Taletrectinib: A New Advance in ROS1-Mutant NSCLC
The landscape of treatment for ROS1-mutant non–small cell lung cancer (NSCLC) has recently seen a significant advancement with the FDA approval of taletrectinib (Ibtrozi).1 This oral, central nervous system (CNS)-active, next-generation ROS1 tyrosine kinase inhibitor (TKI) offers a promising new therapeutic option for patients, particularly those who have developed resistance to prior TKIs or have brain metastases.
ROS1 fusions are oncogenic drivers found in approximately 1% to 2% of NSCLC cases, according to Lyudmila A. Bazhenova, MD. These fusions lead to the downstream activation of signaling pathways that promote tumor cell proliferation and resistance to apoptosis. Prior to the approval of taletrectinib, 3 medications were available in the United States for ROS1-fused NSCLC: crizotinib (Xalkori), entrectinib (Rozyltrek), and repotrectinib (Augtyro). While effective, patients develop resistance to these agents. Common mechanisms of resistance include acquired resistance mutations, such as G2032R, and the development of brain metastases. Consequently, there has been an ongoing need for new agents that can effectively penetrate the brain, demonstrate activity against common resistance mutations, and ideally, have a more favorable adverse event profile.
In an interview with Targeted OncologyTM, Bazhenova, medical oncologist and professor of medicine at UC San Diego Health, discussed taletrectinib’s current and future role in the treatment landscape.
Understanding Taletrectinib: Mechanism of Action and Clinical Investigation
Taletrectinib distinguishes itself through its selectivity over tropomyosin receptor kinase B. This selectivity is hypothesized to translate into a lower incidence of neurological adverse events, a significant concern with some existing ROS1 TKIs.
The efficacy and safety of taletrectinib were investigated in 2 pivotal trials: TRUST-1 (NCT04395677) and TRUST-2 (NCT04919811). Both were open-label, single-arm studies evaluating taletrectinib in patients with ROS1-rearranged metastatic NSCLC.2
The TRUST-1 trial was primarily conducted in China and included 2 cohorts of TKI-naive patients and patients who had previously failed crizotinib. TRUST-2 was a global, multicenter, single-arm trial with a similar design to TRUST-1, also featuring 2 cohorts of TKI-naive patients and patients previously treated with a ROS1 TKI, including crizotinib or entrectinib. In both trials, taletrectinib was administered at a dose of 600 mg once daily.
Efficacy and Safety Data From TRUST-1 and TRUST-2
A combined analysis of the TRUST-1 and TRUST-2 studies, recently published in the Journal of Clinical Oncology, provided compelling evidence for taletrectinib's efficacy. The efficacy population comprised 273 patients (approximately 160 TKI-naive and 113 TKI-pretreated).2
In the TKI-naive cohort, taletrectinib demonstrated a high confirmed objective response rate (ORR) of 88.8%. Importantly, the intracranial ORR was also very high, at 76%, highlighting the drug's effective CNS penetration. Responses were notably durable, with a median duration of response (DOR) of 44.9 months and a median progression-free survival (PFS) of 45.6 months.
As expected, efficacy was lower in the TKI-pretreated cohort.
“In TKI-pretreated patients, efficacy was lower, as expected when we use any drugs in a second line. Post prior TKI, the responses will be lower,” Bazhenova explained.
In this combined analysis of TRUST-1 and TRUST-2, the ORR for TKI-pretreated patients was 56%, still a significant response rate. The intracranial ORR in this cohort was 65.6%, further supporting the drug's CNS activity and “telling us that maybe the prior tyrosine kinase inhibitors do not have as good of a CNS penetration as we could achieve,” according to Bazhenova. The DOR in TKI-pretreated patients was shorter, at approximately 17 months, with a median PFS of about 9.7 months.
A particularly encouraging finding was taletrectinib's activity against the G2032R mutation, a known acquired resistance mechanism. Among 13 patients with this mutation, the response rate was 61%.
“You have to be very careful in using that response rate as a true number, because the number of patients was very small, but I think it is very encouraging to see that response rate in that patient population,” said Bazhenova.
Regarding safety, which was evaluated in a larger cohort of 252 patients, the most common adverse events were gastrointestinal events, including nausea and diarrhea, as well as elevations in liver enzymes. Crucially, and aligning with the drug's selective mechanism of action, neurological adverse events commonly associated with other ROS1 TKIs, such as ataxia and dizziness, were notably less frequent.
“We do not see neurologic adverse events that are common for entrectinib and repotrectinib. We only saw about 21% of patients with dizziness, which is encouraging,” added Bazhenova.
Addressing Brain Metastases in ROS1-Mutant NSCLC
Brain metastases are a significant concern in NSCLC, and particularly in ROS1-positive disease, where reported incidence rates range from 20% to 30%. The high intracranial response rates observed with taletrectinib underscore its critical role in managing this challenging aspect of the disease. The ability of an agent to effectively penetrate the blood-brain barrier and target CNS lesions is paramount for improving outcomes and quality of life for patients with ROS1-mutant NSCLC.
“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," Bazhenova said.
Future Directions
The recent FDA approval of taletrectinib marks a pivotal moment for patients with ROS1-mutant NSCLC. Its unique characteristics, particularly the lower rate of neurological toxicity and robust CNS activity, make it an attractive option.
Looking ahead, Bazhenova believes ongoing and future research will focus on expanding the utility of taletrectinib. Traditional pathways for TKIs often involve investigating their use in adjuvant settings or as consolidation or induction therapy in locally advanced disease. While these trials are currently in various stages of design or underway, clinicians and researchers will be keenly awaiting further data on the compound's potential in these earlier disease stages.
