Navigating Zidesamtinib Safety, Sequencing in ROS1+ NSCLC

Although zidesamtinib (Jideytro; GSK) was designed to be better tolerated than other ROS1 inhibitors, it can still cause adverse effects that require monitoring, and questions remain about how best to sequence it, according to Estelamari Rodriguez, MD, MPH, of the University of Miami Sylvester Comprehensive Cancer Center.

On July 22, 2026, the FDA approved zidesamtinib, a novel, brain-penetrant, ROS1-selective inhibitor, for adults with locally advanced or metastatic ROS1-positive non–small cell lung cancer who have previously received at least 1 ROS1 tyrosine kinase inhibitor (TKI).¹ The decision was based on data from the phase 1/2 ARROS-1 trial (NCT05118789). In part 3 of an interview with The American Journal of Managed Care^®, Rodriguez discussed the drug's safety profile, remaining questions, and its place in treatment sequencing.

Zidesamtinib was designed to limit activity in the tropomyosin receptor kinase pathway and reduce neurologic adverse effects such as dizziness, weakness, confusion, and changes in mental status, which are often seen with drugs like repotrectinib (Augtyro; Bristol Myers Squibb). Rodriguez explained that these effects can complicate management because patients may also have brain metastases. Therefore, clinicians cannot always tell whether a symptom comes from the drug or a metastasis, and sometimes they have to hold treatment to find out. Zidesamtinib causes fewer of these effects, she said, but patients still reported central nervous system (CNS) adverse reactions in the ARROS-1 trial.

Still, Rodriguez said she anticipates fewer dose interruptions for CNS adverse effects with zidesamtinib, which may help patients stay on treatment. Strong intracranial responses may also reduce the need for additional brain-directed treatment in patients with CNS disease, potentially improving quality of life, she added.

One open question is how well zidesamtinib works after newer agents. The ARROS-1 trial mostly enrolled patients previously treated with crizotinib and other first- and second-generation drugs. Few had received repotrectinib or taletrectinib (Ibtrozi; Nuvation Bio), so more data are needed as more patients receive taletrectinib in the first line, Rodriguez noted.

Sequencing raises further questions. Historically, clinicians treated ROS1 fusions the same way regardless of fusion partner. With more drugs on the market, clinicians may gain more insight into which agents work best against specific fusions and resistance pathways.

In general, Rodriguez said, the expanding pool of TKIs means patients may not need chemotherapy for as long. She said clinicians should offer next-generation TKIs up front rather than saving them for later, because these drugs aim to prevent CNS progression. Zidesamtinib offers systemic and CNS control, along with durable responses, she said. It is currently a second-line option, but future data will show whether it moves into earlier lines of treatment.

"I would really encourage people to use it earlier and earlier in the second-line setting, because, again, it was developed for a better safety profile and better CNS responses," Rodriguez concluded.

Reference

1. McCormick B. FDA oks zidesamtinib as new option for resistant ROS1+ NSCLC. AJMC^®. July 22, 2026. Accessed October 6, 2026. https://www.ajmc.com/view/fda-approves-zidesamtinib-offering-new-option-for-resistant-ros1-positive-nsclc