We have witnessed incredible advances in therapy since ALK was discovered in 2007, starting from the pivotal PROFILE 1001 study of crizotinib in advanced ALK positive NSCLC to present day where we now have five approved targeted agents, with increasing potency, selectivity and CNS activity with each successive generation of drug. Despite these advances in therapy, the emergence of treatment resistance in the TKI still remains one of greatest challenges in the clinic. Our TOGA podcast panel discuss the clinical and genetic factors affecting treatment choice, sequencing and resistance patterns, including oligoprogression and local therapy considerations. Dr Rebecca Tay, Medical Oncologist at Royal Hobart Hospital and ICON Hobart, is joined in this discussion by Professor Ben Solomon, Medical Oncologist at Peter MacCallum Cancer Centre & Board member, Scientific Chair of TOGA and Associate Professor Michael Ng, Radiation Oncologist at GenesisCare St Vincents Hospital Melbourne and Head of Stereotactic Radiotherapy at GenesisCare Victoria. References: CROWN: ascopubs.org/doi/10.1200/JCO.24.00581 Gomez paper denovo oligomet SABR pubmed.ncbi.nlm.nih.gov/31067138/ Kroeze – concurrent systemic therapy + SABR consensus sciencedirect.com/science/article/abs/pii/S1470204522007525 Tsai Curb trial RCT for oligoprogression pubmed.ncbi.nlm.nih.gov/38104577/