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Alexa B Schrock,1 Russell Madison,1 Mark Rosenzweig,2 Justin M Allen,2 Rachel L Erlich,2 Siao-Yi Wang,3 Tarek Chidiac,4 Vodur Suresh Reddy,5 Jonathan W Riess,6 Ahmet Ersin Yassa,6 Abdur Shakir,7 Vincent A Miller,1 Brian M Alexander,1 Jeffrey Venstrom,1 Kimberly McGregor,1 Siraj M Ali1 1Foundation Medicine, Department of Clinical Development, Cambridge, MA, USA; 2Foundation Medicine, Department of Translational Oncology and Clinical Reporting, Cambridge, MA, USA; 3Loyola University Medical Cancer, Department of Hematology and Oncology, Maywood, IL, USA; 4Zangmeister Cancer Center, Department of Hematology and Oncology, Columbus, OH, USA; 5Cancer Care Specialists, Department of Hematology and Oncology, Reno, NV, USA; 6UC Davis Comprehensive Cancer Center, Department of Hematology and Oncology Sacramento, CA, USA; 7Sarah Bush Lincoln Health System, Department of Medical Oncology, Mattoon, IL, USACorrespondence: Alexa B SchrockFoundation Medicine, 150 Second Street, Cambridge, MA 02141, USATel +1617-418-2200Email aschrock@foundationmedicine.comBackground: ALK fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring ALK rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex ALK variants that may predict sensitivity to multiple approved ALK inhibitors.Methods: Comprehensive genomic profiling (CGP) of DNA isolated from formalin‐fixed paraffin‐embedded (FFPE) tumor tissue or blood-based circulating tumor DNA was performed for 39,159 NSCLC patients during routine clinical care. For a subset of cases, RNA sequencing was performed, and prior ALK test results and clinical treatment information were collected from treating physicians.Results: We queried the Foundation Medicine NSCLC database and identified ALK internal inversions, as well as internal deletions, as the sole ALK rearrangements in 6 (0.02%) and 3 (0.01%) of cases, respectively. In cases with ALK internal inversions, RNA testing identified an EML4-ALK fusion in 2/2 cases evaluated, and 3/3 patients treated with ALK inhibitors had durable responses. A single patient with an ALK internal deletion and clinical data available responded to multiple ALK inhibitors. RNA data available for a subset of non-NSCLC cases suggest that ALK internal deletions removing a portion of the N-terminus are drivers themselves and do not result in ALK fusions. Fluorescence in situ hybridization (FISH) results were inconsistent for both classes of DNA events.Conclusion: Rare internal inversions of ALK appear to be indicative of ALK fusions, which can be detected in RNA, and response to ALK inhibitors in patients with NSCLC. In contrast, ALK internal deletions are not associated with ALK fusions in RNA but likely represent targetable drivers themselves. These data suggest that CGP of DNA should be supplemented with immunohistochemistry or RNA-based testing to further resolve these events and match patients to effective therapies.Keywords: ALK rearrangement, inversion, deletion, genomic profiling, targeted therapy