Dr Dietrich on the Efficacy and Safety of Taletrectinib in ROS1+ NSCLC

“We have to take the data not as we wish they was, but the way they currently stand. The number of patients who are doing quite well for a long time [with taletrectinib] seems to be the highest [of] what we've seen so far, numerically.”

Martin F. Dietrich, MD, PhD, a medical oncologist at Cancer Care Centers of Brevard; as well as an assistant professor of internal medicine at the University of Central Florida, discussed the role of taletrectinib (Ibtrozi) in patients with ROS1-positive non–small cell lung cancer (NSCLC).

ROS1-positive NSCLC continues to be a significant area of therapeutic need, particularly due to limitations associated with currently available TKIs, Dietrich began. A major concern with existing ROS1-directed therapies has been the incidence of adverse effects (AEs) linked to off-target inhibition, particularly of neurotrophin receptor kinases, such as TrkB, he said. Inhibition of TrkB has been implicated in neurologic toxicities, including impairments in cognition, speech, gait, and overall neurologic function, he noted. Therefore, the emergence of a therapeutic agent with a more selective kinase inhibition profile is of high clinical relevance, he emphasized.

Taletrectinib has a promising safety profile, with notably reduced incidences of neurologically related AEs, such as dizziness and other central nervous system toxicities, compared with earlier-generation ROS1 inhibitors, Dietrich explained. Importantly, these safety data are complemented by encouraging efficacy results, he added. Data from the phase 2 TRUST-I (NCT04395677) and TRUST-II (NCT04919811) registrational studies have shown high objective response rates (ORRs) and durable responses, according to Dietrich. This durability of response positions taletrectinib as a highly competitive agent in an increasingly crowded therapeutic arena, he reported. In support of the June 2025 FDA approval of taletrectinib for the treatment of patients with locally advanced or metastatic, ROS1-positive NSCLC, findings showed that treatment-naive patients achieved an ORR of 90% (95% CI, 83%-95%) in TRUST-I and 85% (95% CI, 73%-93%) in TRUST-II. Patients previously treated with a TKI experienced ORRs of 52% (95% CI, 39%-64%) and 62% (95% CI, 46%-75%), respectively.

The paradigm of ROS1-directed therapy for patients with NSCLC includes several approved agents, with crizotinib (Xalkori) the first to gain approval in this setting, Dietrich stated. Although head-to-head comparisons between these agents are lacking, indirect evaluation suggests taletrectinib exhibits a superior balance of efficacy and tolerability, he continued. Its performance sets a new benchmark in this setting, he said.

Although taletrectinib is included as a preferred option in the National Comprehensive Cancer Network guidelines, those guidelines refrain from establishing a hierarchy among agents due to the absence of comparative trials, Dietrich emphasized. Nonetheless, current clinical data indicate that taletrectinib may offer more favorable long-term outcomes among approved ROS1-targeted therapies, he concluded.