Drug Sensitivity and Allele Specificity of First-Line Osimertinib Resistance EGFR Mutations

Abstract

◥Osimertinib, a mutant-specific third-generation EGFR tyrosine kinase inhibitor, is emerging as the preferred first-line therapy for EGFR-mutant lung cancer, yet resistance inevitably develops in patients. We modeled acquired resistance to osimertinib in transgenic mouse models of EGFR L858R -induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in EGFR-either C797S or L718V/Q. Analysis of circulating free DNA data from patients revealed that L718Q/V mutations almost always occur in the context of an L858R driver mutation. Therapeutic testing in mice revealed that both erlotinib and afatinib caused regression of osimertinib-resistant C797S-containing tumors, whereas only afatinib was effective on L718Q mutant tumors. Combination first-line osimertinib plus erlotinib treatment prevented the emergence of secondary mutations in EGFR. These findings highlight how knowledge of the specific characteristics of resistance mutations is important for determining potential subsequent treatment approaches and suggest strategies to overcome or prevent osimertinib resistance in vivo.Significance: This study provides insight into the biological and molecular properties of osimertinib resistance EGFR mutations and evaluates therapeutic strategies to overcome resistance.

Case Report: Dacomitinib May Not Benefit Patients Who Develop Rare Compound Mutations After Later-Line Osimertinib Treatment

“…Patients typically have more concomitant genetic mutations and greater tumor heterogeneity after multiple treatments, which is an important reason for the discrepancy between cell assays and clinical results. Interestingly, afatinib, which is also a 2G TKI, showed good tumor control not only in in vitro cellular assays (5) on L718X/ L792X mutations but also in clinical application of L718X mutation according to several case reports (Supplementary Table 2) (16)(17)(18)(19)(20). Molecular structural models showed that, unlike dacomitinib, no clashes or spatial conflicts between afatinib in its L858R-bound orientation and the L718Q/V sidechain were observed (17,21).…”

Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance

“…Mouse models are a key system for the advancement of our understanding of lung cancer targeted therapy resistance 11,[19][20][21] . However, recent findings demonstrate that these models lack the mutational heterogeneity present in human tumours [22][23][24] .…”

<p>Osimertinib for Front-Line Treatment of Locally Advanced or Metastatic <em>EGFR</em>-Mutant NSCLC Patients: Efficacy, Acquired Resistance and Perspectives for Subsequent Treatments</p>

“…Similar results were described with erlotinib and afatinib in mice models. 51 Many other EGFR mutations have been described in patients progressing on osimertinib. Similarly to what has been described for the C797S mutation, some of these mutations have been found to respond to EGFR TKI in cellular models.…”

“…52 In vitro, combination of first-line osimertinib and erlotinib prevented the emergence of secondary EGFR mutations. 51 The objective response rate of osimertinib in combination with gefitinib in EGFR inhibitor-naïve advanced EGFR mutant lung cancer is being investigated in the NCT03122717 phase 1/2 trial (Table 3).…”