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Efficacy of Taletrectinib (AB-106/DS-6051b) in ROS1+ NSCLC: An Updated Pooled Analysis of U.S. and Japan Phase 1
Sai-Hong Ignatius Ou1, Yutaka Fujiwara2,3, Alice T Shaw4,5
1Division of Hematology-Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California.
Introduction:
Taletrectinib (AB-106/DS-6051b) is an oral, potent selective ROS1 and pan-NTRK tyrosine kinase inhibitor (TKI). Preclinically, taletrectinib has activity against ROS1 G2032R solvent-front mutation.
Methods:
Patients with ROS1+ NSCLC enrolled into two phase 1 studies conducted in United States (U101, NCT02279433) and Japan (J102, NCT02675491) were analyzed for objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival, and safety.
Results:
A total of 22 patients with ROS1+ NSCLC out of the total 61 patients enrolled were analyzed. Taletrectinib was given at the oral dose of 400 mg, 600 mg, 800 mg, and 1200 mg once daily and 400 mg twice daily as part of the dose-escalation schema. Data cutoff was August 19, 2020. Median follow-up time for all 22 patients was 14.9 months (95% confidence interval [CI]: 4.1-33.8). A total of 18 patients with ROS1+ were assessable for response. The confirmed ORR for ROS1 TKI-naive patients (N = 9) was 66.7% (95% CI: 35.4-87.9) with a disease control rate of 100% (70.1-100). The confirmed ORR for crizotinib pretreated patients (N = 6) was 33.3% (95% CI: 9.7-70.0) with a disease control rate of 88.3% (95% CI: 443.6-97.0). The median progression-free survival for ROS1 TKI-naive patients (N = 11) was 29.1 months (95% CI: 2.6-not reached) and 14.2 months (95% CI: 1.5-not reached) for crizotinib-refractory only patients (N = 8). The most common treatment-related adverse events were alanine transaminase elevations (72.7%), aspartate transaminase elevations (72.7%), nausea (50.0%), and diarrhea (50.0%). Grade 3 or higher adverse events were alanine transaminase elevations (18.2%), aspartate transaminase (9.1%), and diarrhea (4.5%).
Conclusions:
Taletrectinib (AB106/DS6051b) has a meaningful clinical activity in patients with advanced ROS1+ NSCLC who are ROS1 TKI-naive or crizotinib-refractory and a manageable safety profile.
Insights
Taletrectinib demonstrates significant clinical activity in patients with advanced ROS1-positive non-small cell lung cancer (NSCLC), showing promising response rates and manageable safety. This oral tyrosine kinase inhibitor is effective in both treatment-naive and crizotinib-refractory patients.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Taletrectinib is an oral, potent, and selective ROS1 and pan-NTRK tyrosine kinase inhibitor (TKI).
- Preclinical studies indicated taletrectinib's activity against the ROS1 G2032R solvent-front mutation.
Purpose of the Study:
- To evaluate the clinical activity and safety of taletrectinib in patients with ROS1-positive non-small cell lung cancer (NSCLC).
- To assess the objective response rate (ORR), progression-free survival (PFS), and safety profile of taletrectinib in different patient subgroups.
Main Methods:
- Analysis of patients with ROS1-positive NSCLC from two Phase 1 studies (U101, NCT02279433 and J102, NCT02675491).
- Patients received varying oral doses of taletrectinib (400 mg to 1200 mg daily, or 400 mg twice daily).
- Outcomes assessed included ORR, PFS, and safety, with data cutoff August 19, 2020.
Main Results:
- Of 22 ROS1-positive NSCLC patients analyzed, 18 were assessable for response.
- The confirmed ORR for ROS1 TKI-naive patients (N=9) was 66.7%, with 100% disease control.
- For crizotinib-pretreated patients (N=6), the confirmed ORR was 33.3%, with 88.3% disease control.
- Median PFS was 29.1 months for TKI-naive (N=11) and 14.2 months for crizotinib-refractory (N=8).
- Most common adverse events included elevated transaminases (72.7%), nausea (50.0%), and diarrhea (50.0%).
Conclusions:
- Taletrectinib demonstrates meaningful clinical activity in advanced ROS1-positive NSCLC.
- The drug shows efficacy in both ROS1 TKI-naive and crizotinib-refractory patient populations.
- Taletrectinib presents a manageable safety profile for patients with advanced ROS1-positive NSCLC.
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