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Ref Type Journal Article
PMID (39551469)
Authors Zhao S, Zhou H, Yang N, Wang Z, Jin W, Ma Y, Xue J, Li X, Liu Y, Meng R, Zhou J, Cheng Y, Wang Y, Yu Z, Cao Y, Zhao Y, Huang Y, Fang W, Zhang Y, Hong S, Wu B, Shi Y, Cao J, Xu M, Zhang X, Hu L, Peng B, Yang Y, Zhang L, Zhao H
Title Safety, efficacy and biomarker analysis of deulorlatinib (TGRX-326) in ALK-positive non-small-cell lung cancer: a multicentre, open-label, phase 1/1b trial.
Journal Vol Issue Date Pages Journal Short Title
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2024 Nov 15 J Thorac Oncol
URL
Abstract Text Patients with ALK-positive NSCLC developing resistance to second-generation inhibitors have limited treatment options. Deulorlatinib is a highly brain-penetrant, new-generation ALK/ROS1 inhibitor. We evaluated the safety, efficacy and pharmacokinetics of deulorlatinib in ALK-positive NSCLC.This 3-part (dose-escalation/dose-expansion/cohort-expansion), open-label, phase 1/1b trial was conducted at 22 sites in China (ClinicalTrials.gov, NCT05441956). Eligible patients had advanced ALK/ROS1-positive NSCLC. Patients enrolled into dose-escalation/dose-expansion parts were previously treated with ≥1 second-generation ALK inhibitors (ALK-positive) or crizotinib (ROS1-positive); received deulorlatinib 5-125mg once daily. Patients enrolled into cohort-expansion parts were either crizotinib-treated, second-generation TKI-treated or TKI-naïve; received deulorlatinib at recommended phase 2 dose (RP2D). Primary outcomes were safety and tolerability. Here, we report safety analysis in all patients and efficacy analysis in ALK-positive patients.Between April 2021 and March 2023, 198 patients were enrolled (ALK-positive=171, ROS1-positive=27). Most common treatment-related adverse events (TRAEs) were hypercholesterolemia (79.3%), hypertriglyceridemia (77.3%) and weight gain (53.0%). 40.4% of patients had grade≥3 TRAEs. TRAE-associated dose interruptions, reduction and discontinuation occurred in 11.1%, 3.0% and 1.5% of patients, respectively. The RP2D was set at 60mg once daily. A total of 144 ALK-positive patients were treated at RP2D. For crizotinib-treated (n=14), second-generation TKI-treated (n=97) and TKI-naïve (n=33) patients, ORR to deulorlatinib at RP2D was 71.4%, 38.1%, and 87.9%, respectively. Intracranial ORR was 50%, 70.4%, and 75%. Median duration of response was 18.0 months for second-generation TKI-treated patients, and not reached for crizotinib-treated and TKI-naïve patients. Biomarker analyses identified undetectable ALK alterations at baseline and ALK ctDNA clearance at week 6 as potential predictive biomarkers.Deulorlatinib showed desirable tolerability and efficacy in ALK-positive NSCLC, demonstrating the potential to become a new treatment option in this population.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Deulorlatinib Deulorlatinib 4 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
Deulorlatinib TGRX-326|TGRX326|TGRX 326 ALK Inhibitor 33 ROS1 Inhibitor 22 Deulorlatinib (TGRX-326) is a third-generation ALK and ROS1 inhibitor, which potentially inhibits growth of ALK or ROS1-positive tumors (PMID: 39551469).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK G1202R Advanced Solid Tumor sensitive Deulorlatinib Preclinical Actionable In a preclinical study, Deulorlatinib (TGRX-326) inhibited viability of cells expressing EML4-ALK and ALK G1202R in culture and inhibited tumor growth in a transplant model (PMID: 39551469). 39551469
EML4 - ALK ALK L1196M Advanced Solid Tumor sensitive Deulorlatinib Preclinical Actionable In a preclinical study, Deulorlatinib (TGRX-326) inhibited viability of cells expressing EML4-ALK and ALK L1196M in culture and inhibited tumor growth in a transplant model (PMID: 39551469). 39551469
EML4 - ALK Advanced Solid Tumor sensitive Deulorlatinib Preclinical - Cell culture Actionable In a preclinical study, Deulorlatinib (TGRX-326) inhibited viability of cells expressing EML4-ALK in culture (PMID: 39551469). 39551469
ALK rearrange lung non-small cell carcinoma sensitive Deulorlatinib Phase I Actionable In a Phase I/Ib trial, Deulorlatinib (TGRX-326) treatment demonstrated safety in non-small cell lung cancer patients harboring an ALK rearrangement and led to an objective response rate (ORR) of 71.4% (10/14) and disease control rate (DCR) of 100% in Xalkori (crizotinib)-pretreated patients, an ORR of 87.9% (29/33) and DCR of 97.0% (32/33) in TKI-naive patients, and an ORR of 38.1% (37/97) and DCR of 81.4% (79/97) in patients pre-treated with second-generation TKIs (PMID: 39551469; NCT05441956). 39551469