Dr Bazhenova on the Landscape of ROS1 Inhibitors in ROS1+ NSCLC

“In ROS1-rearranged metastatic non–small cell lung cancer, we have several FDA-approved drugs: crizotinib, entrectinib, repotrectinib, and taletrectinib. Currently, there is no head-to-head trials comparing those four medications. Therefore, we have to do a cross-trial comparison.”

Lyudmila A. Bazhenova, MD, a professor of medicine at UC San Diego Health, discussed the evolving treatment landscape in ROS1-rearranged metastatic non–small cell lung cancer (NSCLC).

The treatment landscape continues to evolve with multiple FDA-approved TKIs, including crizotinib (Xalkori), entrectinib (Rozlytrek), repotrectinib (Augtyro), and taletrectinib (Ibtrozi). However, the absence of head-to-head comparative trials among these agents poses a challenge and data gap, Bazhenova explained. Although the ongoing phase 3 TRUST-III trial (NCT06564324) is expected to directly compare taletrectinib with crizotinib, cross-trial comparisons currently guide most treatment decisions.

Key distinctions among ROS1 inhibitors include toxicity profiles, central nervous system penetration, and activity against resistance mutations such as ROS1 G2032R, which commonly emerges following treatment with crizotinib or entrectinib, Bazhenova said. Both repotrectinib and taletrectinib demonstrate activity against this resistance mutation, though emerging efficacy and safety data appear to favor taletrectinib, she added.

In a pooled analysis of the phase 2 TRUST-I (NCT04395677) and TRUST-II (NCT04919811) trials presented during the 2026 AACR Annual Meeting, one of the most compelling findings highlighted was the durability of responses observed with next-generation ROS1 TKIs in treatment-naive patients, Bazhenova reported. Overall response rates exceeded 88%, with median duration of response surpassing 4 years. Progression-free survival in pooled analyses approached the four-year mark as well, underscoring the long-term disease control these agents may provide. Beyond traditional efficacy metrics, durable responses can significantly affect patient well-being by extending periods of stability without disease progression, Bazhenova added.

Bazhenova also underscored the improvements in tolerability that have been seen with newer-generation ROS1 inhibitors, particularly reduced neurologic adverse effects (AEs). These AEs are thought to be linked to inhibition of TRKB signaling, and newer agents such as taletrectinib may offer more selective targeting while maintaining strong ROS1 activity, including against G2032R resistance mutations.

Looking ahead, important unanswered questions remain regarding treatment intensification strategies in ROS1-positive disease, which are similar to approaches now being explored in EGFR-mutant NSCLC. However, the rarity of ROS1 rearrangements presents significant challenges for conducting large randomized clinical trials, Bazhenova concluded.