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Deulorlatinib (TGRX-326) in ALK Gene Fusion Positive NSCLC After Failure of Second-Generation Inhibitors: A
Jie Huang1, Gang Chen1, Zhehai Wang2
1Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
Introduction:
Deulorlatinib (TGRX-326), a potent third-generation anaplastic lymphoma kinase (ALK) inhibitor, has reported promising activity and a favorable safety profile in ALK-positive NSCLC in a phase 1 trial. Here, we report the primary results of the pivotal phase 2 trial (NCT05955391) evaluating deulorlatinib in patients with ALK-positive NSCLC in whom second-generation ALK inhibitors had failed.
Methods:
This single-arm, phase 2 trial was conducted at 36 centers in China. Eligible patients received deulorlatinib 60 mg once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee (IRC). Key secondary end points included disease control rate, progression-free survival (PFS), duration of response, overall survival, intracranial efficacy, and safety. Exploratory biomarker analyses were performed using cell-free DNA.
Results:
The efficacy and safety analysis sets comprised 158 and 163 patients, respectively. The primary end point was met with an IRC-assessed ORR of 43.7% (95% confidence interval [CI], 35.8-51.8). The IRC-assessed median PFS was 11.1 months (95% CI, 8.3-13.7). Among patients with measurable central nervous system (CNS) metastases (n = 43), the intracranial ORR was 55.8% (95% CI, 39.9-70.9). In patients harboring the G1202R mutation (n = 8), robust activity was observed (ORR: 62.5%; disease control rate: 100%; median PFS: 11.0 months). The investigator-assessed results were consistent with the IRC-assessed findings. Treatment-related adverse events occurred in 96.3% of patients (47.2% grade ≥3). Nevertheless, dose modifications were infrequent (interruption, 13.5%; reduction, 11.0%; permanent discontinuation, 0.6%). The incidence of CNS-related treatment-related adverse events was 12.9%, with no patients interrupting or discontinuing treatment owing to CNS toxicity.
Conclusions:
Deulorlatinib indicated encouraging antitumor activity in patients with advanced ALK-positive NSCLC after failure of second-generation ALK inhibitors, including those with the G1202R mutation. Given its favorable safety profile, deulorlatinib represents a promising new option for this population.
Insights
Deulorlatinib shows significant efficacy in advanced anaplastic lymphoma kinase-positive non-small cell lung cancer patients who failed prior treatments. This third-generation ALK inhibitor offers a promising new option with a manageable safety profile.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Deulorlatinib (TGRX-326) is a third-generation anaplastic lymphoma kinase (ALK) inhibitor.
- Previous phase 1 trials indicated promising activity and safety in ALK-positive non-small cell lung cancer (NSCLC).
- This study focuses on patients with ALK-positive NSCLC who have progressed on second-generation ALK inhibitors.
Purpose of the Study:
- To evaluate the efficacy and safety of deulorlatinib in patients with advanced ALK-positive NSCLC.
- Specifically, to assess outcomes in patients who have previously failed second-generation ALK inhibitors.
- To investigate the drug's effectiveness in patients with specific mutations, including G1202R.
Main Methods:
- A single-arm, phase 2 clinical trial (NCT05955391) conducted across 36 centers in China.
- Patients received deulorlatinib 60 mg once daily.
- Primary endpoint: objective response rate (ORR) by independent review committee (IRC); secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.
Main Results:
- The study met its primary endpoint with an IRC-assessed ORR of 43.7% (95% CI, 35.8-51.8).
- Median PFS was 11.1 months (95% CI, 8.3-13.7).
- Intracranial ORR was 55.8% in patients with CNS metastases. Robust activity was observed in patients with the G1202R mutation (ORR: 62.5%). Treatment-related adverse events were frequent but generally manageable, with low rates of dose modification or discontinuation.
Conclusions:
- Deulorlatinib demonstrates significant anti-tumor activity in advanced ALK-positive NSCLC patients resistant to prior therapies.
- The drug shows particular efficacy in patients with the G1202R mutation and in those with brain metastases.
- Deulorlatinib presents a promising therapeutic option for this patient population due to its efficacy and favorable safety profile.
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