Lorlatinib, alectinib, and crizotinib activity in ALK-positive large B-cell lymphoma patient derived xenografts. (A-B) PDX tumors after 4 days of treatment with vehicle show tumor growth in the engrafted left kidney as well as extension and growth into the right kidney (A). (B) PDX tumors treated with lorlatinib show marked regression of tumor in the engrafted kidney in mice after 4 days of treatment with lorlatinib. (C) Lorlatinib induced rapid tumor regression in vivo in RCI PDX tumors. (D) Lorlatinib induced a complete block of ALK phosphorylation, in turn disrupting activation of downstream signaling pathways, including abrogation of STAT3 and SHP2 phosphorylation. (E) Alectinib induced rapid tumor regression in vivo in SCI PDX tumors. (F) Lorlatinib induced rapid tumor regression and crizotinib induced only transient tumor regression followed within 7 days by rapid tumor growth in vivo in SCI PDX tumors. 1, pALK^Tyr1604; 2, pALK^Tyr1278; 3, total ALK and ALK fusion proteins; 4, pSTAT3^Tyr705; 5, total Stat3 protein; 6, pSHP2^Tyr542; 7, total SHP2 protein; and 8, levels of total β-actin.