Investigational ROS1 Inhibitor Zidesamtinib For NSCLC: What to Know

Written by Leslie Fannon

The FDA has accepted the New Drug Application for the zidesamtinib, a brain-penetrant ROS1-selective inhibitor for adults with locally advanced or metastatic ROS1-positive NSCLC who have received treatment with at least one prior ROS1 TKI. On January 12, 2026, the manufacturer Nuvalent announced plans to submit data to the FDA to expand that indication for TKI-naïve patients. 

In trials, the drug has demonstrated promising response rates and researchers say they are optimistic about what’s next.

The Current Landscape for ROS1 Fusion-Positive NSCLC

ROS1 fusions are found in 1% to 2% of NSCLC cases. They tend to be aggressive cancers affecting younger patients who often have no smoking history. Immunotherapy is less effective for this type of NSCLC, but there are several targeted therapies approved to treat it. 

The current FDA-approved ROS-1 selective tyrosine kinase inhibitors (TKIs) include: 

• Crizotinib (Xalkori)
• Entrectinib (Rozlytrek)
• Repotrectinib (Augtyro)
• Taletrectinib (Ibtrozi)

“Each of these drugs has become more selective for ROS1 and more efficacious in the brain, which is unfortunately a common occurrence with ROS-1 fusion-positive NSCLC,” Dr. Ryan Gentzler, a medical oncologist specializing in lung cancer at UVA Health, explains.

But zidesamtinib could solve several unmet needs for these patients, including better treatment of brain metastases, more manageable side effects, and more effective treatments for patients with rare mutations. 

ARROS-1: What Do The Data Show?

There were 514 patients enrolled in the ongoing phase 1/2 ARROS-1 (NCT05118789) clinical trial. The median number of prior therapies was two, and 49% of the participants had CNS involvement. The secondary mutation ROS1 G2032R was found in 36% of patients. The study found: 

• The ORR was 44% in patients with any prior TKI history and 51% with one prior TKI. 
• The DOR rates for those with any prior TKI history were 84% at 6 months, 78% at 12 months, and 62% at 18 months. PFS rates were 57%, 49%, and 40%.
• The DOR rate for those with one prior TKI was 93% at 6, 12, and 18 months. PFS rates for this group were 70%, 68%, and 68%.

ROS1 G2032R resistance mutations are the most common secondary mutations in ROS1 fusion-positive NSCLC. They mediate resistance to some ROS1 TKIs leading to progression during treatment. Alternative treatment options are needed for these patients, either in the first line or after progression on another ROS1 TKI. For the patients with ROS1 G2032R resistance mutations, the DOR rate of 12 months or longer was 60% in the any prior TKI history group and 80% in the one prior TKI group. 

For patients with CNS involvement, the intracranial DOR rate of 12 months or more was 71% in the any prior TKI history group and 91% in the one prior TKI group.

“Zidesamtinib has demonstrated promising response rates and duration of response in patients with ROS1 fusion-positive NSCLC in multiple settings, including first line treatment naïve, after prior earlier-generation ROS1 TKIs, after prior newer generation ROS1 TKIs, in patients with brain metastases, and in patients with acquired ROS1 resistance mutations,” Dr. Gentzler says. 

Zidesamtinib Side Effects

Zidesamtinib has adverse events that are common to other drugs in this class, such as peripheral edema, constipation, and fatigue, but it may have a more manageable safety profile for patients compared to other ROS1 TKIs. ROS1 TKIs are also TRK inhibitors, which can cause more severe adverse events. 

“Importantly, this drug was developed to spare inhibition of TRK, so side effects that are seen with other ROS1 TKIs that have TRK inhibition, such as neuropathy, parathesia, memory impairment, dizziness, and ataxia, appear to be less frequent side effects with zidesamtinib,” Dr. Gentzler says. “Only 10% of patients required dose reduction and 2% treatment discontinuation, which appear to be much lower than with other available agents, indicating this is a tolerable treatment for many patients. 

Zidesamtinib as a First-Line Treatment

This week, Nuvalent announced plans to submit data to expand the indication of zidesamtinib to include TKI-naïve patients. The data from ARROS-1 showed that zidesamtinib was more effective in earlier lines of therapies. 

“Generally, the earlier patients are treated with the most efficacious treatment that is effective against common resistance mutations, the higher degree of benefit. Zidesamtinib will likely have broad benefits in patients who have never received treatment or have already received multiple prior treatments, based on the data presented from the ARROS-1 trial. Those who received no prior treatment or those who received only earlier-generation ROS1 TKIs with less efficacy may have the highest degree of benefit from zidesamtinib, but this will likely be a useful treatment for most patients with ROS1 fusion, regardless of prior treatment exposure,” Dr. Gentzler says. 

What’s Next for Zidesamtinib?

The FDA has set a PDUFA target action date of September 18, 2026 and Nuvalent has announced they will submit additional data on expanding the indication in the second half of 2026. The ARROS-1 clinical trial is also ongoing and still recruiting patients, including those who are TKI-naïve, treatment naïve, and heavily pretreated.

When it comes to how zidesamtinib compares to the latest generation of ROS1 inhibitors, which are effective at treating brain metastases and have less side effects associated with TRK inhibition, more data is needed.

“Zidesamtinib’s positioning — and FDA filing — targets a specific unmet need: CNS penetrating treatment and good activity on G2032R, but it is less clear how it will compare to repotrectinib and taletrectinib, which also have good activity for these patients,” Dr. Vemsi Velcheti, an oncologist at the Mayo Clinic Comprehensive Cancer Center in Florida, says.