“Sandwich” Strategy to Intensify EGFR Blockade by Concurrent Tyrosine Kinase Inhibitor and Monoclonal Antibody Treatment in Highly Selected Patients

Abstract

EGFR TKIs are not curative, and targeted resistance inevitably results in therapeutic failure. Additionally, there are numerous uncommon EGFR mutations that are insensitive to EGFR TKIs, and there is a lack of clinical strategies to overcome these limitations. EGFR TKI and mAbs target EGFR at different sites, and a combination regimen for delaying/preventing resistance to targeted therapy or obtaining more intensive inhibition for uncommon mutations at cellular, animal and human levels has been explored. This review critically focuses on a combination strategy for uncommon EGFR mutation-positive NSCLC, and discuss the preclinical data, clinical implications, limitations and future prospects of the combination strategy.

Case report: EGFR fusion mutation combined with EGFR amplification responds to EGFR-TKI therapy

“…The results of Shigenari et al ( 13 ) show that the amplification of EGFR wild-type (rather than mutant EGFR) alleles may induce acquired drug resistance to third-generation EGFR-TKIs through activation induced by EGFR ligands. We recently reported on the combined targeted therapy-”sandwich” regimen ( 14 ). This strategy was successfully applied in a patient with EGFR-IGR combined with EGFR amplification ( 3 ).…”

Case Report: A patient with the rare third-generation TKI-resistant mutation EGFR L718Q who responded to afatinib plus cetuximab combination therapy

“…EGFR TKIs and EGFR monoclonal antibodies (mAbs) have been combined to increase the intensity of EGFR inhibition because they can exert synergistic antitumor effects and because their combination permits a reduced dose of each drug to be used, allowing AEs to be controlled without impairing the therapeutic effect. In our previous study, we reviewed in detail the potential mechanisms (such as direct inhibition, receptor internalization, and immunological effects) by which cetuximab could increase the efficacy of EGFR TKIs ( 22 ). This combination regimen may be particularly effective for EGFR exon 20 ins mutations ( 1 ), C797S/T790M/sensitive mutations ( 23 ), and EGFR –intergenic region ( IGR ) ( SEC61G ) fusion/ EGFR amplification mutations ( 24 ).…”