Dramatic response to alectinib in a lung cancer patient with a novel VKORC1L1-ALK fusion and an acquired ALK T1151K mutation

Viola W Zhu,1 Alexa B Schrock,2 Thangavijayan Bosemani,3 Bryan S Benn,4 Siraj M Ali,2 Sai-Hong Ignatius Ou1 1Chao Family Comprehensive Cancer Center, Division of Hematology/Oncology, Department of Medicine, University of California, Irvine School of Medicine, Orange, CA, USA; 2Clinical Development, Foundation Medicine, Inc., Cambridge, MA, USA; 3Department of Radiological Sciences, University of California, Irvine School of Medicine, Orange, CA, USA; 4Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, University of California, Irvine School of Medicine, Orange, CA, USA Abstract: ALK-rearranged lung cancer defines a distinctive molecular cohort of patients whose outcomes are significantly improved by the availability of ALK inhibitors. Thus, it is imperative for clinicians to screen appropriate patients for this driver mutation with a molecular testing platform capable of capturing all ALK fusions. Here, we report a novel VKORC1L1-ALK fusion and an ALK T1151K resistance mutation detected in a lung cancer patient who had been on crizotinib for over 8 years. Alectinib induced a dramatic response in this patient demonstrating its clinical activity against T1151K. This case illustrates the importance of performing repeat biopsy to explore mechanism(s) of resistance when patients experience disease progression on an ALK inhibitor. The approach has a direct therapeutic impact particularly when an ALK resistance mutation is identified. Keywords: VKORC1L1, T1151, fusion, resistance, crizotinib, lorlatinib