<![CDATA[Introduction: Mutation in lung adenocarcinoma pose significant challenges in lung malignancy management. Next‑generation sequencing can reveal uncommon variants and drug‑resistance mechanisms that require personalized therapy. Case: First case, 68 years old female diagnosed with lung nodules since 2021 without regular check-ups. In September 2023, the patient diagnosed with Left Lung Adenocarcinoma T4N2M1b stage IVA with EGFR exon 20 insertion but she refused chemotherapy and got afatinib for seven months until the symptoms re-occurred. EGFR with NGS in March 2024 showed additional exon 19 deletion and afatinib continued till the patient showing grade III cutaneous–gastrointestinal adverse effects and followed by dosage adjustment Patient's condition worsened in June 2024. Second case, 61 years old female diagnosed with right lung adenocarcinoma T4N2M1c Stage IVB with exon 21 L858R in January 2022. Patient underwent afatinib therapy showing good results. After 24 months, subsequently became symptomatic, and EGFR testing detected additional T790M EGFR gene leading treatment change to osimertinib with unsatisfactory results. NGS-liquid biopsy in May 2024 showed compound mutation exon 21 L858R - exon 21 V834L with resistance to osimertinib. Patient’s condition worsened in August 2024. Conclusion: Lung adenocarcinoma can mutate to not only uncommon but also rare mutations, such as exon 20 insertion and V834L, leading to TKI resistance despite the patient's clinical improvement. This represents a significant therapeutic challenge in the management of adenocarcinoma and requires a comprehensive, personalized treatment approach. Keywords: Adenocarcinoma, Uncommon mutation, Drug Resistance]]>
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