Dr. Todd Bauer:
Welcome to The ASCO Post Roundtable Series on ALK-Positive Metastatic Non–Small Cell Lung Cancer. I'm Todd Bauer, based in Nashville, Tennessee, where I work for Tennessee Oncology in the Greco Hainsworth Centers for Research. I'm delighted to be joined by Dr. Ignatius Ou and Dr. Narjust Florez on this call today.
Dr. Narjust Florez:
Hi, my name is Dr. Narjust Florez. I'm a thoracic medical oncologist at Dana-Farber Cancer Institute and I'm happy to be here.
Dr. Ignatius Ou:
And I'm Ignatius Ou. I'm at the University of California Irvine School of Medicine in Orange, California.
Dr. Bauer:
It’s great to have you both here. Today, we are going to be discussing the treatment and management of ALK-positive metastatic non–small cell lung cancer with three patient case studies. Our next installment will focus on the management of first-line ALK-positive non–small cell lung cancer with CNS metastases at baseline and CNS toxicity early in treatment for the patient.
Mr. WF is a 76-year-old prior smoker who presented to the emergency room in February of 2024 with complaints of dyspnea. Imaging revealed a 3.2-cm right lower lobe mass in a widely metastatic process including diffuse adenopathy, liver lesions, and bone involvement. Lung biopsy confirmed metastatic non–small cell lung cancer. Liquid NGS did confirm an EML4::ALK variant 3 a/b rearrangement and unfortunately MRI of the brain demonstrated a 4-mm right frontal lobe metastasis without surrounding edema. So two questions as we walk through this case. Does his smoking status surprise you, and do you have any compelling factors in the first line choice of therapy?
Dr. Florez:
I think we had an early conversation about the previous tobacco use and how that is not a reason to exclude NGS, and I think this case solidifies what we just discussed and the importance of it in that patients have diverse tumor types and I believe NGS is the fingerprint of the tumor. And we don't have the full identity of the tumor until that's done. Yes, the tobacco history adds to the history, but that's not the identity of the tumor we're treating. So that's what I tell my patients. "Let me figure out what is the identity of this tumor by NGS." And that also helps with something that we encounter every day, which is the anxiety of being told you have metastatic cancer. But hurry up and wait, we're going to wait for NGS." That's very anxiety-provoking, for example, these patients who have significant disease and CNS disease.
About the second question, February of 2024. This is after first-line approval for lorlatinib, which was March of 2021. And with the presence of CNS metastasis, large burden of disease, positive on liquid biopsy, I think I will be prone to start lorlatinib as first line, but I would love to have a conversation with the two of you that have been around the block a little bit longer than I have.
Dr. Ou:
I will address the smoking question a little bit. Am I surprised that he has ALK and history of smoking? No. If I look at the case, I would expect, let's say, he could have a MET exon 14 mutation. He's 76 years old, that's right around the range that he'll have a mutation like that. So that's why we need to screen with NGS regardless of smoking history. We don't know for better what the patients will have, so that's why we do the NGS on both the tumor and the liquid and the blood, I should say. So a little bit surprised that he has ALK, but not surprised that even with a smoking history there was an actionable driver mutation.
First-line treatment, age should not be determinant, especially it looks like has a good performance status from the description. It was just dyspnea that got him into the ER, so not major morbidity that precludes him from getting any first-line treatment of any kind.
Dr. Bauer:
Okay. As we go on to the case, he was indeed started on lorlatinib, the standard 100-mg daily dosing on March 1, 2024. He had scans 3 1/2 weeks later, which showed decreased conspicuity. They couldn't measure it, but called it decreased conspicuity of the CNS lesion. So responding there. Now, the patient did note some mild confusion and chemo fog after the second cycle had started. So the question then becomes what do we do? Because we continued him on treatment through April, he had restaging scans that did show resolution to the CNS lesion and response in the visceral lesions. So as we think through that, he's having a little bit of toxicity, but he is responding well, so, Dr. Florez, what do you do here and what do you think about dose reduction in this case?
Dr. Florez:
Well, there are two things. Patients will have some type of cognitive changes to lorlatinib. Coming for the perception that they won't notice anything, eventually we see this—day 105, that's what the CROWN data show, but some patients can have it sooner. So I tend to have a conversation with them about how much the adverse event is affecting their executive function and the quality of life because that varies from patient to patient.
I have a patient that is an economist, so she requires her full brain capacity to do this. That really affected her quality of life. So I asked the patient, "How much is this affecting your quality of life? Can we monitor?" Because there are ways to deal with this chemo fog, reminders, meditation, cognitive behavior therapy, that we have used in the past as successful. But if it is affecting his activities of daily living, it's bringing out a lot of distress, dose reduction is possible. And we learned that from CROWN because at 16 weeks we know that the dose reduction to 75 mg didn't affect outcomes overall.
But the main thing is if this is a permanent side effect, is affecting the question of the patient's quality of life, what is the patient comfort level? I have patients that are committed to their dose of lorlatinib, and so I think it's a holistic decision. Is the patient retired? Is the patient responsible for childcare? I have very young women, they're driving their kids around. Need to make sure they're sharp around that. So if it's affecting the quality of life, I will do a dose reduction to first level, which is 75 mg.
Dr. Ou:
I completely agree. We need a holistic approach. I don't want to be say that I'm ageist, this guy is 76 years old, so he probably shouldn't be driving young kids to school or otherwise. And we'll have to ask his social situation. Is he a caretaker for his wife or vice versa? Does he have any children or grandchildren with him? I'm very flexible given the age 76. We know that 75 mg will work very well. For younger patient like an economist, then I would strongly, strongly encourage them to keep it at 100 mg. So the age kind of throws me off a little bit. Depending on where they live in Tennessee, if they live in rural Tennessee, can they take care of themselves? A lot of things, situations like that. But looks like it's not too bad for him. I would probably encourage him to continue unless he's a caretaker for his wife and he's estranged from his family, which happens, and then that will be the situation. But it's safe to reduce and 75 mg is fine with me.
So again, it's a holistic approach. Everybody's different. It's not just themselves, but their social situation.
Dr. Bauer:
I think part of that holistic approach, from my standpoint, is to ensure that as we start lorlatinib in patients is having that discussion with the family members. Because we don't really have great insight into our patient's global mental status in a 15-minute visit and we know that patients often will minimize their side effects because they do want to stay at that dose. So I think it's important to have the caregivers evaluate that. And that's one of the blessings of our job is we get to sit down and have this conversation with patients and dial it in for every single patient. It's not just, "Here's the hard and fast rule."
I think it is important to note that, and you mentioned this, Dr. Florez, there was no change in efficacy if patients required a dose reduction in the first 4 months on treatment and it can continue to be effective. So then I guess the question is, knowing the history of TKIs, do either of y'all start patients at a lower dose and then consider escalation or do you start them at 100 mg and reduce if needed?
Dr. Florez:
I tend to start with a higher dose. When you have the higher clone, the higher need, and you need to control this. ALK disease is destructive for the brain. If you use start low, those cells are going to find another brain cell, another brain travel for these patients. These patients don't tend to have any other competing comorbidities. Yes, there are a few that do, but most of them don't. So this is their main comorbidity. The main cause of this mess is going to be this cancer. So I tend to start at 100 mg, but I fight as hard as I can to start them with 100 mg at the 25-mg tablets because that will give me the freedom to dose reduce. But again, I fight as hard as I can because sometimes we get a pushback from the insurance for the 100-mg tablet vs the 25-mg tablet, but the freedom of be able to dose reduceis priceless. So I fight for it to hope to get the 25-mg tablets. I'm not always successful. I don't know how your experience is with that.
Dr. Bauer:
Well, I actually had this conversation a couple of weeks ago at ASCO and the response I got was there is now a 25-mg packet starter dose that can be obtained through the manufacturer to help ease that concern or worry about it. So that's something we can look into through those connections we have as well.
Dr. Florez:
Yeah. The problem is sometimes that I'm not able to get it and what I get faster in my specialty pharmacy is a 100 mg.
Dr. Bauer:
Absolutely.
Dr. Florez:
You all prefer to start at 25 mg? Is this just me being a little paranoid. Do you all prefer to start with 25-mg tablets for the 100-mg dose?
Dr. Bauer:
No, I don't worry about it as much as I might have a few years back.
Dr. Florez:
Okay.
Dr. Bauer:
As you mentioned, we have been around the block a little bit longer than you, so I had the chance to see this. And I think that if there's a bad CNS toxicity, the rare events of bad depression that come on like that or the kind of one-offs, like truly one or two episodes of a psychotic issue, you're going to stop the drug regardless and wait for it to get better. And that's the reassuring thing is they always do get better when you hold or lower the dose. And so if it's a mild thing, I might try and help them, as we do with a lot of our drugs. Like, "Let's maybe get through this first month at the 100-mg dose and see if you acclimate to it. If you don't, then absolutely we can drop that dose down." So I probably feel more comfortable now starting at the 100-mg tabs than I did maybe 2 or 3 years ago. But I think it's a great safety blanket to have, for sure.
Dr. Florez:
Yeah, I do have very young patients so maybe that may be the reason why a little more hesitant. And I think as we talk about CNS toxicity, it's important to know that 1% of all people were discontinued from the agent and the trial due to CNS toxicity. And I do think it has a bad reputation. A lot of this toxicity gets better.
I had a patient that forgot his wife's name and that's why bringing the caregiver is so important. It wasn't on purpose. It wasn't on purpose. And it's so important for the caregiver. So what I use is, the Lung Cancer Research Foundation have diaries that patients can download and fill about symptoms or things they see every day and they can bring it home. They also can download apps. There's an app called mySymptoms and then they can download it and record their journey because we only see them for that little time. So trying to annotate these symptoms can be very helpful over time.
Dr. Ou:
Yeah, I completely agree. For the dosing, I gave up the battle 2 years ago that I once wrote for four 25-mg tablets and I was told that they do not. And I gave it up, which I think, in a sense, it's unfortunate because if the patient has to dose reduce, then you lost all the 100-mg tablets. It's just a lot of waste. Let's say after 2 weeks they have to dose reduce. You can switch off very quickly now, but that 100 mg is a waste, and it's worth something to somebody.
I'll go back to the one thing that is lost in medicine right now is a social history. Nobody gets a good social history. And I always tell the fellow, you need to know because oncology is logistics. For us who live in Southern California, traffic is a problem. So they need people to drive them back and forth and a lot of our patients have to have their kids to drive them. So how to get to the clinic is one thing. How to take care of themselves is one thing. In Southern California, a lot of people move from other parts of the country, so they don't have a nuclear family here. They have kids in the East Coast, in Chicago, in Seattle, and they're estranged from their brother in Texas and all of that, so it's very important to have the logistics. And when I read the resident and fellows’ notes, the social history, it drives me really nuts because you need to know the family, how they get there, where they live, and that's how we can really dose reduce and manage the side effects much more easily.
Dr. Florez:
I think that brings a very, very important point. And it's the financial toxicity of target therapies that come with. There's a side effect that we often forget and a lot of patients don't mention it because they feel embarrassed. That's the price they have to pay to stay alive. So I think part of the social history is how much is your copay for your drug? Are you getting your drug delivered on time? And I have learned this in the good and the bad way. I had a patient that was stretching out the medication to stretch out the copay. Just to summarize, financial toxicity is another adverse event of all targeted therapies in lung cancer.
Dr. Bauer:
Agreed. Well, guys, I think an interesting case, and as I think through the highlights from this case, some that strike me or as Mr. WF had some mild CNS toxicity, what we probably would describe as chemo fog, but not these big scary things. As you said, Dr. Florez, there's this bad reputation that goes around about lorlatinib. There are side effects for sure, but they're usually not dramatic. In fact, the most common side effects were people had to stop the drug on the CROWN trial, or most common side effect seen, rather, were hypercholesterolemia, hypertriglyceridemia, and edema. And only 5% of patients on the trial came off for adverse events related to the drug.
That the dose reduction of these drugs can and does effectively control the CNS toxicities and that the dose reduction is safe and the drug continues to be effective based on the CROWN data that was presented a couple of weeks ago. This brings us to the end of our second case. I'd encourage you to watch the other cases along with us to get some more information about the ALK-positive non–small cell cancer world.
