Taletrectinib in ROS1 mutated Non–Small Cell Lung Cancer

1 .The objective response rate was 88.8% for TKI-naïve patients and 55.8% for TKI-pretreated patients.

2. Most common adverse events included elevated LFTs and GI side effects, and most were grade 1-2.

Evidence Rating Level: 2 (Good)

Study Rundown: ROS1 gene fusions are rare but actionable drivers in non–small cell lung cancer (NSCLC). Current treatments have limitations such as resistance mutations, CNS progression, and neurologic toxicities. Taletrectinib, a CNS-active next-generation ROS1 TKI with potentially fewer neurologic side effects, has shown promising efficacy and safety. This study is a pooled analysis of two prospective studies of Taletrectinib in the ROS1+ NSCLC population. The primary endpoint was objective response rate (ORR, complete response CR, and partial response PR), and secondary endpoints included disease control rate (DCR), duration of response (DoR), time to response (TtR), progression-free survival (PFS), overall survival (OS), and safety. For TKI-naïve patients (n=160) compared to TKI-pretreated patients (n = 113), the ORR was 88.8% (8 CR and 134 PR) with DCR 95.0% for TKI-naïve patients compared to ORR 55.8% (5 CR and 58 PR), with DCR 87.6% for TKI-pretreated patients. Median DoR in patients with ORR was 44.2 months, with an estimated 36-month DoR rate being 57.7% for TKI-naïve patients compared to a median DoR of 16.6 months with a 12-month DoR of 61.1% for TKI-pretreated patients. Median TtR was 1.4 months in both populations. Median PFS was 45.6 months with an estimated 36-month PFS rate being 52.6% in TKI-naïve patients, compared to a median PFS was 9.7 months with a 12-month PFS rate being 39.7% for TKI-pretreated patients. Median OS was NA in both populations, with an estimated 36-month OS rate being 66.3% for TKI-naïve patients compared to an estimated 12-month OS rate was 77.5% for TKI-pretreated patients. Subset analysis of patients with brain metastases found in TKI-naïve patients (n=17), ORR was 76.5% compared with ORR 65.6% in TKI-pretreated patients (n=32). In patients with the G2032R mutation (n=13), ORR 61.5%. With regards to safety, the most common treatment-emergent adverse events were elevated AST (72%), elevated ALT (68%), diarrhea (64%), nausea (46%), and vomiting (44%); most were grade 1-2. The most common neurologic adverse events were dizziness (21%), dysgeusia (15%), and headache (11%); most were grade 1. The strength of the study was the follow-up time, and the limitations included the non-randomized methodology and the small sample size. Overall, this study found some improved outcomes for taletrectinib in both TKI-naïve and TKI-pretreated patients who have advanced ROS1-mutated NSCLC.

Click to read the study in JCO

Relevant Reading: Efficacy and safety of taletrectinib in Chinese patients with ROS1+ non-small cell lung cancer: The phase II TRUST-I study

In-Depth [prospective cohort]: This is a pooled analysis from two phase II, single-arm, open-labeled, nonrandomized multicenter trials that enrolled adults (n=273) with advanced ROS1-mutated NSCLC (some of whom were TKI naïve and others who failed previous TKI) and started them on taletrectinib. Median follow-up was 21.2 months. For TKI-naïve patients (n=160) compared to TKI-pretreated patients (n = 113), the ORR was 88.8% (95%Cl, 82.8-93.2, 8 CR and 134 PR) with DCR 95.0% (95%CI, 90.4-97.8) for TKI-naïve patients compared to ORR 55.8% (95%CI, 46.1-65.1, 5 CR and 58 PR), with DCR 87.6% (95%CI, 80.1-93.1) for TKI-pretreated patients. Median DoR in patients with ORR was 44.2 months (95%CI, 30.4-NA) with an estimated 36-month DoR rate being 57.7% (95%CI, 45.0-68.5) for TKI-naïve patients compared to median DoR 16.6 months (95%CI, 10.6-27.3) with 12-month DoR 61.1% (95%CI, 46.3-73.1) for TKI-pretreated patients. Median TtR was 1.4 months (95%CI, 1.4-1.4) in both populations. Median PFS was 45.6 months (95%CI, 29.0-NA) with an estimated 36-month PFS rate being 52.6% (95%CI, 41.0-62.9) in TKI-naïve patients compared to median PFS was 9.7 months (95%CI, 7.4-12.0) with 12-month PFS rate being 39.7% (95%CI, 29.6-49.6) for TKI-pretreated patients. Median OS was NA in both populations with an estimated 36-month OS rate being 66.3% (95%CI, 55.3-75.2) for TKI-naïve patients, compared to an estimated 12-month OS rate was 77.5% (95%CI, 68.1-84.5) for TKI-pretreated patients. Subset analysis of patients with brain metastases found in TKI-naïve patients (n=17), ORR was 76.5% (95%CI, 50.1-93.2) compared with ORR 65.6% (95%CI, 46.8-81.4) in TKI-pretreated patients (n=32). In patients with G2032R mutation (n=13), ORR 61.5% (95%CI, 31.6-86.1). With regards to safety, the most common treatment-emergent adverse events were elevated AST (72%), elevated ALT (68%), diarrhea (64%), nausea (46%), and vomiting (44%); most were grade 1-2. The most common neurologic adverse events were dizziness (21%), dysgeusia (15%), and headache (11%); most were grade 1. Overall, this study found some improved outcomes for taletrectinib in both TKI-naïve and TKI-pretreated patients who have advanced ROS1-mutated NSCLC.

Image: PD

©2025 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc.