Treating disease progression with osimertinib in EGFR-mutated non-small-cell lung cancer: novel targeted agents and combination strategies

A precision medicine approach has been successfully applied in medical oncology for the treatment of non-small-cell lung cancer (NSCLC) through the identification of targetable driver molecular aberrations; activating mutations of epidermal growth factor receptor (EGFR) are the most common. Osimertinib, a third-generation, wild-type sparing, irreversible EGFR tyrosine kinase inhibitor (TKI), originally showed a striking activity after progression to first- and second-generation EGFR-TKIs when T790M resistance mutation was identified. Thereafter, upfront use of osimertinib became the standard of care based on overall survival benefit over first-generation TKIs erlotinib and gefitinib as reported in the FLAURA trial. For patients progressing on osimertinib, identification of resistance mechanisms is crucial to develop novel targeted therapeutic approaches. Moreover, innovative drugs or combination therapies are being developed for cases in which a specific resistance mechanism is not identifiable. In this review, the post-osimertinib treatment options for EGFR-mutated NSCLC are analyzed, with an outlook to ongoing clinical trials. An algorithm to guide clinicians in managing progression on osimertinib is proposed.
Highlights • Acquired resistance mechanisms to osimertinib can be EGFR dependent or independent. • First- and fourth-generation EGFR-TKIs are able to overcome EGFR-dependent resistance. • MET and MEK inhibitors may overcome EGFR-independent resistance. • Anti-HER/MET novel monoclonal antibody seems effective across multiple resistance mechanisms. • Carboplatin/paclitaxel ± bevacizumab/atezolizumab represents a feasible option in ‘fit’ patients progressing on osimertinib.