Category

Archives

Mechanisms of Acquired Resistance to AZD9291 A Mutation-Selective, Irreversible EGFR Inhibitor

INTRODUCTION:

AZD9291, a third-generation and mutation-selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is active against patients with EGFR-mutant non-small-cell lung cancer (NSCLC) who failed prior treatment with EGFR TKIs. However, acquired resistance to AZD9291 is inevitable. In this study, we identified the mechanisms of acquired resistance to AZD9291 in EGFR-mutant NSCLC.

METHODS:

Four NSCLC patients with both an EGFR exon 19 deletion and the EGFR mutation after developing acquired resistance to first-generation EGFR TKIs received AZD9291 at doses of 20 to 80 mg/day in a phase I trial (NCT01802632). Paired tumor samples before and after treatment were obtained to evaluate EGFR modifications, alternative pathway activation, and histologic transformation. Genetic alterations were analyzed using Sanger sequencing, fluorescence in situ hybridization, real-time polymerase chain reaction, and targeted exome sequencing.

RESULTS:

All four patients achieved a partial response (median duration of response, 9 months [range, 9-11 months]) and subsequently showed resistance to AZD9291. EGFR-mutant clones depopulated AZD9291-resistant tumors to below 1% (baseline, 14%-36%) in three patients with progression: one with the loss of EGFR-double mutant clones and two accompanied by transformation to small-cell carcinoma and focal fibroblast growth factor receptor 1 (FGFR1) amplification, respectively. EGFR-mutant clones remained and the EGFR ligand was overexpressed in one patient with focal progression to AZD9291.

CONCLUSION:

Acquired resistance mechanisms of AZD9291 in patients with EGFR-mutant NSCLC who failed treatment with first-generation EGFR TKIs include the loss of EGFR-mutant clones plus alternative pathway activation or histologic transformation and EGFR ligand-dependent activation.

Related Products

Cat.No. Product Name Information Publications Customer Product Validation
S1264 PD173074 PD173074 is a potent FGFR1 inhibitor with IC50 of ~25 nM and also inhibits VEGFR2 with IC50 of 100-200 nM in cell-free assays, ~1000-fold selective for FGFR1 than PDGFR and c-Src. (35) (7)
S2183 BGJ398 (NVP-BGJ398|Infigratinib) BGJ398 (NVP-BGJ398) is a potent and selective FGFR inhibitor for FGFR1/2/3 with IC50 of 0.9 nM/1.4 nM/1 nM in cell-free assays, >40-fold selective for FGFR versus FGFR4 and VEGFR2, and little activity to Abl, Fyn, Kit, Lck, Lyn and Yes. Phase 2. (35) (7)
S2814 Alpelisib (BYL719) Alpelisib (BYL719) is a potent and selective PI3Kα inhibitor with IC50 of 5 nM in a cell-free assay, and minimal effect on PI3Kβ/γ/δ. Phase 2. (25) (3)

Related Targets