EGFR and ALK Inhibitors in NSCLC Lead to Resistance Challenge

Gina Battaglia, PhD
Published: Wednesday, Feb 13, 2019
New therapies that inhibit EGFR and ALK gene rearrangements in non–small cell lung cancer (NSCLC) have changed the paradigm of care in these settings. However, their use has involved a frustrating game of one-upmanship, in which these tumors develop new resistance mechanisms that counter successive generations of inhibitors. Resistance mechanisms that thwarted first-generation ALK inhibitor crizotinib (Xalkori) and the first-generation EGFR tyrosine kinase inhibitors (TKIs) erlotinib (Tarceva) and gefitinib (Iressa) created the need for secondand third-generation ALK and EGFR TKIs that could overcome such barriers (Figure 1, 2).1,2 Furthermore, first-generation EGFR and ALK TKIs had key shortcomings, such as a lack of central nervous system (CNS) penetration.

Superior progression-free survival (PFS) and better CNS penetrance of newer agents have led to approval or consideration of these for frontline therapy. However, the mechanisms of resistance that hinder these drugs are distinctly different from those affecting first-generation agents. Now, selecting the optimal therapy regimen for patients has come to involve careful analysis posttherapy, including repeat biopsies and testing, to identify these mechanisms of resistance.

EGFR-Positive NSCLC

Somatic activating EGFR mutations were the among the first to be described in NSCLC and are found in approximately 10% of patients with NSCLC, but more frequently in nonsmokers, adenocarcinomas, women, and patients of Asian descent.3 Mutations in exons 18 to 21 are the most common mutations sensitive to EGFR TKI therapy, with deletions in exon 19 and the L858R point mutation in exon 21 accounting for 85% to 90%.4 Because there are primary resistance mutations, often occurring in exon 20, that do not respond to EGFR TKIs as expected and de novo or acquired resistance mutations, such as T790M, that occur after treatment with a first- or second-generation EGFR inhibitor, differentiating among EGFR resistance mutations has been important for successful targeted treatment.

Resistance to EGFR-Targeted Therapy

Despite the advances in EGFR-targeted therapy over the past decade, resistance to EGFR TKI therapy is virtually inevitable. Resistance mechanisms are broadly categorized as secondary alterations within EGFR, activation of an alternative signaling pathway or downstream effector gene, and phenotypic transformation. Although secondary alterations in EGFR are common mechanisms of resistance to first- and second-generation EGFR inhibitors, mechanisms of resistance to osimertinib, while not fully elucidated, appear to be more diverse and include EGFR-independent mechanisms.
... to read the full story
To Read the Full Story

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Publication Bottom Border
Border Publication
x