P3.01-45 Multifactorial Gene Alterations in EGFR Bypass Pathway are Induced by Afatinib in T790M-Mutant NSCLC Resistant to Osmertinib

Abstract

The 3rd generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) was developed to target the EGFR T790M resistance mutation in non-small cell lung cancer patients resistant to 1st or 2nd generation EGFR-TKIs. Although some mechanisms of acquired resistance to 3rd generation EGFR-TKI such as EGFR C797S mutation have been reported, the effect and resistant mechanisms to afatinib followed by osmertinib has not been well-known. Nine patients with EGFR T790M-mutant NSCLC resistance to 3rd generation EGFR-TKI were enrolled in this study and treated with afatinib. Plasma samples were collected before treatment, 4 weeks after treatment, and at disease progression. Mutation profile and tumor mutation burden (TMB) in plasma cell free DNA (cfDNA) were analyzed by CAPP-seq. The objective response rate and median progression-free survival of afatinib were 0% and 2.0 months, respectively. At the time of 4 weeks after treatment, four patients developed disease progression and five patients showed stable disease. A total of 36 somatic mutations or amplification were detected in plasma cfDNA before afatinib treatment; EGFR activating mutations in 8 patients, T790M mutation in 4, TP53 mutations in 6, PIK3CA mutations in 3, BRAF mutations in 3, MET amplification in 3, CTNNB1 mutations in 2, ERBB2 mutations in 2, C797S mutation in 1, SMAD4 mutation in 1, EGFR minor mutation in 1, KRAS mutation in 1, and APC mutation in one patient. EGFR C797S mutation in cfDNA was detected during afatinib treatment in two cases. In the patients having stable disease at 4 weeks after treatment, mutant allele frequency and TMB tended to decline once, and then increased in association with disease progression. Detection of mutant allele frequency and TMB of ctDNA by CAPP-seq could monitor the effectiveness and resistance to afatinib. Resistant mechanisms to afatinib might be characterized by multifactorial bypass pathway activation.