Efficacy and safety of deulorlatinib (TGRX-326) in patients with locally advanced or metastatic ALK+ non–small cell lung cancer: A multicenter, open-label, pivotal phase 2 trial.

Abstract

8638 Background: Treatment options are limited for anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) patients (pts) who have developed resistance to second-generation ALK inhibitors. Deulorlatinib is a highly potent third-generation ALK inhibitor. The Previous phase 1 study (NCT05441956) found that deulorlatinib had a high overall and intracranial response rate in pts who had progressed on second-generation inhibitors, with encouraging activity against the G1202R mutation and favorable tolerability. Methods: This is a multicenter, open-label pivotal phase 2 study. Pts with locally advanced or metastatic ALK+ NSCLC who had progressed on second-generation inhibitors received deulorlatinib 60 mg orally once daily. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent review committee (IRC). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. The ORR in patients harboring the G1202R mutation was also assessed. Results: Between Jan 18, 2023 and Dec 29, 2023, a total of 163 patients were enrolled and 158 were evaluable for efficacy. Of these pts, the median age was 53.5 years old, 53.2% were female, 95.6% had adenocarcinoma, and 56.2% had baseline brain metastasis; 56.3% of these pts had progressed on alectinib. As of December 16, 2025, the median follow-up was 28.7 months and 44 pts were still on deulorlatinib. The IRC assessed confirmed ORR was 43.7% (95%CI 35.8, 51.8). The median DoR and PFS was 20.7 months (95%CI 15.4, NR) and 13.8 months (95%CI 8.3, 16.5), respectively; median OS was not reached. Of the 43 pts with measurable baseline CNS lesions, confirmed ORR was 55.8% (95%CI 39.9, 70.9). In pts with the G1202R mutation, the ORR was 62.5% (95%CI 24.5, 91.5). Treatment-related adverse events (TRAEs) were reported in 96.3% of pts. The most common TRAEs were hypercholesterolaemia (77.9%), hypertriglyceridaemia (71.2%), and weight gain (52.8%). Grade ≥3 TRAEs were reported in 51.5% of pts. Of note, only 1.2% of pts had Grade ≥3 CNS TRAEs. Conclusions: Deulorlatinib produced robust and durable responses in locally advanced or metastatic ALK+ NSCLC pts with progression on second-generation inhibitors, including those with the G1202R mutation, with low incidence of Grade ≥3 CNS TRAEs. Although across trials comparisons must be interpreted cautiously, deulorlatinib might have a better safety profile than lorlatinib. Altogether these findings suggest that deulorlatinib has a favourable risk benefit ratio and support its further development, particularly in the first-line setting. Clinical trial information: NCT05955391 .