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.