Selecting the Appropriate Treatment in ALK+ NSCLC

EP: 1.Overview of ALK+ NSCLC

EP: 2.Testing for the ALK Rearrangements

EP: 3.Mechanism of Action of ALK-targeting Therapies in NSCLC

EP: 4.Efficacy and Safety of Frontline Treatment Options for ALK+ NSCLC

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EP: 5.Selecting the Appropriate Treatment in ALK+ NSCLC

EP: 6.Treatment Options for Patients with ALK+ NSCLC who Progress on First-line TKIs

EP: 7.Brain Metastasis in ALK+ NSCLC

EP: 8.Unmet Needs and Future Directions

Jyoti Patel, MD: How do you pick one of these? We get to see a fair number of patients with ALK, [rearrangements] we have really enriched populations. But for many people who may be seeing 1 or 2 patients a year, how does this play out? On a very practical level, the world is changing quickly, and if you have something good, it’s hard to change because you’re keeping up with so many new drugs. I would say that for most of the patients that I see, who either generally have no CNS [central nervous system] metastasis or maybe very low burden, like a single CNS metastasis, I start those patients on alectinib. Overall, it’s well tolerated. Although it’s a lot of pills a day at the starting dose, 8 pills a day, I have many patients that come down on their dose. I also have patients historically, before lorlatinib, that we were able to bump the dose on with CNS disease. There’s some personalization there of dosing, which is nice. Certainly, this PFS [progression free survival] benefit is great in J-ALEX. There wasn’t an OS [overall survival] benefit, whether you get it afterwards, but again you want the best quality of life for as long as you can.

I do use a fair bit of brigatinib and I was lucky I got to participate in the phase 1 study. I’m comfortable with brigatinib. To me, the nice upsides for brigatinib are the low incidence of severe toxicities usually happen soon, I know if it’s going to be the pulmonary event or the hypertension. But it’s well tolerated over years, months. I would say one piece I definitely keep in mind is if I have a younger patient or a patient who might have issues with compliance, once a day is nice. This is where patient-centered care is important. For some people, it’s just overwhelming to think about, okay, I’m taking 8 tablets a day for as long as I can, which is essentially the message we give, that we’re going to stay on this until it stops working. For some patients who may have sensitivity with pills, or I worry about getting all of the medication in, certainly I think brigatinib is a superior choice. In the absence of a clinical trial comparing both drugs in terms of efficacy and CNS disease, it’s really hard. We can opine on it a lot. Certainly, brigatinib has nice CNS penetration and good response, but there’s too much of a difference.

Lorlatinib in the frontline setting to me would be someone with a fair burden of CNS disease. We’ve all, unfortunately, met patients who present with leptomeningeal disease or numerous brain metastases, and at least in my practice that’s who I would reserve it for. What’s your take on it?

Karen Reckamp, MD: I would agree with most of what you’ve said. Alectinib clearly has the longest follow-up, it’s an easy one to go to. I have also been using brigatinib more frequently and find it very tolerable. Both alectinib and brigatinib, in my mind, are the most tolerable choices we have and they are both excellent drugs with long progression-free time and excellent CNS penetration. Patients do well on these drugs.

Lorlatinib, again the toxicity profile, almost everybody starts to develop high triglycerides and hyperlipidemia. Then the CNS and mood effects that some patients have from this, as this also gets our neurotrophin tyrosine kinases, that can be challenging for patients. I would agree that those patients with a high CNS burden up front and symptomatic CNS disease up front, that those would be the best patients to have lorlatinib up front.

Jyoti Patel, MD: In terms of toxicity for these patients, there are some unique toxicities certainly with lorlatinib, right, like learning my statins, but there’s also been patients with arthralgias that we’ve had to manage, that are significant. The CNS toxicity for some people is troubling. It can be minor, maybe a little bit shorter fuse, maybe some troubles concentrating, but some patients, unfortunately, can have really deep personality changes, can have hallucinations. You need to, when you’re advising a patient about this, get their family buy in because sometimes they don’t even know it’s happening. But just really do a lot of prep work about what this could look like.

Karen Reckamp, MD: I agree. And the weight gain, which is also a CNS-centric toxicity, is real. I had one patient who gained 20 pounds in a week. Dose reduction did help it, but it was a profound weight gain that we see.

Jyoti Patel, MD: There’s some weird endocrine stuff, too. Certainly, crizotinib we don’t use so often anymore, but people can have low testosterone. The weight gain with alectinib, we see it, and with brigatinib, where it is like full body edema, it’s insidious. Again, if you’re seeing patients over years, which is great, but you need to take into account even the minor toxicities, the grade 1 and 2 toxicities.

Karen Reckamp, MD: Right, I agree. The low testosterone is important. It hadn’t been tested as thoroughly as the reports from crizotinib, but likely we are going to see it with the next generation ALK inhibitors, too. Considering that for people who have low energy or otherwise unexplained adverse effects when they’ve been on the drug over time.

That’s great. This has been extremely informative. Thank you, Dr Patel, for your insightful discussion, and thank you to our audience for watching this Targeted Oncology™ presentation on “ALK Gene Rearrangement as a Therapeutic Target in Non–Small Cell Lung Cancer.” We hope you’ve found this discussion to be useful and informative. Thank you.