Dr Lin on the Efficacy and Safety of Taletrectinib in ROS1 Fusion+ NSCLC

Jessica Lin, MD, associate professor, medicine, Harvard Medical School; attending physician, Center for Thoracic Cancers, Henri and Belinda Termeer Center for Targeted Therapies, Massachusetts General Hospital, discusses key findings from the phase 2 TRUST-I trial (NCT04395677) of taletrectinib (AB-106) in patients with ROS1 fusion–positive non–small cell lung cancer (NSCLC).

TRUST-I, which was conducted in China, evaluated the next-generation ROS1 inhibitor in patients with metastatic ROS1 fusion–positive NSCLC. Currently, 2 first-generation ROS1 inhibitors are FDA approved: crizotinib (Xalkori) and entrectinib (Rozlytrek). Both agents induce median progression-free survival (PFS) outcomes ranging from approximately 16 to 19 months, Lin says. Additionally, the next-generation ROS1 and TRK inhibitor repotrectinib (Augtyro) was approved by the FDA in 2023 for patients with locally advanced or metastatic ROS1-positive NSCLC. In the pivotal phase 1/2 TRIDENT-1 trial (NCT03093116), repotrectinib elicited a median PFS of 35.7 months (95% CI, 27.4-not estimable) in patients who had not previously received a ROS1 TKI.

At the 2024 ASCO Annual Meeting, results from TRUST-I were presented from both the TKI-naive (n = 106) and crizotinib-pretreated (n = 67) patient populations. In the TKI-naive population, taletrectinib generated a confirmed overall response rate (cORR) of 90.6% (95% CI, 83.33%-95.38%), and the median PFS was not reached (NR; 95% CI, 29.1-NR) after a median follow-up of 23.5 months. In crizotinib-pretreated patients, the cORR was 51.5% (95% CI, 38.88%-64.01%), and the median PFS was 7.6 months (95% CI, 5.5-12.0) at a median follow-up of 9.7 months. These findings support the use of taletrectinib as an effective therapy for patients with ROS1 fusion–positive NSCLC who have received prior ROS1 inhibitors. Currently, repotrectinib is the only FDA approved agent for such cases, and additional therapies are needed for this patient population, Lin emphasizes.

Taletrectinib also has central nervous system activity. In TRUST-I, the intracranial cORRs were 87.5% (95% CI, 47.35%-99.68%) and 73.3% (95% CI, 44.90%-92.21%) in patients with baseline brain metastases who were TKI naive (n = 8) and crizotinib pretreated (n = 15), respectively.

The safety profile of taletrectinib is also noteworthy, Lin explains. Entrectinib and repotrectinib, which inhibit both ROS1 and TRK proteins, can accordingly cause neurologic adverse effects (AEs) due to TRK inhibition. In TRUST-I, however, taletrectinib was associated with few neurologic AEs, Lin notes. Although dizziness was observed in the trial, most treatment-related AEs were related to increases in aspartate aminotransferase/alanine aminotransferase levels and gastrointestinal AEs, indicating that taletrectinib may have a more favorable safety profile vs other agents in its class, according to Lin.