Optimizing the Clinical Management of EGFR-Mutant Advanced Non-Small Cell Lung Cancer

A Literature Review

Francesco Passiglia; Paolo Bironzo; Valentina Bertaglia; Angela Listì; Edoardo Garbo; Giorgio Vittorio Scagliotti

Disclosures

Transl Lung Cancer Res. 2022;11(5):935-949. 

In This Article

Abstract and Introduction

Abstract

Background and Objective: Despite several steps forward in the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), however there are still pending issues and upcoming challenges requiring adequate addressing in order to optimize the clinical management of metastatic patients harboring molecular alterations within the EGFR gene. This review aims to summarize the most recent findings regarding the diagnostic testing and therapeutic strategies of EGFR-mutant advanced NSCLC.

Methods: Literature search was conducted using MEDLINE/PubMed, EMBASE, Scopus and Cochrane Library databases, up to December 2021. Relevant studies in English language published between 2004 and 2021 were selected.

Key Content and Findings: The increased detection of uncommon EGFR mutations in the real-word practice along with the clinical development of novel selective inhibitors, highlighted the issue of an adequate selection of the best EGFR-tyrosine-kinase inhibitor (TKI) to the right patient mutation. The advent of osimertinib in first-line has dramatically changed the spectrum of molecular mechanisms underlying both innate and acquired resistance to the EGFR-TKI therapy, accelerating the clinical investigation of novel genomic-driven sequential strategies as well as upfront targeted combinations. The recent approval of potent, selective inhibitors targeting the EGFR exon-20 insertions, renewed interest toward this patients' subset, questioning the diagnostic accuracy of old-standard genomic sequencing technologies and pushing the implementations of next-generation sequencing (NGS)-based molecular profiling in the real word practice scenario.

Conclusions: This review provides evidence-based answers to the aforementioned challenges aiming to optimize the clinical management of metastatic patients harboring molecular alterations within the EGFR gene.

Introduction

Over the past few decades, the identification of oncogenic drivers predicting clinical response to targeted therapies produced a radical shift from histological to molecular subtyping of lung adenocarcinoma, establishing a new paradigm of precision medicine. Tumor molecular profiling is now considered as a crucial step of the diagnostic and therapeutic management of advanced non-small cell lung cancer (NSCLC), allowing to personalize therapeutic strategies and ultimately improve patients' survival.[1] The epidermal growth factor receptor (EGFR) gene activating mutations represented the first molecular predictive biomarker discovered in lung cancer in 2004, underlying clinical responsiveness to the EGFR-tyrosine kinase inhibitors (TKIs).[2,3] Molecular alterations within the EGFR gene have been reported in about 40–60% and 12–15% of Asiatic and Caucasian adenocarcinoma patients, respectively, rarely occurring also in squamous cell carcinoma subtype.[4] The most common targetable alterations include both exon 19 in frame deletion (Del19) and exon 21 L858R point mutation, accounting for about 85–90% of the overall EGFR mutations, predicting meaningful response to targeted agents. Conversely, uncommon alterations include a wide spectrum of mutations, deletions, as well as insertions, occurring among exons 18 to 21 of the EGFR gene (Figure 1), which are characterized by high heterogeneity in terms of response/resistance to the available EGFR-TKIs.[4] Sometimes uncommon variants may occur at subclonal level, coexisting with either common or uncommon EGFR mutations, to define the "complex/compound" molecular subtypes. Co-occurring genomic alterations have been also reported in a significant subset of patients, highlighting the biological heterogeneity of the EGFR-mutant disease.[5] Despite several steps forward in the treatment of EGFR-positive NSCLC, however there are still pending issues and upcoming challenges requiring adequate addressing. The increased detection of uncommon EGFR mutations following the advent of next-generation sequencing (NGS) in the real-word practice, along with the clinical development of novel selective inhibitors, highlighted the issue of adequate selection of the best EGFR-TKI to the right patient. The advent of osimertinib in first-line has dramatically changed the spectrum of both innate and acquired resistance mechanisms related to the EGFR-TKI therapy, accelerating the clinical investigation of novel treatment strategies as well as upfront combinations. The recent approval of potent, selective EGFR exon-20 insertions inhibitors questioned the diagnostic accuracy of old-standard genomic sequencing technologies, pushing the implementations of NGS-based molecular profiling in the real word practice scenario.

Figure 1.

Targetable EGFR oncogenic alterations in advanced NSCLC. EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer.

In this review we summarize the most recent findings regarding diagnostic testing and therapeutic strategies of EGFR-mutant NSCLC, in order to provide evidence-based answers to the aforementioned challenges, aiming to optimize the clinical management of metastatic patients harboring molecular alterations within the EGFR gene. We present the following article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-1/rc).

processing....