Frontline Systemic Therapy for ALK+ mNSCLC


Stephen Liu, MD: Initial therapy for this patient is really guided by the molecular profile. This profiling revealed an EML4-ALK fusion. Of note, it also showed very high—100%—PD-L1 expression. While PD-L1 expression predicts response to checkpoint inhibitors, such as pembrolizumab, atezolizumab, and nivolumab, remember that those studies excluded patients with an ALK fusion.

ALK-positive lung cancer is largely an immune nonresponsive tumor. While PD-L1 plays a predictive role for many tumors, it cannot be interpreted in the setting of an ALK fusion. While immunotherapy is an exciting modality of treatment, it really is an inappropriate treatment for patients with an ALK fusion. If given before the proper targeted therapy, it may increase the toxicity of subsequent TKI [tyrosine kinase inhibitor] therapy.

Sequence of treatment is appropriately done with molecular profiling. In this tumor with an EML4-ALK fusion, the preferred treatment is targeted therapy. For patients with brain metastases, brigatinib has performed particularly well. This is critical for ALK-positive lung cancer, which again has a very high tropism for CNS [central nervous system] metastases. Historically we had considered radiation therapy for patients with brain metastases, but we now know that radiation therapy, even focal SRS [stereotactic radiosurgery], has notable sequalae. And in a patient population where survival is measured in years, the toxicity with radiation is quite high.

I prefer systemic therapy with a CNS-penetrant tyrosine kinase inhibitor. The next-generation kinase inhibitors have excellent activity within the brain. I think brigatinib is an excellent choice for someone with brain involvement at the time of diagnosis.

Transcript edited for clarity.

Case: A 57-Year-Old Man with ALK+ NSCLC

Initial Presentation

  • A 57-year-old man presented with fatigue, anorexia and occasional rib pain
  • PMH: unremarkable
  • PE: mild right-sided chest tenderness on palpation

Clinical Workup

  • Labs: WNL
  • Imaging:
    • Chest x-ray showed 3 right upper lobe masses
    • Chest/abdomen/pelvic CT scan confirmed 3 masses (largest 7.3 cm)
    • PET scan showed activity in the right upper lobe masses
    • MRI of the brain showed widespread scatter small lesions; consistent with brain metastases
  • Bronchoscopy with transbronchial biopsy of the right upper lobe confirmed lung adenocarcinoma
  • Molecular testing: EML4-ALK fusion+, EGFR-, ROS1-, BRAF-, KRAS-, NTRK-, MET-, RET-, PD-L1 100%
  • Staging: IVA adenocarcinoma; ECOG PS 0


  • Patient was started on brigatinib 90 mg qDay for 7 days; well tolerated; dose was increased to 180 mg qDay
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