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Testing and Treatment for ALK+ NSCLC
Best Practices in Testing and Treatment for Advanced ALK-Positive NSCLC and Overcoming Challenges to Implementation in Clinical Practice

Released: April 21, 2025

Expiration: October 20, 2025

Todd M. Bauer
Todd M. Bauer, MD
Jessica J. Lin
Jessica J. Lin, MD
Alexander Craig Mackinnon, Jr.
Alexander Craig Mackinnon, Jr., MD, PhD, MSHA
Beth Sandy
Beth Sandy, MSN, CRNP, FAPO
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Key Takeaways
  • It is important to test for ALK rearrangements as part of broad-based testing for actionable alterations in advanced NSCLC; immune checkpoint inhibitor therapy should not be considered until biomarker tests results are returned
  • If a patient has advanced ALK-positive disease, recommended first-line ALK inhibitors include alectinib, brigatinib, ensartinib, and lorlatinib; each of these has unique AEs to monitor for and manage as needed during treatment

In this focused commentary, experts discuss contemporary testing and treatment for advanced ALK-positive NSCLC and reflect on real-world clinical needs in these areas.

Testing for ALK Rearrangements in Advanced NSCLC

Alexander Craig Mackinnon, Jr., MD, PhD, MSHA:
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.

Jessica J. Lin, MD:
We can detect ALK rearrangements using a number of different methods: immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), RT-PCR, or next-generation sequencing (NGS).

Alexander Craig Mackinnon, Jr., MD, PhD, MSHA:
Most laboratories now rely on molecular-based next-generation sequencing (NGS) to evaluate 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 a small biopsies, which limit the amount of tissue available for molecular testing.

The key is to maximize biomarker detection using minimal tissue. Broad-based NGS testing should include ALK rearrangements alongside other actionable biomarkers. Alternative methods for detecting ALK rearrangements, such fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), require skilled experts to interpret require considerable tissue that may be needed for NGS testing, making them less practical in settings with limited specimen. Molecular testing using tumor-derived DNA or RNA and an NGS-based sequencing library provides a reliable and sensitive approach to identify ALK gene rearrangements.

Ensuring that sufficient tissue is available for comprehensive testing is essential. Consider a patient with advanced-stage lung cancer and a limited biopsy specimen. If multiple high-demand tests, such as whole exome sequencing, whole transcriptome analysis, IHC, and FISH, are performed simultaneously, the risk of encountering quantity not sufficient (QNS) results increases substantially. This presents a clinical dilemma, as retesting is not possible without obtaining an additional biopsy, which may not be feasible or safe for every patient. 

As a molecular pathologist, my team evaluates each case prior to testing to determine whether to send out the specimen for a broad, comprehensive panel or to test in-house using a smaller, targeted panel. When tissue is limited, we often pivot to the smaller, targeted panel and proactively communicate with our oncology colleagues. An practical advantage of the smaller panel is the faster turnaround time, with results typically available within 3 to 4 days.

Jessica J. Lin, MD:
Having limited tissue available for testing is an issue that we often run into. At my institution, we are always careful about communicating with proceduralists to emphasize trying to get enough tumor tissue for all the molecular testing that we need to do. Often, because of, for example, necrosis in the tumor or the location or the challenging aspects of biopsy, it may not be possible to secure enough tissue.

In that case, it is always hard to ask the patient who is dealing with all the stresses of a new diagnoses of cancer to then say we need another biopsy. We often do then pursue liquid biopsies to see if that yields the results that we need. Sometimes this approach ends up obviating the need for a repeat biopsy. Sometimes it does not. If liquid biopsy is nondiagnostic because, for example, patients had low tumor DNA shedding into plasma, then we need to actually discuss considering repeating the tumor biopsy. At our institution, we actually do both tissue and liquid biopsy from the beginning in order to expedite the process of biomarker testing.

Beth Sandy, MSN, CRNP, FAPO:
The one thing that I think is specific to ALK rearrangement testing is that RNA-based NGS is important, because ALK is a fusion gene. There are data that show that with DNA-based sequencing alone, actionable fusions, such as those that can occur with ALK, ROS1, RET, and NTRK, may not be detected as reliably. If you reflex negative DNA testing with RNA fusion testing, you will often detect more of these fusions.

Jessica J. Lin, MD:
We know that RNA-based NGS is better overall for fusion detection compared with DNA-based NGS. In an ideal scenario, if DNA-based NGS is the only one that is done and it is negative, especially among patients with a minimal smoking history, I would definitely encourage RNA-based NGS if there is enough nucleic acid or tissue left over to allow that testing. I think the first step is assess actionable biomarkers with NGS in all patients; RNA vs DNA-based NGS can then be considered.

Todd M. Bauer, MD:
I think that most patients with metastatic lung cancer are now getting tested at the time of diagnosis with solid tissue and/or liquid-based biopsies. Results really do inform first-line treatment. Most HCPs appropriately should not use any immunotherapy in patients until we know that they do not have an alteration, to prevent the risk of pneumonitis that was noted in patients with EGFR alterations.

Jessica J. Lin, MD:
In the real-world setting, there are different kinetics to the return of biomarker testing results, such that frequently we see the PD-L1 test result come back faster, because that is simple immunohistochemistry, while it can take several days or weeks for NGS results to come back. However, you will have your patient in front of you, and that patient may be stressed physically and emotionally because of their new diagnosis. You may get the PD-L1 test result back saying that there is high PD-L1 expression. I see some of these patients in the community getting started on immunotherapy upfront or chemotherapy plus immunotherapy when the NGS results are not back yet, especially when they have a heavy burden of symptomatic disease.

This is a risky approach, because if ALK testing subsequently comes back positive and patients need to switch to an ALK inhibitor, you can see augmentation in toxicities when patients have had prior exposure to anti-PD-1 or PD-L1 immune checkpoint inhibitors. It is important for clinicians to wait for the NGS results to come back. If you need to start treatment clinically because of symptoms before NGS results reutrn, I favor holding the immunotherapy and proceeding first with chemotherapy alone.

Optimal Treatment for Advanced ALK-Positive NSCLC

Todd M. Bauer, MD:
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.

Beth Sandy, MSN, CRNP, FAPO:
At my institution, we recommended first-line alectinib for many years, but I feel  the best data is now with lorlatinib; we have switched over to using this agent as our frontline therapy now for the majority of patients with ALK positive NSCLC.  

Jessica J. Lin, MD:
In terms of the ALK inhibitor selection, since the presentation of the 5-year update of CROWN data at ASCO 2024, I have seen an increase in the uptake of lorlatinib in the academic and community settings. I would say that certainly in the community, many clinicians used to previously start therapy with a second-generation ALK inhibitor like alectinib or brigatinib. Part of that may be due to familiarity with the agent. I think educating the oncology community about what data are available for each next-generation ALK inhibitor in terms of efficacy and safety is critical.

Second-line therapy is very much individualized. I would say if lorlatinib is used first-line, we really need to understand better what the resistance landscape is to understand if we can use another ALK inhibitor. In my mind, the standard treatment after first-line lorlatinib therapy remains chemotherapy at this time; we will benefit from seeing more follow-up data from the CROWN trial.

Identifying and Managing AEs Associated With ALK Inhibitors

Jessica J. Lin, MD:
With each of the approved ALK inhibitors, there are unique specific AEs that I counsel patients about. With alectinib, for example, it is important to be aware of side effects including, but not limited to, fatigue, anemia (including hemolytic anemia, which is not common but can happen), and weight gain. With brigatinib, being aware of a unique toxicity like early onset pulmonary toxicity is important. 
The safety profile of lorlatinib is distinct from other ALK inhibitors. Hyperlipidemia, cognitive/CNS effects, and weight gain are 3 AEs that can occur with this agent.  

Beth Sandy, MSN, CRNP, FAPO:
With lorlatinib, management of hyperlipidemia is important. It is important to educate patients that when they come in for their lab work on lorlatinib, they have to be fasting for 12 hours because they will need a lipid panel. When I first started using lorlatinib, I was too conservative with my dosing of rosuvastatin. In some patients, cholesterol and triglyceride levels can be elevated and may not respond to 5 mg of rosuvastatin, which is where I was starting. I have generally started at 10 mg when needed, although you could argue to start at 20 mg. There is also a discussion in the field regarding starting rosuvastatin the day you start lorlatinib vs starting when cholesterol levels increase; I have been more reactive in my use of this agent and will check cholesterol levels at 2 weeks.

Jessica J. Lin, MD:
Cognitive and mood changes can also occur. Cognitive changes can include forgetfulness, difficulty multi-tasking or concentrating, or speech changes, and mood changes can include irritability, depression, and euphoria.

Todd M. Bauer, MD:
Regarding dosing, I tend to start nearly all patients at the recommended lorlatinib starting dose of 100 milligrams daily, but I have a low threshold to reduce that dose for side effects such as depression, confusion, weight gain, or neuropathy. The 75 milligram dose of lorlatinib is likely almost as effective as the 100 milligram dose in most patients who do not have the G1202R resistance mutation.

I think additional education regarding the toxicity of lorlatinib is important. For reference, lorlatinib was in phase I studies when alectinib was in phase III studies. There were patients in these clinical trials who ended up on lorlatinib after 3 or 4 prior therapies, and some of the side effects that we saw early on were more of a testament to that than the true toxicity of the drug. Educational events to talk ALK inhibitor efficacy and safety, including common AEs and management, are a good way to improve the overall field.

Jessica J. Lin, MD:
Referring to the package insert regarding dose reduction—and putting this in the context of how bothersome the side effects are to the patient in front of you—is important. There should be a low threshold to dose reduce if patients are experiencing intolerable side effects that are bothersome to them and affecting day-to-day functioning. I think counseling patients and caregivers that most do need dose reduction of lorlatinib is important, so that when patients do need dose reduction, they are not too scared to do so. Clinicians should counsel patients that dose reduction may very well happen and that it is the best way to try to strike the right balance between efficacy and tolerability to maximize the chances of keeping patients on an effective therapy for as long as possible.

Your Thoughts
Do you test all of your patients with advanced NSCLC for ALK rearrangements? How do you approach the use of ALK inhibitors in your practice today? Answer the polling question and join the conversation by leaving a comment. 

Want to know more? Join Todd M. Bauer, MD, and Christine Bestvina, MD, for a live webinar on Wednesday, May 7 as they discuss of contemporary treatment of advanced ALK-positive NSCLC, as well as answer your questions.

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In your current practice, which of the following ALK inhibitors do you use most frequently as first-line therapy for advanced ALK-positive NSCLC? 

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