Path Less Traveled: Targeting Rare Driver Oncogenes in Non–Small-Cell Lung Cancer

Abstract

Over the past decade, tremendous efforts have been made in the development of targeted agents in non–small-cell lung cancer (NSCLC) with nonsquamous histology. Pivotal studies have used next-generation sequencing to select the patient population harboring oncogenic driver alterations that are targetable with targeted therapies. As treatment paradigm rapidly evolves for patients with rare oncogene-driven NSCLC, updated comprehensive overview of diagnostic approach and treatment options is paramount in clinical settings. In this review article, we discuss the epidemiology, molecular testing, and landmark clinical trials addressing the targeted agents for ROS1 rearrangement, METex14 skipping mutation, EGFR exon 20 insertion, KRAS G12C mutation, HER2 mutation, RET fusion, NTRK fusion, and BRAF mutations.

Effective Treatment of Lung Adenocarcinoma With a Novel SLC44A1-BRAF Fusion Using Pembrolizumab Followed by Trametinib: A Case Report

“…The RAF protein family plays a crucial role in cellular proliferation signaling, with the BRAF protein being a significant subtype. Predominantly, RAF mutations are linked to the BRAF gene [ 3 ], with the V600E mutation comprising approximately half of the BRAF mutations in NSCLC [ 11 ]. BRAF possesses three conserved regions (CR): CR1 contains the RAS-binding domain, CR2 is followed by hinge regions containing a cluster of phosphorylation sites that negatively control BRAF signaling, and CR3 encompasses kinase activity through involvement in RAF dimerization [ 8 ].…”

“…Patients with NSCLC harboring the BRAF V600E mutation have demonstrated significant clinical improvement following combination therapy with dabrafenib and trametinib [ 5 ]. Nevertheless, there is a lack of established targeted therapies for NSCLC patients with non-V600E BRAF mutations [ 3 ].…”

“…Aberrations in the BRAF gene serve as oncogenic drivers in a variety of solid tumors, notably non-small cell lung cancer (NSCLC), while also presenting as viable therapeutic targets [1]. BRAF mutations are identified in approximately 1-4% of NSCLC cases [1][2][3], with the V600E point mutation being the most prevalent subtype, accounting for over half of NSCLC cases with BRAF mutations [4]. Patients with NSCLC harboring the BRAF V600E mutation have demonstrated significant clinical improvement following combination therapy with dabrafenib and trametinib [5].…”

Commemorating the 20th anniversary of the discovery of epidermal growth factor receptor mutation in lung cancer: Translational research at its best

“…The most common driver events are KRAS, EGFR, ALK, and mesenchymal epithelial transition factor (MET); a plethora of less common but treatable alterations including RET, ROS1, HER2, BRAF V600E, and neurotropic tyrosine receptor kinase were also identified. 11 In parallel, drug development has proceeded at an incredible pace, which has resulted in several mutation-selective small-molecule inhibitors that induce clinical responses with relatively minimal adverse events. These agents were conducive to being used by patients for several months to a few years without undue impact on their quality of life.…”