Non-invasive molecular testing of osimertinib acquired resistance in T790M-positive advanced non-small cell lung cancer

Data on acquired resistance to osimertinib in Asian patients with EGFR ( epidermal growth factor receptor ) T790M-positive advanced non-small cell lung cancer (NSCLC) remain limited. We used Non-invasive Molecular Testing (NIMT) to characterize resistance-associated alterations and explore their clinical associations. Patients with advanced EGFR T790M-positive NSCLC who received osimertinib after progression on first- or second-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) were prospectively enrolled at Ramathibodi Hospital between January 2016 and December 2019. Paired plasma samples collected before osimertinib treatment and at disease progression were analyzed using a targeted 52-gene next-generation sequencing panel. Clinical outcomes were subsequently correlated with the molecular findings. Fifty patients with paired plasma samples were analyzed. Nineteen patients (38%) had more than one resistance-associated alteration. Plasma T790M was detected at baseline in 32 patients; 16 (50%; 32% of the overall cohort) had undetectable T790M at progression. Genomic alterations detected at progression included TP53 (22%), PIK3CA (14%), EGFR C797S (10%), and BRAF (8%) mutations and MET amplification (2%). Median time to treatment failure (TTF) and overall survival (OS) were 9.3 and 16.4 months, respectively. T790M loss was associated with numerically shorter TTF than retained T790M (6.0 vs. 10.1 months; P = 0.21). Among patients with T790M loss, those with co-occurring alterations also had numerically shorter TTF than those without co-alterations (4.1 vs. 10.6 months; P = 0.06). In univariable analyses, baseline brain metastasis was significantly associated with subsequent plasma T790M loss ( P = 0.04), uncommon-site metastasis with EGFR C797S ( P < 0.01), and brain progression during osimertinib treatment with BRAF mutations ( P = 0.01). Plasma NIMT identified heterogeneous resistance-associated alterations after osimertinib. T790M loss and co-alterations were associated with numerically shorter TTF, while specific alterations were associated with metastatic patterns. These exploratory findings require validation in larger cohorts with tissue-based analyses.