The most common kind of lung cancer, non-small cell lung cancer (NSCLC), is diagnosed in more than a million individuals worldwide each year. Roughly 1% to 3% of patients with NSCLC are thought to be ROS1-positive. Up to 35% of people newly diagnosed with metastatic ROS1-positive NSCLC have tumors that have spread to their brain (brain metastases), increasing up to 55% for those whose cancer has progressed following initial treatment. While people with other types of lung cancer have seen great advances, there has been limited progress for people with ROS1-positive NSCLC who remain in need of new options. 

Taletrectinib is an oral, potent, central nervous system-active, selective, next-generation ROS1 inhibitor specifically designed for the treatment of patients with advanced ROS1-positive NSCLC. TRUST-I is one of two registrational Phase II studies evaluating taletrectinib for the treatment of patients with advanced ROS1-positive NSCLC. The updated data from the pivotal TRUST-I (NCT04395677) study in China, one of the largest clinical trials to date conducted in people living with ROS1-positive NSCLC was revealed at ASCO 2024. 

High and durable responses were observed, including high intracranial ORR. Prolonged PFS was observed regardless of the line of therapy. Taletrectinib demonstrated activity against acquired resistance mutations including G2032R. According to data, 91% of patients with advanced ROS1-positive NSCLC who were treated with taletrectinib and were not previously treated with ROS1 TKI and 52% of those who were pretreated with ROS1 TKI in the trial had reduced tumors. Moreover, at two years, 71% of patients who had not yet received a TKI remained progression-free.  After a median follow-up of 9.7 months in TKI-pretreated patients, median duration of response and median progression-free survival were 10.6 months and 7.6 months, respectively.

Taletrectinib demonstrated a favorable safety profile: rates of dose reduction and treatment discontinuation due to TEAEs continued to be low. The rate of neurologic TEAEs was low and most were Grade 1. 

KOL insights

“Current treatments for advanced ROS1-positive NSCLC have significant limitations, and people living with this disease remain in need of new options that are both well tolerated and offer durable responses. These TRUST-I results reinforce taletrectinib's strong efficacy and favorable safety profile, underscoring its potential to become a new treatment option for patients.” – Expert Opinion.

“The updated data of the TRUST-I study shows remarkably durable response and meaningful clinical benefits of taletrectinib for ROS1-positive NSCLC patients. Hoping to bring this new generation of targeted therapy to patients with ROS1-positive NSCLC in China.” – Expert Opinion.

Conclusion

For patients with ROS1-positive NSCLC, ROS1 tyrosine kinase inhibitors (TKIs) are the current standard of care. However, most patients progress within 2 years due to acquired resistance mutations (i.e., G2032R) or brain metastases. 

The results from the TRUST-I study underscore taletrectinib's potential as a valuable treatment option for patients with ROS1-positive NSCLC, offering promising efficacy, management of brain metastases, and acquired resistance mutations, along with a favorable safety profile. The ongoing global pivotal Phase II study, TRUST-II (NCT04919811), is further evaluating the efficacy and safety of taletrectinib in patients with ROS1-positive NSCLC in the United States, Europe, and Asia. The Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) of China has accepted two new drug applications (NDAs) of taletrectinib and granted priority review designations for first- and second-line treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC, based on positive results from the pivotal Phase II TRUST-I study. With its impressive ORR in both first and second-line patients, taletrectinib is going to become the new standard of care for ROS1-positive adult NSCLC patients in China by 2025.

China has a number of key players in the ROS-1 NSCLC market. In 2013, XALKORI was granted NMPA approval for NSCLC, and in 2022, ROZLYTREK was granted authorization. The China-based Zai Lab Ltd.'s AUGTYRO (repotrectinib) was approved by the NMPA of China in May 2024 for use in adult patients with locally progressed or metastatic ROS1-positive NSCLC. This regulatory decision was based on data from the open-label, single-arm, phase I/II TRIDENT-1 trial (NCT03093116), in which repotrectinib produced an ORR of 79% in treatment-naive patients with ROS1-positive NSCLC. In the population of patients who had received 1 prior ROS1 TKI and had never received chemotherapy), the ORR was 38%. When comparing the effectiveness of AUGTYRO with taletrectinib, it seems as though AUGTYRO may be able to compete with taletrectinib. Because of their lower-than-expected ORRs and unreliability about second-line performance, XALKORI and ROZLYTREK are less competitive.