Molecular Evolutionary Insights Allow a Sequential Precision Medicine Strategy for Acquired Osimertinib Resistance in <scp> <i>EGFR</i> </scp> Mutant Non‐Small Cell Lung Cancer: Lessons From Longitudinal Tumor Sampling

ABSTRACT Osimertinib acquired resistance is a significant clinical challenge in the treatment of metastatic epidermal growth factor ( EGFR ) mutated non‐small cell lung cancer (NSCLC) patients and strategies to overcome it include further tumor sequencing, to identify the exact mechanisms of drug resistance, which may be potentially targetable. MET amplification is the commonest acquired resistance mechanism in this population cohort and can be further drugged with the selective MET inhibitor tepotinib in combination with osimertinib. We present the case of a metastatic, exon‐19 deletion EGFR mutant NSCLC patient, treated with combination osimertinib‐carboplatin‐pemetrexed, as per the FLAURA2 trial regime, in the first‐line setting. Upon development of resistance to osimertinib, with multiple sites of disease progression, MET amplification was identified by tissue NGS, from biopsy sampling of a metastatic tumor site, in addition to circulating tumor DNA (ctDNA) sequencing. The patient was treated with combination osimertinib‐tepotinib, leading to a durable partial response. On further progression, acquired resistance mechanisms were further investigated and a competing FGFR fusion clone was identified, leading to a switch to combination erdafitinib with osimertinib, with subsequent good response. This report highlights the importance of understanding and investigating osimertinib resistance mechanisms, exploiting these for effective patient management, alongside limitations of this approach.