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"The KRAS oncogene is believed to be the most common single nucleotide variant oncogene in human cancer. Historically, efforts to target KRAS and the other RAS GTPases have struggled. More recently, efforts have focused on identifying and exploiting features unique to specific oncogenic mutations. This has led to the first FDA approval for a RAS targeted therapy. This new agent is a covalent inhibitor that reacts with the cysteine residue created by a codon 12 glycine to cysteine (G12 C) mutation within KRAS. Mutant-specific strategies may also exist for other KRAS single nucleotide variants, and recent studies provide examples and mechanisms"--

The recent advances in the field of molecular diagnostic techniques have led to the identification of targetable alterations prompting a paradigm shift in the management of non-small cell lung cancer (NSCLC) and an era of precision oncology. This Element highlights the most clinically relevant oncogenic drivers other than EGFR, their management and current advancements in treatment. It also examines the different challenges in resistance to targeted therapies and diagnostic dilemmas for each oncogenic driver and the future direction of NSCLC management.

Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a clinically important driver alteration affecting approximately one-third of lung cancer patients. Treatments for EGFR-exon 19 deletion and exon 21 L858R NSCLC have evolved over the last decade from first-generation reversible tyrosine kinase inhibitors (TKI) to third-generation irreversible TKIs, of which osimertinib has been the widely accepted as first-line therapy. Despite survival improvement seen with osimertinib and its efficacy against acquired T790M mutation, resistance through on-target and off-target pathways eventually develop. This Element describes the structural biology and pathophysiology of EGFR-mutant NSCLC and discusses past, current, and future treatment options in the metastatic, neoadjuvant, and adjuvant settings. It describes the biology and recently approved treatment for EGFR-exon 20 insertion mutation and the treatment for the uncommon exon 18 (G719X), 20 (S768I), and 21 (L861Q) mutations. It also outlines the promising clinical applications of circulating tumor DNA (ctDNA).

Despite considerable advances in our understanding of the biology that underlies tumor development and progression of cancer and the rapidly evolving field of personalized medicine, cancer is still one of the deadliest diseases. Many cancer patients have benefited from the survival improvements observed with targeted therapies but only a small subset of patients receiving targeted drugs experience an objective response. Because cancer is a complex and heterogeneous disease, the search for effective cancer treatments will need to address not only patient-specific molecular defects but also aspects of the tumor microenvironment. The functional tumor profiling directly measures the cellular phenotype, in particular tumor growth, in response to drugs using patient-derived tumor models and might be the next step toward precision oncology. In this Element, the authors discuss the personalized drug screening as a novel patient stratification strategy for the determination of individualized treatment choices in oncology.