Benjamin Levy, MD: That’s interesting. I’ve seen brigatinib used post-alectinib, and it doesn’t look bad. It hasn’t been out there as much as lorlatinib. Becca, what are your thoughts on optimal frontline drugs? I agree with Lyuda. We have alectinib and brigatinib. There may be some differences in the CNS [central nervous system], in toxicity, and in terms of how many pills to take a day. What are your thoughts? What you do at the time of progression?

Rebecca Heist, MD: For my first-line patients, I am an alectinib person. It is such a well-tolerated drug in terms of toxicity, and with those updated survival data, it’s very compelling. Alectinib has great CNS penetration, and given how well tolerated it is, it’s hard for me to switch from that to anything else. One of my issues, and the reason why I didn’t switch to brigatinib, is very funny—rare, but I don’t want to have to deal with it—toxicity. Some people can get an ILD [interstitial lung disease] or dyspnea-type event early on. That can be managed with the new dosing guidelines. That was much better, but it’s 1 of those situations where you’re starting a patient and don’t want to have to deal with a toxicity of respiratory issues, because we’re starting a new lung cancer patient when I have an agent with which I don’t see that. Alectinib has remained my first-line choice.

In the second-line setting, lorlatinib definitely has activity after alectinib. That tends to be what I go to. I will rebiopsy patients as much as is feasible. There have been bypass mechanisms of resistance seen, and that’s important to know about. In those situations, you would want to target those bypass mechanisms as well, and use clinical trials as much as possible.

Benjamin Levy, MD: Josh, what are your thoughts on optimal frontline approaches and sequencing strategies for ALK-rearranged lung cancer?

Joshua Bauml, MD: It’s interesting. My experience in using alectinib has not been completely rosy. I will say that the rate of LFT [liver function test] abnormalities—I’ve seen it pretty frequently. I’ll look at the patient individually. I would say that alectinib is the most common drug I give in this space. But if I had a patient who had some liver issues or concerns about pills, it’s 8 pills a day, as opposed to 1 pill a day. That’s a big difference. These are variables that might affect my decision-making, but at the end of the day, I end up giving alectinib most often. As Lyuda said very eloquently, I don’t have a reason to overcome that inertia and change for the vast majority of my patients.

In the second line, I tend to repeat testing to evaluate what molecular targets may be appropriate for targeted therapy. I end up using lorlatinib more often. My concern moving forward, having seen the data on brigatinib in the second line, is that lorlatinib is not well tolerated. Having brigatinib as an option there is very nice. For my next patient who is progressing on alectinib, I may be more likely to use brigatinib.

Benjamin Levy, MD: What are some of the issues you’re running into with lorlatinib toxicity that would change your practice? What is it specifically about lorlatinib that’s a challenge for you?

Joshua Bauml, MD: Lorlatinib causes hypercholesterolemia. That is not as big of an issue. The larger issue is the CNS effect and the mental slowing. There are case reports of people having real psychiatric problems on the medicine, so my patients are a bit resistant to receive the drug. In regard to the toxicity with brigatinib and those pulmonary events that Becca was commenting on, Lyuda wrote a fantastic paper on how to manage those and her experience in that space. I’d love to hear you talk about it. I think it’s 1 of the most important papers in this space.

Benjamin Levy, MD: Lyuda?

Lyudmila Bazhenova, MD: Thank you, Josh. The pulmonary toxicity with brigatinib is real, but if you have experience with it, you start realizing that it seems scarier than it actually is. It is not pulmonary toxicity that makes me worry about brigatinib. It’s just, as Josh pointed out, inertia. I have a drug that I’m already using. Why do I want to change? The pulmonary toxicity or early onset pulmonary events usually happen on day 2 of brigatinib. They’re well managed, and that is the reason why brigatinib has 90 mg followed by a 180-mg dosing cohort. The incidence is dose related. The purpose of the paper was to show that you can actually treat through that without having to interrupt the drug if your toxicity is mild. The 1 point I also want to make, to feed off what Josh said, is that brigatinib is a welcome addition for our patients without fusions. Before, if I was giving alectinib and the patient had a liver toxicity or a horrible allergy, which sometimes happens, I tended to hold off, dose reduce, then start. Now I just move on and go to brigatinib if a patient has severe liver toxicity, without playing with the dose.

Transcript Edited for Clarity