ROS1-positive NSCLC is a rare and aggressive type of NSCLC, accounting for approximately 2% of new NSCLC cases or about 3,000 new diagnoses of advanced disease annually in the United States.
Supporting Clinical Trials
The FDA approval of taletrectinib is supported by the TRUST-I and TRUST-II studies in ROS1-positive NSCLC, with more than 300 patients enrolled—one of the largest global clinical trials programs in this specific lung cancer study population.
In TRUST-I, taletrectinib achieved a confirmed overall response rate of 90% in patients naive to tyrosine kinase inhibitors. These findings were reinforced by the TRUST-II results, with a confirmed overall response rate of 85% in these patients. The median duration of response was not yet reached for either trial, based on a cutoff date that is nearly 5 months later than that of the pooled TRUST-I and TRUST-II analysis published in the Journal of Clinical Oncology.
For TRUST-I, with a median follow-up for responses of 40 months, the longest duration of response was observed at 46.9 months and is ongoing. For TRUST-II, with a median follow-up for responses of 19 months, the longest duration of response was observed at 30.4 months and is ongoing as of October 2024. Given the single-arm nature of the TRUST clinical studies, median progression-free survival is not provided in the label.
Across these studies, consistent results were also observed among patients who were previously treated with a ROS1 tyrosine kinase inhibitor (TKI-pretreated). In TRUST-I, treatment with taletrectinib achieved a confirmed overall response rate of 52% and a median duration of response of 13.2 months for patients pretreated with a tyrosine kinase inhibitor, with median follow-up for responses of 33 months. In TRUST-II, treatment with taletrectinib achieved a complete overall response rate of 62%, and as of October 2024, the median duration of response was 19.4 months in these patients, with a median follow-up for responses of 19 months.
Brain metastases are among the most common complications in advanced ROS1-positive NSCLC. Taletrectinib was designed to penetrate the central nervous system and has demonstrated consistent intracranial responses in patients with measurable brain metastases at baseline. An intracranial response was achieved in 73% of patients who were naive to tyrosine kinase inhibitors (11 of 15 patients) and 63% of patients pretreated with a tyrosine kinase inhibitor (15 of 24 patients).
Safety
Taletrectinib was reported to be generally well tolerated, with most adverse events being low grade, transient, and manageable. A total of 7% of patients discontinued treatment because of treatment-emergent adverse events. The most common adverse reactions (≥ 20%) included diarrhea (64%), nausea (47%), vomiting (43%), dizziness (22%), rash (22%), constipation (21%), and fatigue (20%). Overall, the majority of central nervous system (CNS) events were mild to moderate (~90%) and resolved within days; dose modifications as a result of these events were few (~5%).
Approximately 90% of reported cases of dizziness were grade 1 and transient. Liver enzyme elevations (aspartate transaminase, 87%; alanine transaminase, 85%) and QT prolongation (19%) were manageable with standard monitoring and dose modifications. Taletrectinib is approved as a 600-mg once-daily oral dose, supported by a half-life of approximately 66 hours and broad tissue distribution, including the brain, enabling sustained systemic and CNS exposure.
The median age at diagnosis for patients with this type of lung cancer is approximately 50 years old, and the disease is more likely to occur in people who have never smoked. Brain metastases are common and a leading cause of disease progression and mortality in this population.Summary
“Patients living with advanced ROS1-positive non–small cell lung cancer and their health-care providers are in need of new treatment options,” added Nathan Pennell, MD, PhD, TRUST study investigator and Professor of Medicine at the Cleveland Clinic. “[Taletrectinib’s] durability of response and ability to effectively penetrate the brain, coupled with a well-characterized and manageable safety profile, further address these critical needs for patients. I believe this now-approved therapy offers providers and patients a promising new option for the treatment of advanced ROS1-positive non–small cell lung cancer.”
Disclosure: Dr. Pennell is a compensated member of Nuvation Bio’s advisory committee.
