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Osimertinib + repotrectinib is an investigational combination therapy under clinical evaluation for advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR mutations. Osimertinib is a third-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that selectively targets activating EGFR mutations and the T790M resistance mutation, while sparing wild-type EGFR. Repotrectinib is a next-generation small molecule tyrosine kinase inhibitor that potently inhibits ALK, ROS1, and TRK family kinases as well as other kinases implicated in resistance to EGFR TKIs such as JAK2, SRC, and FAK. The rationale for combining these agents is to overcome acquired resistance mechanisms in patients who have progressed on prior EGFR TKI therapies[2][1][10]. The combination is currently being studied in phase I trials for safety, tolerability, pharmacokinetics, and preliminary efficacy in this patient population[2][4].
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