Taletrectinib demonstrated high response rates and was well tolerated among patients with ROS1+ non-small cell lung cancer (NSCLC).
The FDA approved taletrectinib (Ibtrozi; Nuavtion Bio Inc) for the treatment of adult patients with locally advanced or metastatic ROS1-positive (ROS1+) non–small cell lung cancer (NSCLC). It demonstrated high response rates with durable benefit and intracranial activity and was well tolerated among patients, according to the FDA.1
TRUST-I
TRUST-II
“For people living with advanced ROS1+ lung cancer, who tend to be diagnosed at a younger age, having another treatment option can make a real difference for them and their loved ones,” Janet Freeman-Daily, cofounder and president of The ROS1ders, said in a news release. “The approval of this new targeted therapy is a meaningful step forward for the advanced ROS1+ lung cancer community and offers hope for patients facing the added challenge of cancer spreading to the brain.”2
ROS1+ NSCLC is a rare and aggressive form of lung cancer, and in the US, it accounts for approximately 2% of new NSCLC cases, or about 3000 new diagnoses of advanced disease annually. The median age at diagnosis for patients is about 50 years. Notably, it is more likely to occur in people who do not have a history of smoking. Brain metastases are common and a leading cause of disease progression and mortality in this population.
Taletrectinib is an oral, potent, central nervous system (CNS)–active, selective, next-generation ROS1 inhibitor approved for the treatment of adults with advanced ROS1+ NSCLC. Its efficacy was evaluated in the 2 multicenter, single-arm open-label phase 2 clinical trials TRUST-I (NCT04395677)3 and TRUST-II (NCT04919811).1,2,4 Taletrectinib is approved as a 600-mg once-daily oral dose, supported by a half-life of about 66 hours and broad tissue distribution—including the brain—that enables sustained systemic and CNS exposure. Additionally, taletrectinib was granted priority review, breakthrough designation, and orphan drug designation for this indication.1,2
These clinical trials enrolled a total of 157 patients (TRUST-I: n = 103; TRUST-II: n = 54) who were naive to treatment with a ROS1 tyrosine kinase inhibitor (TKI) and 113 patients (TRUST-I: n = 66; TRUST-II: n = 47) who had previously received at least 1 ROS1 TKI. Additionally, patients may have received prior chemotherapy for advanced disease. For both trials, the major efficacy outcomes were confirmed overall response rate (cORR) and duration of response (DOR).1-4
TRUST-I findings showed that taletrectinib achieved a cORR of about 90% in patients who were TKI-naive. TRUST-II had affirmed these findings, with a cORR of about 85% among this population. Although the median DOR has not yet been reached, the longest DORs at the time of data cutoff were about 46.9 and 30.4 months in the TRUST-I and TRUST-II trials, respectively. Median progression-free survival is not being assessed because of the trials’ single-arm nature, according to the investigators.2
Further, consistent results were also observed among patients who were previously treated with a ROS1 TKI. In TRUST-I, treatment with taletrectinib achieved a cORR of approximately 52% and a median DOR of about 13.2 months for TKI-pretreated patients, with a median follow-up for responses of 33 months. In TRUST-II, treatment with taletrectinib achieved a cORR of 62%, and as of October 2024 (the time of data cut-off), the median DOR was 19.4 months with a median follow-up of 19 months.1,2
Notably, brain metastases are among the most common and devastating complications in patients with advanced ROS1+ NSCLC. In these trials, taletrectinib demonstrated consistent intracranial responses in patients with measurable brain metastases at baseline. An intracranial response was achieved in 73% of TKI-naive patients (n = 11) and 63% of TKI-pretreated patients (n = 15).2
“The FDA approval of [taletrectinib] marks a major milestone in the evolution of targeted therapy for advanced ROS1+ NSCLC. We believe one of the greatest threats to [patients with] ROS1+ lung cancer is disease progression, especially in the first-line setting. In pivotal trials, [taletrectinib] delivered high response rates with sustained durability—truly meaningful benefits for patients. With its clinically proven efficacy and safety profile, we believe [taletrectinib] has the potential to become a new standard for what targeted therapies can achieve in this type of lung cancer,” David Hung, MD, founder, president, and CEO of Nuvation Bio, said in the news release. “With approvals for [taletrectinib] now in the US and China, and additional global filings under way, we remain committed to delivering innovative therapies that help patients stay ahead of their disease.”2
Generally, taletrectinib was well tolerated by patients in the TRUST trials, with adverse events (AEs) considered low-grade, transient, and manageable. Discontinuation because of treatment-emergent AEs was considered infrequent (7%). The most common AEs included diarrhea (64%), nausea (47%), vomiting (43%), dizziness (22%), rash (22%), constipation (21%), and fatigue (20%). Further, the FDA states that taletrectinib’s prescribing information warns of hepatotoxicity, interstitial lung disease or pneumonitis, QTc interval prolongation, hyperuricemia, myalgia with creatine phosphokinase elevation, skeletal fractures, and embryo-fetal toxicity.1
“Patients living with advanced ROS1+ NSCLC and their health care providers are in need of new treatment options. [Taletrectinib]’s DOR and ability to effectively penetrate the brain, coupled with a well-characterized and manageable safety profile, further addresses these critical needs for patients,” study investigator Nathan Pennell, MD, PhD, professor of medicine at Cleveland Clinic, said in the news release. "I believe this now-approved therapy offers providers and patients a promising new option for the treatment of advanced ROS1+ NSCLC."2
