dacomitinib + osimertinib

The combination of dacomitinib and osimertinib is an investigational therapy for EGFR-mutant non-small cell lung cancer (NSCLC), particularly in the context of primary or acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Dacomitinib is a second-generation irreversible pan-ErbB TKI that inhibits EGFR/HER1, HER2, and HER4. Osimertinib is a third-generation irreversible EGFR TKI that selectively targets both sensitizing mutations and the T790M resistance mutation in EGFR. The rationale for combining these agents is to provide dual inhibition of the EGFR pathway to prevent or overcome on-target resistance mechanisms such as secondary mutations (e.g., T790M or C797S) that arise during monotherapy with either agent. Clinical studies have evaluated this combination as initial therapy and after progression on osimertinib; while it showed promising response rates as initial therapy (overall response rate 73%), toxicity was significant and efficacy in reversing established acquired resistance was limited[1][3]. The combination remains under investigation.