The Future of ALK+ Non–Small Cell Lung Cancer


Lyudmila Bazhenova, MD: The ALTA-1L trial had built-in health-related quality-of-life end points. Brigatinib showed an increase in median time to worsening quality-of-life scores of almost 27 months, versus 8 months with crizotinib. Also, patients who were randomized to brigatinib had a longer duration of improvement in quality of life, which is expected because the durability of response on the brigatinib arm was much better than the durability of the response on the crizotinib arm.

My personal experience is very consistent with what the quality-of-life metrics show in the study. In patients who have ALK-fusion non–small cell lung cancer, once you start them on ALK TKIs [tyrosine kinase inhibitors], you’ll usually see improvements in cancer-related symptoms within 2 to 3 weeks. That’s what was shown in brigatinib. The median improvement in cancer-related symptoms was higher in the brigatinib arm compared with the crizotinib arm, again consistent with the fact that brigatinib may have deeper responses than crizotinib.

ALK-mutant non–small cell lung cancer, in my opinion, is a poster child for drug development in oncogenic driven tumors. In a very short time from the discovery of ALK fusions, we now have 5 ALK tyrosine kinase inhibitors approved. Even though those medications are actually quite effective and responses are durable, we still can improve on those in the first line. There have been some thoughts on maybe testing the combination of tyrosine kinase inhibitors and chemotherapy to see if adding chemotherapy to tyrosine kinase inhibitors will improve outcomes.

What still is unsettled in patients with stage IV non–small cell lung cancer who have ALK fusions is how to correctly sequence agents. For example, if you give the patient alectinib as a first-line therapy, what should your second-line choice be? Should you go to lorlatinib, which has data, or should you try brigatinib first and then go to lorlatinib later?

I do want to put in a plug for something that’s called the Lung Cancer Master Protocol. There is an NCI [National Cancer Institute] effort going on right now trying to learn what the correct sequencing is, so when the patients are treated with ALK tyrosine kinase inhibitors, upon progression a biopsy is performed and treatment assignment is done based on what was found in the post-progression biopsy.

For example, if you find that the patient has a MET amplification, it makes complete sense to use crizotinib as a second-line drug because crizotinib should have ALK efficacy and also inhibits MET. At this point, the sequencing is pretty much trial and error, and we do not have any results from the comprehensive clinical trials telling us what should be our drug A and what should be our drug B.

Transcript edited for clarity.

Case: A 58-Year-Old Woman With ALK+ NSCLC

Initial presentation

  • A 58-year-old woman presented with cough, fatigue and anorexia
  • PMH: unremarkable
  • PE: unremarkable

Clinical Workup

  • Labs: WNL
  • Imaging:
    • Chest x-ray showed multiple left upper lobe mass and mediastinal lymphadenopathy
    • Chest/abdomen/pelvic CT scan confirmed left upper lobe mass measuring 6.2 cm
    • PET scan showed PET positivity in bilateral LUL mass and mediastinal LN
    • MRI of the brain showed widespread scattered small lesions; consistent with multifocal brain metastases
  • Bronchoscopy with transbronchial biopsy of the left upper lobe confirmed lung adenocarcinoma
  • Molecular testing: ALK fusion+, EGFR-, ROS1-, BRAF-, KRAS-, NTRK-, MET-, RET-
  • Staging: IVA adenocarcinoma; ECOG PS 1


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

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