The association between ctDNA shed and prognosis can lead to counter-intuitive findings; for example, in a ctDNA analysis of the ALEX trial in advanced ALK-positive NSCLC, patients had better outcomes if they were ALK-negative by ctDNA in both the alectinib and crizotinib arms [113]; such improved outcomes in “biomarker negative” patients is merely because the tissue biomarker is positive, while the ctDNA shed is low. This evidence concerns the gene ALK and non-small cell lung carcinoma.