Transcript

The transcript has been lightly edited for grammatical purposes.

What are the latest guidelines for patients with ROS1 fusions?

Dr. Stephen Liu: These changes to the guidelines are really important for ROS1 fusion-positive lung cancer, especially when it comes to avoiding the class of drugs we call immunotherapy. I’m a strong believer in immunotherapy. The power of it is that for some people, when it works, it will keep working. It’s a really transformative benefit. But the reality is that this drug class does not work well for ROS1 fusion–positive lung cancer, and there are better options out there.

When we use immunotherapy, it’s often guided by the expression of a protein called PD-L1. When that protein is very high, then immunotherapy is more likely to work. ROS1 can have very high PD-L1 expression, but unlike other cancers, immunotherapy is largely ineffective. So, we need to ignore PD-L1 in the context of a ROS1 fusion. When ROS1 fusions are present, we really need to go toward ROS1-targeted therapy.

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Why it’s so important that immunotherapy has been taken out of those guidelines is because the sequence of treatment matters. If we use a ROS1 inhibitor, it’ll have certain side effects, but in general, it’s well tolerated. 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. There are more side effects when we use them after immunotherapy.

It’s not just a matter of getting the drugs right, we need to get them in the right order as well. We should be starting with targeted therapy, and not using immunotherapy beforehand, or else it’ll render those drugs much more toxic, which is why, when we’re starting treatment, we need to know if a ROS1 fusion is present.

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. So not only do all cancers need that genomic testing, they need it early, really as part of the initial diagnosis. A ROS1 fusion–positive lung cancer is a different type of lung cancer altogether, and it needs to be treated as such.

Taletrectinib is a ROS1 inhibitor, and it is selective for TRKB. What that means is it will block that ROS1 signal, which is a good way to treat ROS1 fusion–positive lung cancer, but it has fewer of the TRK-related activities, which translates to fewer side effects.

So if patients have a ROS1 fusion–positive lung cancer, I think this is a very good drug to start with. The chance of response in some trials was 90%, with a significant reduction. And these are very durable responses as well.

If someone was on an older ROS1 inhibitor and having a lot of side effects, this may be something to consider switching to because, in theory, it should have fewer side effects than some of the older ROS1 inhibitors that had a lot more activity at TRK.

What are newly approved options for ALK-positive, metastatic NSCLC?

Dr. Stephen Liu: So, ensartinib is a newly approved ALK inhibitor. This is an effective agent, and we’ve known about it for quite some time. [It’s] a drug that was approved in other parts of the world and is now approved in the U.S. This drug is superior to crizotinib. I would call this a next-generation or second-generation ALK inhibitor, effective in the body and effective in the brain, and a well-tolerated drug.

I think it should be used very similarly to drugs like alectinib and brigatinib. Compared to a drug like lorlatinib, it probably wouldn’t work as long for the average person, but it likely has a more favorable side effect profile. I think the specific drug of choice is something that really needs to be discussed with your doctor.

Learn more about what you should look for in your ROS1-fusion positive or ALK-positive treatment plan in Chapter 2 of Precision Minute.

More about ROS1 and ALK-positive NSCLC:

• Is targeted therapy right for me with NSCLC?
• ALK-positive lung cancer: what it means and targeted treatment options
• What does a ROS1 fusion mean in non-small cell cancer?
• ALK-positive and ROS1 NSCLC: can you have both?

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