CNS Activity of Third-Generation ALK TKIs Influence Approach in NSCLC


During a Case-Based Roundtable® event, Yasir Y. Elamin, MD, discussed with participants how they select treatment for a patient with ALK+ non–small cell lung cancer and brain metastases in the first article of a 2-part series.


Yasir Y. Elamin, MD (Moderator)

Assistant Professor, Department of Thoracic/Head and Neck Medical Oncology

Division of Cancer Medicine

The University of Texas MD Anderson Cancer Center

Houston, TX


A 53-year-old Asian American woman presents to her primary care physician with complaints of a persistent, productive cough mixed with scant amounts of blood and associated with chest discomfort upon deep inspiration. ​She denied fever, night sweats, headache, or recent upper respiratory infection. ​She is a never smoker with no family history of malignancy.

Chest X-ray showed right, upper lobe opacity and mediastinal enlargement. She was referred to a thoracic oncologist for further evaluation. CT of chest, abdomen, and pelvis revealed multiple peripheral nodules in the right upper lobe, the largest measuring 3.7 cm ´ 3.4 cm in diameter with ipsilateral mediastinal lymphadenopathy of varying nodal size between 2.2 cm and 2.8 cm. There was no evidence of hepatic involvement.

Contrast-enhanced staging MRI of the brain demonstrated discreet intracranial lesions in the parietal (2.6 cm) and frontal (1.2 cm) lobes. Her disease staging was T2aN2M1b (metastatic). She underwent endobronchial ultrasound-guided transbronchial needle aspiration and endoscopic ultrasound-guided fine needle aspiration of the lungs and mediastinal lymph nodes. The disease’s histopathology included tumor cell clusters with high nucleus to cytoplasmic ratio; pleomorphic nuclei and granular chromatin; acinar structure with signet-ring cell morphology consistent with adenocarcinoma; and short axis diameter of mediastinal node specimen of 2.1 cm. Immunohistochemistry showed the disease was TTF-1+, Napsin A+; CEA+; PD-L1 tumor proportion score = 27%

Tissue next-generation sequencing revealed an (EML4)-ALK fusion​; the remainder of the broad-based panel was negative.


  • In this case of non–small cell lung cancer (NSCLC), what would you select as first-line therapy?​
  • Would the absence of baseline central nervous system (CNS) metastases influence your treatment choice?​

YASIR ELAMIN, MD: This patient has ALK-positive lung cancer with 2 brain metastases. Assuming that we may do stereotactic radiosurgery or Gamma Knife [radiation] to the brain, what ALK inhibitor would you have chosen?

CHIRAG JANI, MD: I have good luck with alectinib [Alecensa]. In our 3 patients right now, it's very well tolerated. There are some data of it preventing CNS metastases with that phase 3 trial.1 So I think the third-generation ALK [TKI; tyrosine kinase inhibitor] would be my preference.

ELAMIN: You don't differentiate if a patient has brain metastases or no brain metastasis? You're comfortable enough with using alectinib for both indications, which most of us do?

JANI: Yes.

VENU MADHAV KONALA, MD: I would use alectinib as well in this situation. When I moved here 2 years ago, I saw a patient who was already treated with lorlatinib [Lorbrena]. I struggled to find what [to give] next after the patient’s disease progressed. I referred the patient for clinical trials with fourth-generation [TKIs] if we could find them, but eventually I had to treat the patient with chemotherapy. So I think the best thing is alectinib, and we have other options if the patient's disease did not respond to alectinib.

ELAMIN: Exactly. We have 3 drugs approved by the FDA. Lorlatinib, brigatinib [Alunbrig], and alectinib.


  • Do the intracranial responses to brigatinib in patients with ALK-positive metastatic NSCLC with baseline brain metastases resonate with your own clinical experience?​

ELAMIN: Considering the data, do the intracranial responses to brigatinib in ALK-positive lung cancer with or without baseline metastases influence your decision when it comes to selecting which ALK inhibitor to use?

ALEJANDRO CALVO, MD: I think the newer-generation TKIs have better CNS penetration, so they make a big difference. This is applicable even for the EGFR-positive population. I've had a couple of patients on crizotinib [Xalkori] who were doing so well, and they were so comfortable that when the newer-generation drugs appeared, they were reluctant to change. I [now] use alectinib, but I don't have experience with brigatinib.

ELAMIN: Do you have experience with lorlatinib? It has CNS activity, [so] it seems that lorlatinib may have an edge there.

CALVO: Yes, I have. I have a couple of my patients who had CNS progression who I recently transitioned to lorlatinib. Interestingly, in one of them, I did molecular testing because they had resection of lung and brain lesions, and they had a MET exon 14 [skipping mutation]. I'm still trying to figure out what to do for her, but this is short term. I haven't seen any major issues with toxicity that caught my eye.

DAVID KAHN, MD: Maybe I'm just lucky, but I don't see too many patients who have ALK positive intracranial disease. The data are impressive. I've only [treated these patients] twice. One was [treated with] crizotinib back when that was the only [option]. They did OK with it. I’ve used brigatinib once, but I don't know how the patient did because they moved out of state afterwards.

Gadgeel S, Peters S, Mok T, et al. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol. 2018;29(11):2214-2222. doi:10.1093/annonc/mdy405
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