Targeted Therapies for Lung Cancer Patients With Oncogenic Driver Molecular Alterations

Abstract

Lung cancer has traditionally been classified by histology. However, a greater understanding of disease biology and the identification of oncogenic driver alterations has dramatically altered the therapeutic landscape. Consequently, the new classification paradigm of non–small-cell lung cancer is further characterized by molecularly defined subsets actionable with targeted therapies and the treatment landscape is becoming increasingly complex. This review encompasses the current standards of care for targeted therapies in lung cancer with driver molecular alterations. Targeted therapies for EGFR exon 19 deletion and L858R mutations, and ALK and ROS1 rearrangements are well established. However, there is an expanding list of approved targeted therapies including for BRAF V600E, EGFR exon 20 insertion, and KRAS G12C mutations, MET exon 14 alterations, and NTRK and RET rearrangements. In addition, there are numerous other oncogenic drivers, such as HER2 exon 20 insertion mutations, for which there are emerging efficacy data for targeted therapies. The importance of diagnostic molecular testing, intracranial efficacy of novel therapies, the optimal sequencing of therapies, role for targeted therapies in early-stage disease, and future directions for precision oncology approaches to understand tumor evolution and therapeutic resistance are also discussed.

Trial Watch: combination of tyrosine kinase inhibitors (TKIs) and immunotherapy

“… 28 Here, we focus on bona fide tyrosine kinase inhibitors (TKIs) 29–32 that have been approved by the FDA since the turn of the millennium and have meanwhile entered into clinical practice. 33 , 34 …”

Daily Practice Assessment of KRAS Status in NSCLC Patients: A New Challenge for the Thoracic Pathologist Is Right around the Corner

“…Among the lung cancer histological subtypes, non-small cell lung carcinoma (NSCLC) is the most frequent histological subtype, representing at least 85% of all cases [ 5 ]. The therapeutic strategy of advanced-stage or metastatic NSCLC, notably of non-squamous (NS)-NSCLC, has evolved dramatically in the last few years, thanks to the development of new targeted therapies and immune checkpoint inhibitors (ICIs) administered alone or in association with chemotherapy and targeted therapies [ 6 , 7 , 8 ]. These different therapies have significantly increased the overall survival of NS-NSCLC patients [ 9 , 10 ].…”

“…Different drugs target genomic alterations in EGFR , ALK , ROS1 , BRAF , and NTRK , or more recently in RET and MET [ 11 , 12 , 13 ]. In the case of absence of oncogenetic addiction, ICIs are now widely used as significant alternative therapeutic options [ 7 , 8 ]. Moreover, besides the different promising ICIs, new molecules are currently being evaluated in many clinical trials and recent results suggest the coming soon administration of additional targeted therapies for NS-NSCLC in daily practice [ 10 , 12 , 14 , 15 , 16 , 17 ].…”

“…KRAS has been added to the list of genes that certainly must be characterized for advanced-stage NS-NSCLC at diagnosis, progression, and recurrence [ 8 ]. One of the consequences is a modification of the diagnostic algorithms used by most of the clinical and molecular pathology laboratories.…”

Immune Landscape and Classification in Lung Adenocarcinoma Based on a Novel Cell Cycle Checkpoints Related Signature for Predicting Prognosis and Therapeutic Response

“…Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancers, and lung adenocarcinoma (LUAD) is the most common subtype of NSCLC, with a high degree of heterogeneity and aggressiveness ( Thai et al, 2021 ). Despite improvements in multiple therapies, LUAD patients still have poor prognosis, due to local recurrence and distant metastasis ( Tan and Tan, 2022 ). Therefore, it is necessary to develop a risk stratification method and find reliable molecular signature for early diagnosis, prognostic prediction, and treatment options of LUAD.…”