Expert consensus on the use of third-generation EGFR-TKIs in EGFR-mutated advanced non-small cell lung cancer with various T790M mutations post-resistance to first-/second-generation EGFR-TKIs

Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have emerged as the mainstay of treatment for advanced EGFR-mutant advanced non-small cell lung cancer (NSCLC), effectively overcoming the problems of acquired threonine-to-methionine (T790M) mutations associated with the first- or second-generation TKIs. Evidence from several studies suggests that these agents, including osimertinib and aumolertinib, also show potential benefits in T790M-negative or unknown populations, particularly those with brain metastases, where the high permeability of the blood–brain barrier allows effective control of intracranial lesions. Despite the encouraging results, further high-quality research, including prospective trials, is warranted to fully elucidate the efficacy profiles of these third-generation TKIs in T790M-negative or unknown NSCLC patients after first- or second-line TKI failure. The present expert consensus highlights the evolving role of third-generation EGFR-TKIs in overcoming therapeutic resistance and optimizing patient outcomes. Plain language summary Experts agree on treating lung cancer with specific gene changes using advanced medicines Newer medicines called third-generation EGFR inhibitors have become key treatments for a type of advanced lung cancer that has specific genetic changes. These drugs, such as osimertinib and aumolertinib, solve a problem encountered with older drugs: resistance caused by a mutation known as T790M. They’re especially promising for patients whose cancer has spread to the brain, because they can pass through the brain’s protective barrier and help control tumors there. While current evidence suggests these new drugs can help even when the T790M mutation isn’t present or hasn’t been tested for, more research is needed to fully understand how well they work in these situations. After other treatments have stopped being effective, using these advanced medicines may offer new hope by tackling treatment resistance and improving patients’ chances. This expert agreement outlines how these newer drugs are changing the way we overcome therapy challenges and enhance patient care.