NCCN Guidelines® for ROS1 fusion–positive non–small cell lung cancer (NSCLC) have evolved in important ways, and for patients, these changes can have a real impact on outcomes and quality of life.
We asked Georgetown University’s Dr. Stephen Liu to explain what these updates mean for your care and the topics you should be bringing to your care team. Here’s what we discussed:
An emphasis on avoiding immunotherapy
Immunotherapy has transformed cancer care and remains a powerful option for many patients. Dr. Liu emphasizes, “I’m a strong believer in immunotherapy.” He says. “The power of it is that for some people, when it works, it will keep working. It’s a really transformative benefit.”
However, ROS1-fusion positive lung cancer is a clear exception.
“The reality is that this drug class does not work well for ROS1 fusion–positive lung cancer, and there are better options out there,” Dr. Liu says.
In many types of lung cancer, doctors rely on a biomarker called PD-L1 to guide immunotherapy decisions. Higher PD-L1 levels usually suggest a better chance of response, but in ROS1-positive disease, that rule doesn’t apply.
“ROS1 can have very high PD-L1 expression,” Dr. Liu explains, “but unlike other cancers, immunotherapy is largely ineffective. So, we need to ignore PD-L1 in the context of a ROS1 fusion.”
Instead, the guidelines now recommend moving directly to ROS1-targeted therapy when a fusion is present.
Why the order of treatment matters
The updated guidelines also include more details on how treatment sequence affects safety, not just effectiveness.
“If we use a ROS1 inhibitor, it’ll have certain side effects, but in general, it’s well tolerated,” Dr. Liu says. “If we use immunotherapy first, not only does it not work, but then when we go to a ROS1 inhibitor, for some reason, those drugs become more toxic.”
Patients who receive immunotherapy first may experience more severe side effects once they eventually switch to targeted therapy. “It’s not just a matter of getting the drugs right,” Dr. Liu notes. “We need to get them in the right order as well.”
For patients with ROS1 fusions, that means starting with targeted therapy and not using immunotherapy beforehand.
Where taletrectinib fits into the guidelines
Among ROS1-targeted therapies, taletrectinib represents a newer, more selective option that was received FDA approval in 2025.
“Taletrectinib is a ROS1 inhibitor, and it is selective for TRKB,” Dr. Liu explains. In practical terms, this means it effectively blocks the ROS1 signal driving the cancer while limiting activity against other proteins that can cause unwanted side effects.
“It will block that ROS1 signal, which is a good way to treat ROS1 fusion–positive lung cancer,” he says, “but it has fewer of the TRK-related activities, which translates to fewer side effects.”
Clinical trial data have been especially encouraging. “The chance of response in some trials was 90%, with a significant reduction,” Dr. Liu notes. “And these are very durable responses as well.”
Because of its selectivity, taletrectinib may also be an option for patients who struggled with side effects on older ROS1 inhibitors. “If someone was on an older ROS1 inhibitor and having a lot of side effects, this may be something to consider switching to,” Dr. Liu says.
The role of early genomic testing
These guideline changes underscore why comprehensive genomic testing needs to happen early, ideally at the time of diagnosis.
“If we just guess and start immunotherapy, and it doesn’t work, and then do our testing, we might find out too late that a ROS1 fusion is present,” Dr. Liu warns.
By the time the correct diagnosis is made, patients may already have been exposed to a treatment that was unlikely to help and that could complicate future care.
“That’s why not only do all cancers need that genomic testing, they need it early, really as part of the initial diagnosis,” he says. “A ROS1 fusion–positive lung cancer is a different type of lung cancer altogether, and it needs to be treated as such.”
What new research means for you
The latest guidelines for ROS1-positive lung cancer reinforce a simple but powerful message: test early, target precisely, and treat in the right order.
By identifying ROS1 fusions at diagnosis and starting with ROS1-targeted therapy, rather than immunotherapy, patients can avoid ineffective treatment, reduce unnecessary toxicity, and access therapies that offer high response rates and durable benefit.
To learn more from Dr. Stephen Liu, watch the full video here.
