ResearchTreatments

New Mechanisms Under Study to Overcome Osimertinib Resistance in EGFR+ NSCLC

By November 12, 2021No Comments

*October 2021*

Several small molecule EGFR tyrosine kinase inhibitors (TKIs) are now available for the treatment of EGFR-mutated non–small cell lung cancer (NSCLC). However, progression after TKI therapy—including with the third-generation TKI osimertinib (Tagrisso)—is inevitable. Results of several studies targeting new treatment strategies were reported at the recent International Association for the Study of Lung Cancer 2021 World Congress on Lung Cancer (WCLC).

Approximately 10% to 15% of patients with NSCLC in the United States and Europe and 45% of patients with NSCLC in Asia have disease with EGFR-sensitizing mutations.1 The most common sensitizing mutations are deletions in exon 19 (45%) and a point mutation in exon 21 (L858R, 40%). Tumors with these mutations initially respond to EGFR TKIs, including erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), osimertinib, and dacomitinib (Vizimpro), but they ultimately develop resistance mutations and stop responding to EGFR TKIs, usually within months.2,3

Mechanisms of Resistance

The most common mechanism of acquired resistance is the development of a second mutation in exon 20 of EGFR, known as T790M.4 EGFR T790M develops in approximately 60% of cases of NSCLC upon treatment with TKIs5 and decreases the affinity of EGFR-TKI binding to the adenosine triphosphate binding pocket of EGFR.6

Osimertinib is a third-generation EGFR TKI that targets both sensitizing and resistant T790M mutations.7 According to National Comprehensive Cancer Network guidelines, osimertinib is the preferred first-line EGFR TKI option for patients with EGFR-positive metastatic disease.2 In addition, osimertinib is indicated for adult patients with EGFR T790M mutation–positive NSCLC whose disease has progressed on or after EGFR TKI therapy.8 Although osimertinib has been shown to overcome T790M-mediated mutations in the second-line setting,9 as with other EGFR TKIs progression on osimertinib is inevitable.

In addition to T790M, other EGFR-dependent pathways of osimertinib resistance include new development of EGFR C797S mutations and multiple others, including L792X, G796S, L718Q, S768I, G796R, G796D, and G724S (FIGURE).10-18 EGFR amplification and copy number alteration also are EGFR-dependent mechanisms for the secondary drug resistance of osimertinib.4,19,20 EGFR-independent mechanisms of resistance include MET amplification, which accounts for 5% to 10% of acquired EGFR-TKI resistance cases,10,21 HER2 amplification, and KRAS and PIK3CA gene mutations.22 Currently, approximately 50% of resistance mutations are unknown.23

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