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.