Novel Targeted Treatment for NSCLC Effective Across Multiple Regions and Populations

Taletrectinib, an experimental oral next-generation tyrosine kinase inhibitor (TKI), has demonstrated robust clinical activity in the treatment of ROS1-positive non-small cell lung cancer (NSCLC) that is consistent across subgroups, including those stratified by prior TKI treatment (pretreated or naive), race and geography.

These newest findings come from a retrospective subgroup analysis of two pivotal phase 2 clinical trials, known as TRUST-I and TRUST-II, conducted in patients with locally advanced or metastatic NSCLC with evidence of a ROS1 fusion. The subgroup analyses were presented at the 2025 Annual Meeting of the American Society of Clinical Oncology.

The U.S. Food and Drug Administration (FDA) granted a breakthrough therapy designation for taletrectinib for the treatment of NSCLC with the ROS1 gene fusion, which is present in about 2% of patients with NSCLC. It is most common in younger patients with adenocarcinoma and in nonsmokers, according to study co-investigator Nathan A. Pennell, MD, PhD, Director of Cleveland Clinic's Lung Cancer Medical Oncology Program and Vice Chair of Clinical Research for Cleveland Clinic Cancer Institute.

Cleveland Clinic was a major center that enrolled patients into the global TRUST-II study. (TRUST-I was conducted exclusively in China.)

Enhanced brain penetration

“Currently, several drugs are approved in this space but some of the older drugs have poor brain penetration, and some of the newer drugs that do penetrate the brain to prevent and treat brain metastases have significant neurologic side effects that go along with them, such as dizziness and mental status changes,” says Dr. Pennell.

Because of its selectivity for ROS1, neurologic side effects such as dizziness and mental status changes are much less common in this medication compared with other ROS1 TKIs.

Responses to taletrectinib have proven to be durable, with a median duration of response of almost four years and a median progression-free survival of four years. It has demonstrated efficacy in patients in whom resistance to previous ROS1 TKIs has developed, including resistance due to a G2032R mutation, Dr. Pennell adds.

Efficacy across all subgroups examined

Pooled analysis of TRUST-I and TRUST-II revealed that taletrectinib elicited a confirmed overall response rate (cORR) of 85.2% in TKI- naive patients and 57.1% in TKI-pretreated patients.

In a comparison of response rates between TRUST-I and TRUST-II, cORRs were consistent for TKI-naive (91% vs. 85%; RR: 0.94 [95% CI: 0.83, 1.07]) and TKI-pretreated patients (52% vs. 62%; RR: 1.20 [95% CI: 0.87, 1.66]).

In a pooled analysis stratified by race, Asian and non-Asian patients had similar cORRs in both TKI-naive (89% vs. 84%; RR: 0.94 [95% CI: 0.77, 1.15]) and TKI-pretreated (52% vs. 68%; RR: 1.30 [95% CI: 0.93, 1.82]) groups.

Within the TRUST-II study, cORRs were high in TKI-naive patients regardless of region (Western: 81%; Asia: 88%), prior chemotherapy (yes: 90%; no: 84%) and race (Caucasian: 83%, Asian: 86%, other races: 86%).

Similarly, within TRUST-II, major safety profiles were comparable between Asian and Western patients, as well as between races.

Responses in the brain in patients with measurable disease in the brain were “virtually as good as in the lung and other areas of metastasis,” says Dr. Pennell. “The response in the brain is important because as patients with NSCLC live longer as a result of the availability of novel effective treatments, they tend to develop brain metastases over time. The improved response in the brain is responsible for the lengthy duration of response and progression-free response that we’re seeing.”

Expected to be “treatment of choice”

With its efficacy and enhanced safety profile, Dr. Pennell expects taletrectinib to become the treatment of choice for most patients with ROS1-positive NSCLC, regardless of race or geography.

The FDA is expected to render its decision on the approval of taletrectinib on June 23, 2025.