Frontline ALK TKIs in NSCLC: The CROWN Trial


Focusing on the CROWN clinical trial in ALK+ NSCLC, expert panelists consider the role of frontline lorlatinib therapy in this setting.


Stephen Liu, MD: Jyoti, let’s talk a little bit about lorlatinib. At ACR [American College of Radiology annual meeting] someone presented an update from the CROWN data and after quite a bit of follow up we still don’t have a median PFS [progression-free survival]. It might be out to close to 5 years now. What are your thoughts about the efficacy of lorlatinib relative to brigatinib and alectinib?

Jyoti Patel, MD: Clearly, lorlatinib is a great drug that has a ratio of 0.27 compared to about 0.4 and 0.5 for brigatinib and alectinib. My assumption is that we will see it at around 5 years. So clearly this is a drug that is quite effective. We’ll talk a little bit about the toxicities and why some of us may be hesitant to use it as our frontline drug. But I can’t stress enough that patients are on these therapies for a long time so really thinking about even the grade 1 or 2 toxicities everyday chronically has to factor in your decision-making.

Stephen Liu, MD: Let’s talk about the toxicities now. The response rates are high as they are with all these drugs. It works for a very long time and hazard ratio relative to lorlatinib is objectively the lowest. It will be the longest median PFS. I don’t think there’s any argument about that. But it does have different toxicities. Jyoti, you mentioned that it sort of colors your thoughts about this drug. What are some of the side effects you’ve seen with lorlatinib?

Jyoti Patel, MD: So a very predictable and easy [side effect] to take care of is hypercholesterolemia and the hyperlipidemia. Almost all of our patients end up on a statin at some point. Patients can also have weight gain and some peripheral neuropathy. I think the 1 that is really troublesome for a subset of patients—not everyone has it—but a large number of patients do have cognitive effects, and whether that goes from subtle personality changes to delirium, it’s a wide spectrum. So that can be really tough when you’re thinking about what it will look like for 5 years.

Stephen Liu, MD: That’s a pretty big range there, subtle personality changes to delirium. Ross, what’s been your experience in terms of the cognitive effects specifically for lorlatinib?

Ross Camidge, MD, PhD: I think Jyoti made a comment earlier that we as oncologists have to kind of educate ourselves as the drugs change. I think very early the cognitive side effects were missed because people didn’t know what to ask. The patients usually don’t volunteer [that their personality has changed], people don’t say that. And of course the other thing is we never asked the spouse who would probably be a great source of information on that. The current rate from a recent study from [Massachusetts General Cancer Center, Boston, MA] is running at about 60%. We’re getting some kind of higher cognitive side effect. Clearly, its dose related, but they are reversible.

My biggest worry is when you looked in that study, the dose reduction rate in CROWN was like 21%. So a lot of people are just putting up with this and maybe not telling their doctors about it. If you’re going to be on the drug for years, is that the right thing to do?

Stephen Liu, MD: Jillian, any experience with any of those side effects with lorlatinib?

Jillian E. Thompson, NP: Yes. We did have a patient who—and I will point back to what Dr Camidge said about making sure that we involve family members because they may be the best measure of changes. We had that circumstance happen where the family members said that the patient was aggressive and had the personality changes and that was something that we noted. With a dose reduction that reversed itself and we were able to proceed with that treatment.

Stephen Liu, MD: Very unique.

Ross Camidge, MD, PhD: Steve, let me throw out one other thing. So one of the things when we’re talking about these that people are going to be on for years, is when they write up the study, they’re writing up it up here with 18 months of follow up. The trouble is they don’t keep the toxicity assessments going in any kind of detail after 5 years. What if there is a cumulative effect? What if there was a long-term effect on your neurology? Certainly, I have patients who [have been on the drug] for 5 or 6 years who are saying that. Is this because they’re 5 years older and they can’t remember why they went into the room before they sit down, or is it the lorlatinib effect? And I think we’re still learning.

Stephen Liu, MD: Do we have any predictive markers as to who’s going to get this kind of toxicity?

Ross Camidge, MD, PhD: If you have preexisting psychiatric conditions or preexisting significant brain damage it can be. Largely brain metastases don’t seem to predict their other issues, but I think it’s the people who are a little towards the eccentricities of normality to begin with, who manifested more clearly.

Stephen Liu, MD: I want to be sort of clear though, Jyoti, while there are some cognitive toxicities and it’s very important to be aware of, it’s not preventing you from using this drug, correct?

Jyoti Patel, MD: Absolutely. Thanks for stressing that. No. It’s remarkably effective. We’ll certainly use lorlatinib, but again it’s a long conversation with education stating these are the things that we need to look for. This is sometimes an instance in which I will have a patient who is a great advocate for themselves and well educated, ask me can we start low and increase the dose. That is something that I feel very comfortable doing or will recommend rather than starting at a higher dose of 100 mg I might start at 75 mg, see how they do, and then consider dose increase if I need to.

Stephen Liu, MD: It does respond to dose reduction. As you mentioned, Ross, the key as everyone has mentioned is recognition. Understanding this is what we’re looking for, this is what they warn people about. But because there’s not always insight into the toxicity especially if it’s sort of an existential cognitive personality type of change, you may not realize it’s happening for patients that are living on their own or that really don’t have a big support network sometimes it’s going to get missed. All of us have busy clinics and I think that in a 10-, 15-minute visit are we really going to be able to sort of get to some of these changes?

Transcript edited for clarity.

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