Frontline ALK TKIs in Patients With NSCLC: Treatment Selection and AE Management


Following their review of clinical trial data behind frontline ALK TKIs in NSCLC, key opinion leaders share practical insight on selection and use of these agents.


Stephen Liu, MD: Ross, not to put you on the spot, what are you using in the frontline setting?

Ross Camidge, MD, PhD: Alectinib. The reason is it’s well-tolerated, similarity to brigatinib. Brigatinib has some efficacy post alectinib. But I’m actually molecular profiling the patients and it’s kind of using brigatinib as essentially a lorlatinib delaying tactic for those with on-target resistance.

Stephen Liu, MD: Jyoti, you as well?

Jyoti Patel, MD: I would say some brigatinib, primarily alectinib. Brigatinib, particularly for younger patients who are worried about compliance or if I’m worried about compliance. Once-a-day dosing might be a little bit easier.

Stephen Liu, MD: It is something to keep in mind. I don’t want to brush it under the rug. I was given a course of antibiotics for a week and I think it lasted a month. I just can’t remember. It was just there it would never go away. Jillian, lorlatinib in the frontline setting or alectinib and brigatinib?

Jillian E. Thompson, NP: From what I can recall from our practice, I see alectinib early or first line.

Stephen Liu, MD: Now, in this case, as we mentioned alectinib and brigatinib are both fairly interchangeable. Brigatinib was started. We did see that 90 mg for a week and then escalated to 180 mg a week to really reduce the risk of the early onset pulmonary events. [The patient] was instructed to avoid grapefruits as they may affect levels. How are you talking to patients about side effects? We touched a little about this, but with brigatinib, Jillian, what are you counseling patients with regard to toxicity?

Jillian E. Thompson, NP: I always start with the most common side effects that we see like fatigue, but I also stress any sudden changes. But typically with our patients we’re going to see them back in clinic after 2 weeks of starting so that we can evaluate, ask specific questions, do blood work because we see elevation of LFTs [liver function tests]. Really encouraging follow up and asking those questions, making sure if there’s something that comes up new to report those things and not necessarily having to wait until that next clinic appointment. We have some [patients] that are much better at doing that than others.

Stephen Liu, MD: Ross, any tips on talking about these TKIs [tyrosine kinase inhibitors] to patients?

Ross Camidge, MD, PhD: No. It’s funny that when they had these first early onset pulmonary events there are all sorts of pieces of advice like you should phone the patient and see if they’re short of breath. But it’s not subtle if you get it. If you’re in the 5% that’s symptomatic then you just tell the patient that if you feel that bad go to the emergency room. If we can, we’ll support you through it, keep the drug going, and it’ll go away in a few days’ time. So I think people got all bent out of shape about it. But I think the key thing is to tell people what to look out for, as Jillian said. Also say, look if anything else weird is going on just [call].

Stephen Liu, MD: Making yourself available for these types of side effects. Let’s shift it from brigatinib to lorlatinib. Jyoti, if there was a case for every reason we’re starting lorlatinib in the frontline setting, how do you counsel the patient to keep an eye out for those important side effects?

Jyoti Patel, MD: I think, again, education is important so we’ll usually see them similarly to I think all of your practices for a toxicity check-in in a couple of weeks. Often the lipids will be up by then anyway so you’re starting another drug or a statin. In terms of the cognitive effects, again explain to family members what to look out for. For a lot of our patients we encourage them to keep symptom diaries. Those can be really helpful for reporting against some of these subtle changes. Then perhaps doing a lower dose and then increasing if patients tolerate it. So it’s close communication, a lot of us get MyChart’s and to keep those messages going, but that sort of closed loop conversation is important.

Stephen Liu, MD: They are. All 3 of you have a lot of experience using these ALK kinase inhibitors. We see dramatic improvements. Do you think maybe you could share, without any use of names obviously, any experiences of treating patients with these ALK TKIs? Ross, you have any interesting experiences you want to share?

Ross Camidge, MD, PhD: I remember 1 person in particular who was on crizotinib, was doing really well, and then had sort of a catastrophic brain metastases. The midline shift was essentially hemiparetic. That was the case that I told you where we had to convince the surgeons not to operate on her. We put her on alectinib and she went from literally not being able to walk across the room to running marathons. She is now 10 years on alectinib and doing great.

Stephen Liu, MD: Ten years that is quite inspiring. The ceiling is quite high with these drugs. Jyoti, your experiences using ALK inhibitors?

Jyoti Patel, MD: Very similarly these patients can be profoundly symptomatic. A young woman with tamponade bilateral effusions could barely come in and we started her on brigatinib because we were worried about compliance and GI [gastrointestinal] issues. Here she is 6 years later and NED [no evidence of disease] and fully functional. So it’s really gratifying as well. I think existentially for many of these patients who have a great response, there’s a whole different set of survivorship issues that we’re learning to grapple with and how to follow these patients or starting to think about consolidation or intensification. But that is an area I think that we’ll probably see a lot of research in and hopefully shared decision-making in these next years.

Stephen Liu, MD: Yes, andI think led by all of you. Jillian, any of your experiences you’d like to share?

Jillian E. Thompson, NP: I think again I will go back to their patient shared earlier about having the cognitive changes. Simply being able to reduce the dose and being able to continue with a very efficacious drug and being able to tolerate it. Considering the fact that we want these patients to be able to be on these medications for years to come but making sure that it is tolerable to do so. So I think that’s a very significant piece of how we’re managing and treating these patients.

Stephen Liu, MD: Definitely an important part of management here. I can remember one of the earlier cases of alectinib use, I think ALEX had just been reported and as is often the case, you see an ALK sort of the next day. We were trying to get alectinib because it wasn’t approved yet in the frontline settings. We really had to fight for it. I wasn’t sure we’d get it, but we did get it and right away his LFTs went from 0 to like a million. They went straight up through the roof. We held the drug, they came back down, we checked for hepatitis and all these things but of course it wasn’t that. We restarted at a dose reduction to 450 mg twice a day and he’s been on that for like 6 or 7 years. So don’t be afraid to drop the dose if we need to. It doesn’t mean it’s the wrong drug, it’s just the wrong dose and we can really see long durable effects.

We do need to improve care. We think of this particular case as a patient who started brigatinib with a frontline setting. In the brain, the enlarged lymph nodes that disappeared, after 3 months the lung lesions nearly gone, no neurologic visual, no functional deficits, tolerating treatment for about 6 months, but then the headaches increased. I’ve noticed some headaches may be associated with high blood pressure. It’s not clear. We dose reduced here to 120 mg, important to remember rather the dose come in 30 mg as well, that reduce frequency. And so this is another case where dose reduction led to prolonged treatment success story. We have many in ALK. It really has been a success story. It wasn’t the first target that we have success in for lung cancer but I think arguably we have the best outcomes here and [there is] a lot of exciting work being done.

Transcript edited for clarity.

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