Dr Camidge on the Rationale for the TRUST-II Trial in ROS1+ NSCLC

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D. Ross Camidge, MD, PhD, discusses the rationale for the ongoing phase 2 TRUST-II trial of taletrectinib in patients with non–small cell lung cancer harboring ROS1 mutations. 

D. Ross Camidge, MD, PhD, director, Thoracic Oncology Clinical Program, director, Thoracic Oncology Clinical Research Program, University of Colorado Health Lung Cancer Clinic – Anschutz Medical Campus, discusses the rationale for the ongoing phase 2 TRUST-II trial (NCT04919811) of taletrectinib (AB-106) in patients with non–small cell lung cancer (NSCLC) harboring ROS1 mutations. 

Taletrectinib is a second-generation ROS1 inhibitor in the same class as repotrectinib, Camidge says. The phase 1/2 TRIDENT-1 trial (NCT03093116) showed an overall response rate (ORR) of 79% (95% CI, 68%-88%) with repotrectinib in TKI-naïve patients with ROS1-positive NSCLC. Additionally, in TKI-pretreated patients with baseline ROS1 G2032R mutations, the ORR was 59% (95% CI, 33%-82%). Based on these data, repotrectinib was granted priority review by the FDA in May 2023.

The TRUST-I trial (NCT04395677), which was conducted in China, showed similar efficacy data with taletrectinib in this population. The agent elicited an ORR of 92.5% (95% CI, 83.4%-97.5%) in patients who were ROS1 TKI–naive and 50.0% (95% CI, 33.4%-66.6%) in those with ROS1 TKI–pretreated disease. In 12 patients with measurable central nervous system metastases at baseline, the intracranial ORR was 91.7% (95% CI, 61.5%-99.8%). Furthermore, among 5 patients with ROS1 G2032R mutations, 4 achieved a partial response and 1 achieved stable disease, Camidge notes. Based on these data, the FDA granted breakthrough therapy designation to taletrectinib for patients with ROS1-positive NSCLC in 2022. The ongoing TRUST-II trial aims to validate the findings from TRUST-I in a global population, Camidge emphasizes.

The rate of neurological toxicities with taletrectinib in TRUST-1 was low and needs verification in a global trial, according to Camidge. At the 2023 IASLC World Conference on Lung Cancer, findings from a phase 2 study (NCT03909971) of lorlatinib (Lorbrena) in Chinese patients with previously treated, ALK-positive NSCLC were presented. Although lorlatinib is associated with an approximately 60% rate of neurological toxicities in Western populations, investigators reported no neurological adverse effects (AEs) with the agent in this study, Camidge says.

One potential explanation for this disparity between the data is that Chinese patients are more resistant to these AEs. because Additionally, the management of these AEs may require nuanced conversations between oncologists and patients that clinics in other parts of the world may approach differently, thereby garnering different results, Camidge explains. Similarly, 1 aim of the TRUST-II trial will be to determine how the safety profile of taletrectinib in a global population compares to that seen in the Chinese population in TRUST-I, Camidge concludes.

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