Oncogene-Addicted Non-Small-Cell Lung Cancer: Treatment Opportunities and Future Perspectives

Abstract

Before the introduction of tyrosine kinase inhibitors (TKIs) for a particular subgroup of patients, despite platinum-based combination chemotherapy, the majority of patients affected by non-small-cell lung cancer (NSCLC) did not live longer than one year. With deeper understanding of tumor molecular biology, treatment of NSCLC has progressively entered the era of treatment customization according to tumor molecular characteristics, as well as histology. All this information allowed the development of personalized molecular targeted therapies. A series of studies have shown that, in some cases, cancer cells can grow and survive as result of the presence of a single driver genomic abnormality. This phenomenon, called oncogene-addiction, more often occurs in adenocarcinoma histology, in non-smokers (except BRAF mutations, also frequent in smoking patients), young, and female patients. Several different driver mutations have been identified and many studies have clearly shown that upfront TKI monotherapy may improve the overall outcome of these patients. The greater efficacy of these drugs is also associated with a better tolerability and safety than chemotherapy, with fewer side effects and an extremely good compliance to treatment. The most frequent oncogene-addicted disease is represented by those tumors carrying a mutation of the epidermal growth factor receptor (EGFR). The development of first, second and third generation TKIs against EGFR mutations have dramatically changed the prognosis of these patients. Currently, osimertinib (which demonstrated to improve efficacy with a better tolerability in comparison with first-generation TKIs) is considered the best treatment option for patients affected by NSCLC harboring a common EGFR mutation. EML4-ALK-driven disease (which gene re-arrangement occurs in 3–7% of NSCLC), has demonstrated to be significantly targeted by specific TKIs, which have improved outcome in comparison with chemotherapy. To date, alectinib is considered the best treatment option for these patients, with other newer agents upcoming. Other additional driver abnormalities, such as ROS1, BRAF, MET, RET and NTRK, have been identified as a target mirroring peculiar vulnerability to specific agents. Oncogene-addicted disease typically has a low early resistance rate, but late acquired resistance always develops and therefore therapy needs to be changed when progression occurs. In this narrative review, the state of art of scientific literature about targeted therapy options in oncogene-addicted disease is summarized and critically discussed. We also aim to analyze future perspectives to maximize benefits for this subgroup of patients.

The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer

“…AEs more common with crizotinib than with brigatinib included nausea (crizotinib 56% vs. brigatinib 26%), diarrhea (55% vs. 49%), constipation (42% vs. 15%), peripheral edema (39% vs. 4%), vomiting (39% vs. 18%), a higher alanine aminotransferase level (32% vs. 19%), anorexia (20% vs. 7%), photopsia (20% vs. 1%), dysgeusia (19% vs. 4%), and visual impairment (16% vs. 0%) [ 67 ]. Even if data comparing alectinib with brigatinib are lacking, when indirectly comparing ALTA-1L and ALEX alectinib is associated with fewer grade ≥ 3 adverse events (41% alectinib vs. 61% brigatinib) [ 75 ].…”

Chasing the Target: New Phenomena of Resistance to Novel Selective RET Inhibitors in Lung Cancer. Updated Evidence and Future Perspectives

“…Treatment with MKIs in RET fusion-positive NSCLC demonstrated both modest clinical activity and limited response durability. Moreover, the response rates achieved in clinical experiences were lower compared with outcomes with therapies targeting other oncogenic drivers (i.e., EGFR mutations, ALK and ROS-1 fusions) [ 57 ]. Several MKIs inhibitors, that have been investigated in the treatment of RET-rearranged NSCLC, are approved for the treatment of thyroid cancers (i.e., vandetanib, cabozantinib, lenvatinib and sorafenib) or are approved for other indications (i.e., ponatinib, alectinib and sunitinib).…”

Identification of a novel prognostic DNA methylation signature for lung adenocarcinoma based on consensus clustering method

“…As major driver mutations in LUAD, KRAS and EGFR mutations are critically implicated in the pathogenesis of LUAD, and these two genes have emerged as important therapeutic targets for the treatment of LUAD. 23,24 Hence, we extracted the somatic mutation data of EGFR and KRAS, processed using the VarScan software, from TCGA database and used them for stratified analysis together with clinicopathological parameters, including AJCC stage, lymph node metastasis (LNM) status, distant metastasis (DM) status, and diagnostic age. We also analyzed the relationships between risk score model and important risk factors for patients with LUAD using the Wilcoxon test.…”