Transcript

The transcript has been lightly edited for grammatical purposes.

What does it mean if your tumor has a ROS1 fusion?

ROS1 fusions are present in about 1% of lung cancers. This is a genomic alteration, a chromosomal rearrangement, that occurs independently of smoking. It’s not linked to smoking. When we see this in lung cancer, it means the cancer is using this ROS1 signal to survive. ROS1 plays a role in early development; it tells our cells to migrate, survive, and grow.

In adult life, that ROS1 signaling is shut off. We don’t need it anymore. When a ROS1 fusion is present, it inappropriately turns that signal back on. Now, we have a cancer that’s using ROS1 to survive, grow, and spread. When we see a ROS1 fusion–positive lung cancer, we know we can treat it by blocking that ROS1 signal. For that, we use a ROS1 inhibitor, also known as a ROS1 tyrosine kinase inhibitor, or TKI. These targeted drugs are very effective and we think better tolerated and more effective than chemotherapy.

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This is a type of cancer where immunotherapy is largely ineffective. It just doesn’t work very well. Targeted drugs are very effective and we’re fortunate to have several available to us now.

In the U.S., crizotinib and entrectinib were some of our first approved ROS1 inhibitors. These are drugs that work very well, work quickly, and for many patients, work for a long time. A newer drug that’s been approved is repotrectinib, another effective option for ROS1+ lung cancer. Most recently, taletrectinib has also been approved for treating ROS1-positive disease.

These are all ROS1 inhibitors, but here’s an important distinction: are they only ROS1 inhibitors? When we look at repotrectinib and entrectinib, they’re approved for the treatment of ROS1-positive lung cancer, but they’re also approved to treat something called NTRK-positive cancer.

NTRK is a totally different protein. It shares some similarity, some homology, with ROS1, so if you design a drug that blocks ROS1, it could also block NTRK. These are called dual inhibitors, drugs that do both. That’s useful, but it can come with consequences. If you block ROS1, since it doesn’t play a big role in the adult body, there are relatively few side effects.NTRK is actually important in adult physiology, so when we block NTRK, we can kill the cancer cells that rely on it, but we’re also affecting normal cells that use it. That leads to side effects.

One side effect is increased appetite. That might sound like a good thing, since cancer often leads to weight loss, but the weight gain can be significant, to the point that it becomes a health problem. We can also see a withdrawal pain syndrome because NTRK plays a role in how we perceive pain.

Most concerning is problems with something called proprioception, which is your sense of where your body is in space. So if I raise my hand and close my eyes, I still know my hand is raised. If you block that proprioceptive sense, you kind of lose track of where your body is. That’s not a big deal for your hand, but for your feet, it can be dangerous. If I don’t know where my foot is, I might fall. That’s what we see with NTRK inhibition: ataxia, or unsteady gait, falls, and real quality-of-life issues.

When we block NTRK, those are the side effects we worry about. Now, if the cancer is using NTRK, then blocking it is necessary, we just have to manage the side effects. If we’re trying to block ROS1, and we incidentally block NTRK, that’s a problem we didn’t need.

Ideally, we want a drug that blocks only ROS1. Taletrectinib, which is a more modern drug, does just that; it spares most normal NTRK function. As a result, it has fewer of these unwanted side effects. As our drugs become more selective with fewer off-target effects, we get a wider therapeutic window, meaning they’re more likely to work and less likely to cause harm.

ROS1 is a relatively uncommon, but important subtype of lung cancer. It’s critical that we find these cancers when they’re present. If we miss the ROS1 fusion, we’d default to standard treatment, immunotherapy, which largely doesn’t work for these cancers.

Even if the PD-L1 expression is high, which it often is in ROS1+ cancers, immunotherapy doesn’t deliver good outcomes here. That’s why it’s essential to test every lung cancer for ROS1 fusions. If they’re present, we need to steer patients away from immunotherapy and toward targeted therapies (ROS1 TKIs) that are far more effective.

Learn more about ALK+ and ROS1 NSCLC from Dr. Liu in the full video here.