In the present study, we created in silico systems biology-based mechanistic models of two first-line approved second generation ALKi, brigatinib and alectinib, in order to explore the potential differences between them with the aim of providing information or raising hypotheses towards the identification of strengths and weaknesses of the mechanisms of action of both drugs as first-line treatment for ALK+ NSCLC patients. The gene discussed is ALK; the disease is non-small cell lung carcinoma.