Background: TGRX-326, a deuterated derivative of lorlatinib (LOR), is a potent 3rd generation ALK and ROS1 dual TKI with high potency against multiple ALK-resistant mutations...In D-ESCAL and D-EXP, ALK+ pts prior failed on 2nd gen ALK-TKIs or ROS1+ pts resistant to crizotinib (CRZ) were enrolled; in C-EXP, ALK+ pts progression after CRZ (C-EXP-A1),progression after ≥1 2nd gen TKIs (C-EXP A2), ROS1+progression after CRZ (C-EXP-B) and pts with ALK TKI naïve (C-EXP-C) were enrolled... TGRX-326 was well tolerated in pts with advanced ALK+NSCLC and showed promising clinical antitumor activity irrespectively of ALK+ resistance to CRZ and 2nd gen TKIs, especially among those with brain metastases. Impressive activity was seen in ALK TKI naïve NSCLC. TGRX-326 demonstrated antitumor activity against multiple ALK mutations including G1202R.