Zidesamtinib Added to NCCN Guidelines for Pretreated ROS1+ NSCLC

Zidesamtinib (Jideytro; GSK), a next-generation, brain-penetrant ROS1 inhibitor, has been added to the National Comprehensive Cancer Network (NCCN) Guidelines for non–small cell lung cancer (NSCLC) as a subsequent therapy option for ROS1-positive disease, including as a preferred choice for patients whose cancer has progressed in the brain.¹ The listing gives clinicians another ROS1-selective option for patients whose disease progresses on earlier targeted therapy.

ROS1-positive NSCLC accounts for about 3000 new advanced diagnoses in the United States each year, with a median age at diagnosis of about 50 years,² and patients frequently develop brain metastases.³

The update follows the FDA approval of zidesamtinib on July 22, 2026, for adults with locally advanced or metastatic ROS1-positive NSCLC who have received at least 1 prior ROS1 tyrosine kinase inhibitor (TKI).^4,5

Where Zidesamtinib Fits in the NCCN Algorithm

NCCN made the following changes to the NSCLC guidelines in Version 7.2026:

• Systemic progression: Zidesamtinib was added as an option for asymptomatic patients and for symptomatic patients with systemic progression after entrectinib (Rozlytrek; Genentech), crizotinib (Xalkori; Pfizer), repotrectinib (Augtyro; Bristol Myers Squibb), or taletrectinib (Ibtrozi; Nuvation Bio).
• Symptomatic brain progression: Zidesamtinib was added as a preferred option, alongside repotrectinib (if not previously given), taletrectinib (if not previously given), and lorlatinib (Lorbrena; Pfizer). Entrectinib remains useful in certain circumstances for patients previously treated with crizotinib.
• Resistance mutations: A revised footnote states that repotrectinib, taletrectinib, or zidesamtinib is an option for resistant mutations such as ROS1 G2032R.
• Biomarker-directed therapy: Zidesamtinib was added to the list of subsequent therapies for ROS1 gene fusions.

All recommendations are category 2A—meaning the treatment is considered appropriate based on lower-level evidence and there is a uniform NCCN consensus of at least 85% support from the panel—unless otherwise indicated.

What the ARROS-1 Data Showed

The addition is supported by the phase 1/2 ARROS-1 trial (NCT05118789), which included 117 patients previously treated with a TKI.⁵ The objective response rate (ORR) was 44% with 78% of responders still responding at 12 months and 62% at 18 months. The ORR was 54% in those with G2032R-mutant disease. The intracranial ORR was 48%, including 20% complete intracranial responses. Dose reductions due to adverse events occurred in 10% of patients, and 2% discontinued treatment.

Zidesamtinib was designed to avoid inhibiting the tropomyosin receptor kinase family,⁶ which has been linked to central nervous system (CNS) adverse effects with other ROS1 TKIs. The recommended dose is 100 mg once daily.

How Clinicians View Its Place in Sequencing

Estelamari Rodriguez, MD, a hematologist and oncologist at Sylvester Comprehensive Cancer Center, whose center participated in ARROS-1, told The American Journal of Managed Care® the drug expands options for a rare population.

“ROS1 fusion-positive lung cancer is still a small subset of patients, but a really important one,” she said. “They’re usually younger patients, never-smokers, that have a predisposition for progression in the brain.”

Rodriguez said she expects zidesamtinib to “probably go at the top as a second-line option” because it was built to overcome resistance, including to crizotinib, and to act in the brain.

She cautioned that monitoring is still needed. CNS adverse reactions, interstitial lung disease, myalgia and creatine phosphokinase elevations, pancreatic toxicity, and QTc prolongation have been reported or are class concerns.

“I do anticipate that patients on this drug probably will not need as many dose interruptions, at least for the central nervous [system] side effects, so that will hopefully be better for patients that they will stay on the drug,” she said.

Open Questions on Sequencing

Few ARROS-1 participants had received repotrectinib or taletrectinib, so it is unclear how well zidesamtinib works after those agents, Rodriguez said. Future data may also clarify whether it will move into the first-line setting and whether specific ROS1 fusions or resistance pathways respond better to certain drugs.

She also emphasized early testing so that patients are not treated with immunotherapy before a ROS1 fusion is found.

“These patients will do better if this is identified earlier and acted on,” Rodriguez said.

References

1. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 7.2026. National Comprehensive Cancer Network. Accessed October 27, 2026.
2. What is ROS1-positive in lung cancer and how is it treated? Lung Cancer Foundation of America. Updated August 16, 2024. Accessed October 27, 2026. https://lcfamerica.org/about-lung-cancer/diagnosis/biomarkers/ros1/
3. Camidge DR. Choosing treatment for brain metastases in ROS1-altered non–small cell lung cancer. Expert Perspectives. September 30, 2025. Accessed October 27, 2026. https://expertperspectives.com/choosing-treatment-for-brain-metastases-in-ros1-altered-non-small-cell-lung-cancer/
4. Jideytro (zidesamtinib) approved in the US for previously treated ROS1-positive non-small cell lung cancer. News release. GSK. July 22, 2026. Accessed October 27, 2026. https://www.gsk.com/en-gb/media/press-releases/jideytro-zidesamtinib-approved-in-the-us-for-previously-treated-ros1-positive-non-small-cell-lung-cancer
5. McCormick B. FDA approves zidesamtinib, offering new option for resistant ROS1-positive NSCLC. AJMC®. July 22, 2026. Accessed October 27, 2026. https://www.ajmc.com/view/fda-approves-zidesamtinib-offering-new-option-for-resistant-ros1-positive-nsclc
6. Lee S, Hu L. Zidesamtinib (Jideytro): a new selective, brain-penetrant ROS1 inhibitor approved for the treatment of ROS1-positive non-small cell lung cancer. Med Chem Res. 2026;35(9):1543-1547. doi:10.1007/s00044-026-03606-6