Primary resistance to osimertinib despite acquired T790M

Abstract

Current National Comprehensive Cancer Network (NCCN) guidelines suggest plasma-based testing (liquid biopsy) for T790M in epidermal growth factor receptor (EGFR)-mutated non-small cell lung carcinoma (NSCLC) with acquired resistance to first-/second-generation EGFR tyrosine kinase inhibitors (TKIs). Positivity for resistant mutation on liquid biopsy may obviate the need for invasive tissue biopsy. We report a rare case of primary resistance to osimertinib, although liquid biopsy revealed EGFR T790M positivity. A 63-year-old male, never smoker, was diagnosed with stage IV lung adenocarcinoma with EGFR exon 19 deletion. Treatment started with erlotinib and was continued for 15 months until disease progression. Osimertinib was initiated when liquid biopsy showed EGFR T790M positivity. However, primary resistance to osimertinib was noted on follow-up imaging. Re-biopsy revealed small cell lung cancer. Detection of T790M via liquid biopsy among NSCLC patients with acquired resistance to EGFR-TKI might miss other possible resistant mechanisms. Tissue biopsy should be considered to exclude small cell lung carcinoma (SCLC) transformation.

Transformation of advanced lung adenocarcinoma to acquired T790M resistance mutation adenosquamous carcinoma following tyrosine kinase inhibitor: a case report

“…The most common mechanism is T790M, which accounts for about 40%-50% of all subtypes. 6,7 According to recent research, converted squamous cell carcinoma has a high frequency of p.T790M mutation, which consists with our case. The authors put forward the hypothesis that in patients carrying p.T790M, osimertinib may exert a peculiar function in the transformation of pathologic types in tumor.…”

Serial Plasma Cell-Free Circulating Tumor DNA Tests Identify Genomic Alterations for Early Prediction of Osimertinib Treatment Outcome in EGFR T790M–Positive NSCLC

“…Mechanisms of primary resistance, such as small cell transformation, ERBB2 exon 16 skipping or amplification, MET amplification, BIM deletion polymorphism, EZH2 mutation, and KRAS G12D mutation, have been reported. [33][34][35][36][37] To the best of our knowledge, this is the first report of inferring PTEN alteration as a potential mechanism of primary resistance by using plasma ctDNA analysis.…”

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

“…Osimertinib works best against the L858R/T790M EGFR double mutant but not as well as afatinib against L858R single mutant, the Exon 19del mutant or WT EGFR. At least one report found that osimertinib may not be efficient for patients that harbor both the T790M and the exon 19 deletion [88]. As expected, resistant mutations in response to osimertinib treatment arise by inactivating cysteine 797 (C797G or C797S) [89,90] ( Figure 1E).…”