Precision Medicine: Key Updates for Treatment of NSCLC - Episode 12

ROS1-Rearranged Non–Small Cell Lung Cancer

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Benjamin Levy, MD: Let’s move on to another rearrangement that’s actionable with new therapies, and that’s ROS1 rearrangement in lung cancer. Becca, do you want to talk about how you treat these patients, some of the emerging data, and which drugs you use?

Rebecca Heist, MD: Yes. ROS1 rearrangements are described in lung cancer like many of the other driver rearrangements. They are more often in people who have a very light or no-smoking history and no carcinoma. ROS1 shares a lot of homology with ALK, so many similar drugs can be used, but it is important to know that it’s not exactly the same. For example, we talked a lot about alectinib in ALK. Alectinib does not have activity in ROS1, and it’s important to recognize that there are different drugs with different levels of activity against ROS1 and ALK.

There have been data in the past using crizotinib in this setting with a nice response rate. The response rate was over 70% in a series done with crizotinib in ROS1 patients. One of the things we’ve noticed about ROS1 patients is that their duration of response to a drug like crizotinib was longer than, for example, ALK patients using crizotinib. For some reason, they seem to have more prolonged benefit. More recently, entrectinib is another drug that’s entered the ROS1 field. Entrectinib hits ROS1. It also hits NTRK and ALK, and it reported a response rate of 77% in a pooled analysis.

To answer the question of whether I would use entrectinib or crizotinib, which I’m sure is coming, I don’t have a lot of experience using entrectinib. The toxicity profile is a bit daunting. It does have great CNS [central nervous system] penetration in a patient with CNS metastases, whereas we know crizotinib doesn’t have great penetration into the brain, so I would consider it. But there have been adverse effects, such as dizziness and cognitive changes, so it wouldn’t be clear that everyone gets entrectinib in my mind. It would be a case-by-case decision, depending on where the disease is and the patient’s general functioning, whether I would with crizotinib or entrectinib.

Benjamin Levy, MD: That’s a good review. The entrectinib data do look as though there is some CNS penetrance. I don’t know if we saw the intracranial response with crizotinib in the ROS1 papers. But it seems as though there may be better CNS penetration. The other thing about entrectinib—correct me if I’m wrong—is that the drug doesn’t really work postcrizotinib. It’s probably not the best drug to give. If that’s the case, what do you do next if you start with either of these drugs?

Rebecca Heist, MD: There are data for lorlatinib after crizotinib. Lorlatinib has activity in both treatment-naïve and postcrizotinib settings for ROS1 patients. In the treatment-naïve setting, the response rate was 60% or so. Even postcrizotinib, the response rate to lorlatinib was about 35%. That definitely has activity.

There are also other drugs that are being investigated in clinical trials that look interesting. There’s TPX-0005 [repotrectinib], which is being looked at. That was designed to deal with some of the solvent front mutations that can come up in resistance. That’s an interesting trial to think about in someone who is progressing, especially if they have a solvent front mutation. There are a lot of drugs being developed in that space.

Benjamin Levy, MD: Josh, what are your thoughts on which of these drugs you usually reach for when treating ROS1-rearranged lung cancer, and what you do next?

Joshua Bauml, MD: I tend to use crizotinib in the first line. Crizotinib is highly active and is well tolerated in this space. Entrectinib introduces toxicity, as Becca very accurately said. In later lines, the only drug that’s approved and has efficacy against those solvent front mutations is cabozantinib, which I try to keep my patients as far away from as humanly possible, given its toxicity. But the repotrectinib, which is the TPX-0005 drug, is a really exciting agent in this space with substantial activity. That’s the analogous drug to something like osimertinib or alectinib in this space, and I’m really excited for that drug to become more widely available.

Benjamin Levy, MD: Yes, we’re part of that trial and the drug has real activity in the ROS1-rearranged lung cancer patients. We saw that at ASCO [American Society of Clinical Oncology Annual Meeting] last year. There was a nice response rate with repotrectinib in ROS1-rearranged lung cancer postcrizotinib. We’ll see more.

Lyudmila Bazhenova, MD: I’m sold on the CNS efficacy, having had experience with entrectinib as part of a clinical trial. In my experience, the dizziness is real, but it gets better with time. I’ve never had to dose reduce for dizziness with entrectinib, so I switched.

Benjamin Levy, MD: So you’re an entrectinib user in the front line for most patients?

Lyudmila Bazhenova, MD: Yes, almost.

Transcript Edited for Clarity