First-in-human, multicenter phase Ⅰ study of TGRX-326 in patients with advanced ALK-positive non-small cell lung cancer.

Abstract

9113 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. Deuteration of the key metabolic site of the molecule allows to achieve a higher exposure than with LOR and this may result in alleviated toxicities and better efficacy. Methods: The study comprised 3 phases: dose escalation (D-ESCAL), dose expansion (D-EXP) and cohort expansion (C-EXP). 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. Results: Up to Jan 13, 2023, 185 pts (median age 53 years, 45.9% male) were enrolled; Median treatment and follow-up was 5.5 and 6.7 months, respectively. There were no DLT observed and no MTD identified in D-ESCAL (5-125mg QD, n=19). Based on the safety, efficacy and PK exposure data of 42 pts in D-ESCAL and D-EXP, 60 mg QD was selected as the RP2D for C-EXP,the average AUCtau of 60mg QD reached to 5443ng*hr/mL. Treatment-related adverse events (TRAEs) occurred in 87.5% patients (162/185), the most common TRAEs were hypercholesterolemia (74.1%), hypertriglyceridemia (68.1%), weight gain (36.2%), peripheral edema (15.7%), peripheral neuropathy (14.1%). As for R2PD, 132 of 155 (85.2%) experienced TRAEs, Grade ≥3 TRAEs occurred in 19.7%, most frequent were hypertriglyceridemia (11%) and hypercholesterolemia (8.4% ). Dose interruptions and dose reductions associated with TRAEs were reported in 10 (5.4%) and 5 (2.7%) pts respectively. Confirmed response were observed in 142 ALK+pts enrolled in C-EXP, results are shown in the Table (Efficacy of B-ROS1+ pts will be reported separately). Eleven ALK mutations were detected in 16 pts (either alone or in combination); 50.0% pts achieved PR. Out of 6 pts who were positive for G1202R, 50.0% experienced PR. Conclusions: 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. Clinical trial information: NCT05441956 . [Table: see text]