FDA Approves Taletrectinib for ROS1-Positive Non-Small Cell Lung Cancer
Taletrectinib gains FDA approval as a groundbreaking treatment for ROS1-positive non-small cell lung cancer, offering hope for patients with CNS involvement.
US FDA
- Taletrectinib (Ibrtrozi) is now an FDA-approved agent for the treatment of locally advanced or metastatic ROS1-positive non–small cell lung cancer (NSCLC).
- The approval is supported by 2 phase 2 clinical trials (NCT04395677; NCT04919811).
- Taletrectinib is notable for its central nervous system (CNS) penetration and activity in patients with treatment-naive and pretreated disease.
The FDA has granted approval for taletrectinib, a novel oral tyrosine kinase inhibitor (TKI), for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC.1
This approval addresses a critical unmet need for patients with this specific oncogenic driver, particularly those who have developed resistance to prior TKI therapies or present with central nervous system (CNS) metastases.
The approval of taletrectinib marks an important advancement in the therapeutic landscape for ROS1-positive NSCLC, a subset of lung cancer characterized by rearrangements in the ROS1 gene. These fusions lead to constitutive activation of the ROS1 kinase, driving uncontrolled cellular proliferation and tumor growth.
The FDA's approval is primarily supported by compelling data from a pooled analysis of 2 pivotal phase 2 clinical trials: TRUST-I and TRUST-II. These multicenter, single-arm, open-label studies evaluated taletrectinib at a dose of 600 mg orally once daily in patients with advanced ROS1-positive NSCLC.
The integrated analysis included 273 efficacy-evaluable patients, encompassing both TKI-naive and TKI-pretreated cohorts.2 The primary end point for both studies was confirmed objective response rate (cORR) as assessed by an independent review committee. Key secondary end points included intracranial cORR, duration of response (DOR), progression-free survival (PFS), and safety.
Taletrectinib demonstrated a cORR of 88.8% in the TKI-naive population (n = 160). The median DOR was 44.2 months, and the median PFS was 45.6 months. In patients with measurable baseline brain metastases, the intracranial cORR was 76.5%.
In the TKI-pretreated cohort, the cORR was 55.8%. The median DOR was 16.6 months, and the median PFS was 9.7 months. Notably, in patients with the ROS1 G2032R mutation, the cORR was 61.5%. Intracranial cORR in this group was 65.6%.
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The safety analysis, based on 352 patients treated with 600 mg once daily, indicated that taletrectinib was generally well tolerated. The most frequent treatment-emergent adverse events (TEAEs) were primarily gastrointestinal events (88%), followed by elevated aspartate aminotransferase (72%) and alanine aminotransferase (68%), with most cases being grade 1. Neurologic TEAEs were infrequent, with dizziness reported in 21% and dysgeusia in 15% of patients, predominantly grade 1 in severity. Treatment discontinuations due to TEAEs occurred in 6.5% of patients.
“I think the unique characteristics of taletrectinib is [the] lower rate of neurological toxicity that might made it make it attractive for patients with newly diagnosed ROS1-mutant non–small cell lung cancer," said Lyudmila Bazhenova, MD, medical oncologist and professor of medicine at UC San Diego Health, in an interview with Targeted OncologyTM.
Bazhenova underscored the importance of taletrectinib’s CNS penetration for these patients.
“The reported incidence [of brain metastases] is about 20 to 30%, so it's relatively common to see brain mets in the [ROS1-mutant] population,” according to Bazhenova.
The favorable efficacy, durable responses, robust intracranial activity, and manageable safety profile underscore taletrectinib's potential as a significant therapeutic option for patients with ROS1-positive NSCLC, addressing both TKI-naive and TKI-pretreated populations, including those with CNS involvement. An ongoing phase 3 trial (NCT06564324) is comparing taletrectinib head-to-head with crizotinib (Xalkori) in TKI-naive patients to further elucidate its role in this patient population.3
About Taletrectinib
Taletrectinib is a next-generation, oral, CNS-active TKI designed to selectively inhibit the activity of the aberrant ROS1fusion protein.2 Unlike some earlier generation ROS1 TKIs, taletrectinib demonstrates enhanced potency against acquired resistance mutations, including the common G2032R mutation, which can emerge following prior TKI treatment. Its design also contributes to superior penetration of the blood-brain barrier, offering robust intracranial activity and potentially mitigating neurological adverse events associated with less selective inhibitors.
Taletrectinib functions by binding to the ATP-binding site of the ROS1 kinase, thereby inhibiting its phosphorylation activity. This action prevents the activation of downstream signaling pathways, such as PI3K/AKT and MAPK/ERK, which are essential for cancer cell survival and proliferation. The drug's selectivity for ROS1 over other kinases, such as tropomyosin receptor kinase B (TRKB), is hypothesized to contribute to its favorable safety profile regarding neurologic adverse events.
