Second-line and Beyond: Treatment of ALK+ mNSCLC


Managing patients with who progress on a TKI, the role of re-biopsy at progression of disease, and the future treatment landscape for ALK+ mNSCLC.

Joshua M. Bauml, MD: Treating patients who are progressing on a first-line tyrosine kinase inhibitor [TKI] for ALK-positive non–small cell lung cancer is very tricky. We have data on some second-line TKIs, most notably lorlatinib is approved in this space. The approval for lorlatinib officially depends upon which TKI was used in the first line. Functionally, I do not change what I use in the second line. If we look at mechanisms of resistance to first-line TKI, the most common ALK-based mutation is G1202R; it is much more common with alectinib and brigatinib than it is with crizotinib. Lorlatinib is the only drug on the market that has substantial activity on G1202R in vitro. Though I will say that in vivo in humans it does seem like brigatinib has some efficacy. If I have a patient who’s on crizotinib, develops G1202R, I might be more likely to reach for brigatinib than I will to reach for lorlatinib based on the fact that brigatinib tends to be better tolerated, in my experience. Understanding this mutation is very important. If we look at the lorlatinib study, the response rate in the later lines of treatment after prior TKIs is double in a patient who has an ALK-based resistance mutation to what it is in a patient who does not have an ALK-based resistance mutation. Any time I have a patient who is on an ALK TKI or an EGFR TKI, I do a repeat molecular testing, often utilizing liquid biopsy. If the liquid biopsy is not illuminating, I will often reach for a tumor biopsy to better understand why a patient is progressing.

ALK+ non–small cell lung cancer remains a major problem for our patients around the world. There have been so many advances in terms of ALK TKIs; however, to me the critical element that is still missing is the fact that we have these highly active drugs and yet resistance is inevitable. We must figure out a way to overcome and prevent that resistance so our patients can have prolonged disease responses and hopefully one day cures as well.

This transcript was edited for clarity.

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 
  • Chest x-ray showed multiple right upper lobe masses
  • Chest/abdomen/pelvic CT scan confirmed 3 masses (largest 6.5 cm)
  • PET scan showed activity in the right upper lobe masses
  • MRI of the brain showed multiple scattered lesions, consistent with multifocal brain
  • Bronchoscopy with transbronchial biopsy of the right upper lobe mass confirmed lung adenocarcinoma, invasive mediastinal
  • Stage IV adenocarcinoma; ECOG PS 0
  • Molecular testing: ALK fusion+, EGFR-, ROS1-, BRAF-, KRAS-, NTRK-, MET-, RET-, PD-L1 0% by IHC


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

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