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.


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.

The introduction of second- and third-generation EGFR inhibitors, initially designed to target common resistance mutations that developed from erlotinib and gefitinib, also yielded better outcomes in the frontline setting. Afatinib (Gilotrif) showed superior PFS (11.0 vs 10.9 months; HR, 0.73) and time-to-treatment failure (13.7 vs 11.5 months; HR, 0.73) compared with gefitinib in the LUX-Lung 7 trial,5 and dacomitinib (Vizimpro) showed an improvement in PFS (14.7 vs 9.2 months; HR, 0.59) over gefitinib in the ARCHER 1050 trial.6

The third-generation EGFR inhibitor osimertinib (Tagrisso), initially approved for patients with the EGFR T790M mutation on exon 20—the most common mechanism of resistance to erlotinib, gefitinib, or afatinib—also demonstrated numerically longer median PFS compared with gefitinib or erlotinib (18.9 vs 10.2 months; HR, 0.46; 95% CI, 0.37-0.57; P <.001) and was approved for frontline treatment for patients whose tumors have EGFR exon 19 or exon 21 L858R mutations in April 2018.7

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.

Secondary Alterations Within EGFR

The T790M mutation on exon 20 occurs in approximately half of patients treated with erlotinib or gefitinib.8 Osimertinib was initially designed to target this mutation and demonstrated superior PFS compared with platinum/pemetrexed (Alimta) chemotherapy (10.1 vs 4.4 months; HR, 0.30) in patients with disease progression and the EGFR T790M mutation after first-line EGFR TKI therapy in the AURA3 trial.9 Other secondary mutations in EGFR associated with acquired resistance to first-generation EGFR TKIs include EGFR D761Y and T854A.10,11

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Online CME Activities
TitleExpiration DateCME Credits
Year in Review™: Reflecting on Recent Evidence With an Eye to the Future of Lung Cancer ManagementMar 30, 20191.5
Online Medical Crossfire®: 5th Annual Miami Lung Cancer ConferenceMay 30, 20196.5
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