Sequencing and Management Considerations for ALK TKIs in NSCLC

Chul Kim, MD

Associate Professor

Georgetown University School of Medicine

Washington, DC

DISCUSSION QUESTIONS

• What is your experience using brigatinib (Alunbrig) in patients with ALK-positive non–small cell lung cancer (NSCLC)?

Chul Kim, MD: Has anyone used brigatinib in your practice as first-line or second-line therapy? What have you seen in terms of efficacy and safety for these patients? I have patients who are on brigatinib now for several years and doing pretty well. I didn't see the pulmonary events in those 2 patients, but I wonder if anyone else used or has experience with brigatinib?

Yanyan Lou, MD: I have some patients who in the beginning I was treating with alectinib [Alecensa], but later on experienced progression prior to the lorlatinib [Lorbrena] data. They started on brigatinib. The patients tolerated it well, but did have hypertension, so we had to start on some hypertension medicines to manage and also had some dose reduction, but overall, the patient is doing well for the last few years.

DISCUSSION QUESTION

• What are your insights and perspectives of the ALEX trial (NCT02075840) of alectinib?
• How do you monitor patients for myalgia and edema?

Kim: A lot of us have used alectinib in clinical practice. What is your interpretation of the outcomes that you see in the ALEX clinical trial? Does it sound like good treatment?

Richa Dawar, MD: For alectinib, I've had a very good experience in patients with ALK-positive stage IV disease, and it is very well tolerated drug. I have been using alectinib before the approval of lorlatinib for first line. Many of my patients have been on alectinib for [a long time] with stable disease. If I have patients with ALK-positive stage IV disease, I usually start them on alectinib. That's my drug of choice; they can tolerate it [well].

If patients have brain metastases, then I would do lorlatinib in those cases. I also look at how much disease burden these patients have. If I feel that patients won't be able to tolerate lorlatinib, then alectinib becomes my treatment of choice, but I have been using alectinib, and then if the patient is on alectinib, then I reserve lorlatinib for second line.

Kim: Thanks for sharing your experience and insights. Myalgia is one of the most common adverse events [AEs] of alectinib and then edema, etc, and laboratory abnormalities like anemia, creatine elevation, and things like that [are also common]. Has anyone had patients who had severe myalgia or some of the hematological AEs?

Dawar: I had a patient who [did not show] myalgia, but he was complaining of severe fatigue. He did have anemia. His hemoglobin dropped to 9 g/dL so I was concerned about the anemia. I was attributing his fatigue to anemia. I had discussed with him about the AE of myalgia. It can happen. He had creatine phosphokinase [CK] level tested by his primary care physician, and it was very high, in the 500s. I don't check CK levels unless I see a clinical presentation of myalgia in such patients. I did hold the drug for some time until his CK resolved. His fatigue was from anemia, and he had no symptoms. He had no muscle pain or tenderness. His creatinine was OK, but that that's something I have seen. Do you check CK level at frequent intervals with these patients?

Kim: I check once in a while, probably not every time. Sometimes I see them every 3 to 4 months, or sometimes every 6 months, depending on how they are doing. I think about checking. I always ask about myalgia. [I ask,] “Do you have any pain in the muscles?”

Norland Ng, MD: I have pretty good experience with alectinib. In patients I checked, the CK levels also slightly elevated. Patients are asymptomatic, and I just keep as is. I have 1 patient who developed hemolytic anemia, but the anemia is mild. I did some dose adjustments, and they are able to stay on the therapy.

Kim: I agree that dose interruption and then reduction, if necessary, is quite effective for further AEs.

DISCUSSION QUESTION

• What are your impressions of the efficacy data for lorlatinib?
• What is your management approach for the lipid abnormalities associated with lorlatinib?

Kim: Do you use lorlatinib as first-line therapy at this point, or would you still prefer second-generation inhibitor therapy, such as alectinib or brigatinib in your in your practice? Have the 5-year progression-free survival data changed your practice at all?

Nuruddin Jooma, MD: I recently tried starting a patient on the third-generation [tyrosine kinase inhibitor (TKI)], but the insurance denied it. She presented with brain metastases [but] she had to try alectinib first and [not benefit] or not tolerate it before they would approve the third-generation TKI. But my previous experience with that drug has been great, [with] excellent intracranial control of disease.

Kim: [For] the lipid abnormalities, we check cholesterol, triglyceride levels, and then prescribe a statin. There are certain drug-drug interactions. You have to pick the right statin to use with lorlatinib. Weight gain and cognitive effects are usually dealt with dose reduction and interruption. There were some data presented in terms of supportive care for these AEs with the lorlatinib during the 2024 World Conference on Lung Cancer that I thought was helpful.¹

Ng: I used lorlatinib and saw an increase in cholesterol. Do you start them preemptively on some sort of cholesterol medication if they're not on it? If they're already on cholesterol medication, do you increase the dose?

Kim: I don't prescribe statin as a prophylactic approach. I check their cholesterol, and some people don't like to take a lot of medicines, which is understandable, and then they like to try lifestyle modification, diet, exercise, and I let that happen. But if that doesn't control the cholesterol then I start prescribing statin. That's been my practice. I don't know if anyone prescribes statin when you start lorlatinib from the beginning, or if you watch and then depending on the levels you can act on it.

Jennifer Wu, MD: What statin do you prefer for when patients experience hypercholesterolemia?

Kim: I think about using rosuvastatin [Crestor] or pitavastatin [Livalo]. I don't think atorvastatin [Lipitor] is a good choice because of the CYP3A pathway interaction.²

_References:

_{1. Watson AS, Taormina JM, Yoder B, et al. Characterizing the severity and timing of real-world ALK-inhibitor associated weight gain in non-small cell lung cancer. J Thorac Oncol. 2024;19(suppl 10):S643-644. doi:10.1016/j.jtho.2024.09.1213}

_{2. Lorbrena. Prescribing information. Pfizer, 2023. Accessed December 10, 2024. https://labeling.pfizer.com/ShowLabeling.aspx?id=11140}