Fig. 4

Targeted therapy for osimertinib resistance. a Different treatment regimens targeting on-target resistance mechanisms (mainly EGFR tertiary mutations). C797S/T790M in cis: osimertinib-resistant NSCLC responds to brigatinib in combination with cetuximab, and such a regimen has been proven in several case reports. C797S/T790M in trans: NSCLC patients become sensitive to combination therapy of osimertinib and first-generation EGFR-TKIs. C797S alone and the other tertiary EGFR mutations: patients may resensitize to early-generation EGFR-TKIs. Novel EGFR inhibitors are under way to overcome C797S-mediated resistance to osimertinib, regardless of the C797S/T790M allelic context. b Targeting common off-target resistance mechanisms. Based on current available preclinical and clinical evidence, combination treatments of osimertinib plus inhibitors of corresponding targets are the major therapeutic strategies.