for guanosine triphosphate (the activator for KRAS) is so shallow. Work by Ostrem and colleagues identified a cysteine residue in the binding groove of the KRAS G12C mutation that has allowed the development of very potent KRAS G12C mutant inhibitors that bind cysteine covalently. This finding is exciting because KRAS mutations are associated with smoking and are seen in approximately 13% of lung cancers. There are currently 2 drugs under development that target G12C: AMG 510 and MRTX849. Initial data in small numbers of patients show that approximately 50% of patients have a response to these KRAS G12C inhibitors, although it is so early that, at this time, the median duration of response is yet to be determined. A key worry is that redundant pathways could take over very quickly. Because of this, combination therapy may become the norm. Theoretically, you could combine a G12C inhibitor with an MEK inhibitor, a PI3 kinase inhibitor, an SHP2 inhibitor, or with immunotherapy.  

References

Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217‐223. 

Degirmenci U, Wang M, Hu J. Targeting aberrant RAS/RAF/MEK/ERK signaling for cancer therapy. Cells. 2020;9(1):198. 

Fakih M, O’Neil B, Price TJ, et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors. J Clin Oncol. 2019;37:3003.

Hallin J, Engstrom LD, Hargis L, et al. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 2020;10(1):54‐71. 

Lu H, Liu C, Velazquez R, et al. SHP2 inhibition overcomes RTJ-mediated pathway reactivation in KRAS-mutant tumors treated with MEK inhibitors. Mol Cancer Ther. 2019;18(7):1323-1334. 

Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548-551.

Planchard D, Besse B, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. Lancet Oncol. 2016;17(7):984-993.

Ryan MB, Fece de la Cruz F, Phat S, et al. Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS G12C inhibition. Clin Cancer Res. 2020;26(7):1633-1643. 

Stinchcombe TE, Johnson GL. MEK inhibition in non-small cell lung cancer. Lung Cancer. 2014;86(2):121-125. 

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