Ask AI
Back Back
ALK Positive Advanced NSCLC
Experts Discuss Optimal Treatment for ALK-Positive Advanced NSCLC

Released: July 28, 2025

Expiration: January 27, 2026

Todd M. Bauer
Todd M. Bauer, MD
Christine Bestvina
Christine Bestvina, MD
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • It is important to test for ALK rearrangements as part of broad-based testing with tumor tissue and/or ctDNA for actionable alterations in advanced NSCLC; immune checkpoint inhibitor therapy should not be considered until biomarker tests results are returned
  • For a patient progressing on adjuvant alectinib, it is important to consider resistance testing; lorlatinib may be considered in this setting

For patients with advanced ALK-positive non-small-cell lung cancer (NSCLC), targeted therapies have been associated with improved outcomes. In this commentary, expert faculty discuss some of the nuances of using ALK inhibitors to treat advanced ALK-positive NSCLC via questions asked at live CME events.

If circulating tumor (ct)DNA results show an ALK rearrangement for a patient with NSCLC, would you start an ALK inhibitor or wait for the results of tissue testing?

Todd M. Bauer, MD: To set the stage, ALK rearrangements are present in approximately 5% of advanced NSCLC cases and represent an important therapeutic target. Therefore, it is essential that ALK testing be performed for all patients with advanced NSCLC to ensure appropriate treatment options are considered. Many centers now rely on molecular-based next-generation sequencing (NGS) to evaluate tumor tissue for a broad range of actionable biomarkers that correspond with FDA-approved targeted therapies. A major challenge with NSCLC is that many patients present with advanced-stage disease and are often diagnosed using small biopsies, which limit the amount of tissue available for molecular testing. As such, we may also order ctDNA testing to assess actionable biomarkers.

To answer the question, in my mind, a positive liquid biopsy or positive ctDNA test is positive. If testing is negative, I will likely wait on the RNA-based tissue testing to confirm.

Christine Bestvina, MD: I agree. To have a false positive is very rare with ctDNA testing. I have proceeded with  ALK inhibitor treatment based on ctDNA testing results. Of course, it is always nice to confirm ctDNA results with tissue test results, but I would reemphasize that for a negative ctDNA test—meaning a test in which an actionable alteration was not found—I will wait on the results of tissue testing before treating, as ctDNA sensitivity can be limited.

Do you ever start a patient on treatment before biomarker test results are available?

Todd M. Bauer, MD: Prior to the return of biomarker test results, if a patient requires treatment immediately, I will consider chemotherapy with carboplatin and pemetrexed for cycle 1. When testing results return and there are no actionable biomarkers present, then I will add in an immune checkpoint inhibitor (ICI). Why do I not include an ICI before test results come back? In studies of patients with NSCLC with an EGFR alteration who were exposed to an ICI and then switched to an EGFR TKI, the risk of pneumonitis was increased. In addition, ICIs are less effective for ALK-positive disease, regardless of PD-L1 status.

Christine Bestvina, MD: I agree. Sometimes when PD-L1 testing shows very high expression, it can be tempting to start an ICI even if mutational testing is pending. I have had patients who ended up having a targetable alteration initially ask for chemotherapy or immunotherapy, so it certainly can be a long discussion with the patient about why we are holding off on treatment or why we are just giving chemotherapy alone for a cycle as we wait on those results.

Todd M. Bauer, MD: Of note, national guidelines currently list the following as preferred treatment options for first-line therapy for patients with advanced ALK-positive NSCLC: alectinib, brigatinib, ensartinib, and lorlatinib. For my patients with advanced ALK-positive NSCLC, I tend to use lorlatinib as a first-line agent based on data from the randomized phase III CROWN trial. In this trial, first-line lorlatinib significantly improved PFS vs crizotinib in patients with advanced ALK-positive NSCLC. There is also a matching adjusted indirect comparison suggesting lorlatinib is associated with improved PFS vs alectinib and brigatinib for this population.

With the ALK inhibitor alectinib now approved as adjuvant treatment for patients following tumor resection of ALK-positive NSCLC, if a patient progresses with this treatment, what would be the choice in the metastatic setting?

Christine Bestvina, MD: I have given adjuvant alectinib, although I have not yet had a patient progress during that time. If they did, my plan would be to get a biopsy at progression to determine the resistance profile and make decisions based on that. It is important to know that lorlatinib is approved in the post-alectinib setting and that most likely would be the default next line of therapy.

Todd M. Bauer, MD: I agree that lorlatinib is the default second-line agent if a patient has received alectinib in the past, and I think it is important to understand resistance and subsequent lorlatinib dosing. Why do people fail alectinib and brigatinib? Often, it is due to in-frame resistance mutations. The G1202R resistance mutation is the most difficult to overcome; however, lorlatinib has been shown to be effective against NSCLC with this mutation. Looking at lorlatinib dosing, in early trials 100 mg was selected as the recommended phase II dose because of increased on-target time against G1202R. In that resistant population, 100 mg is a better dose. In a front-line population without resistance, there is probably not a significant difference between 100 mg and 75 mg. However, I still start everybody at 100 mg.

What is your opinion regarding starting lorlatinib in patients experiencing minor cognitive troubles?

Christine Bestvina, MD: For background, the prescribing information for lorlatinib lists central nervous system (CNS) effects (including changes in cognitive function) in the warnings and precautions section. In the phase III CROWN trial of lorlatinib, cognitive effects were reported in 27% of patients, with most of these were grade 1 or 2. For a patient with minor cognitive troubles, I might consider starting lorlatinib at 75 mg as opposed to 100 mg in the treatment-naive setting. I would take the same approach for patients who have a history of psychiatric disorders or other concerning baseline CNS effects.

Todd M. Bauer, MD: I agree. I think for these patients, it is important to ask what their social support looks like. I live and practice in Nashville and I can drive 20 minutes away and be in a rural setting. If I have an 80-year-old patient whose closest family member is 30 minutes away, I am less optimistic that this patient will have someone who will be able determine that this patient is beginning to experience any CNS effects. So this is something to pay attention to.

Your Thoughts
Have you treated a patient with an ALK inhibitor? If so, what has been you experience? Were there any barriers to optimal treatment with this drug class? Please join the discussion by answering the polling question or leaving a comment.

Continue

Poll

1.

For which of the following topics regarding ALK-positive NSCLC would you most like additional education?

Submit