Sequencing ALK Inhibitors


An expert in the treatment of lung cancer gives insight for the sequencing of ALK inhibitors following disease progression, highlighting the instances of the development of brain involvement and rebiopsy.

Karen Reckamp, MD: When we think about sequencing ALK inhibitors, that’s a big area of discussion at this time. There are some studies that are evaluating the sequencing. We do need to think about resistance and overcoming resistance. A drug that is more specific and can overcome resistance mechanisms, generally has turned out to have longer progression-free survival because these drugs continue to be developed and patients have many options following frontline therapy. The overall survival continues to get longer, so it is more difficult to compare overall survival across these different trials. For patients who have brain involvement and have progression within the brain, lorlatinib has the best efficacy post–third-generation ALK TKI [tyrosine kinase inhibitor], and sometimes we have to move toward radiation for the brain if they’re progressing on our current therapies.

When a patient has systemic progression, we consider rebiopsy. Many of these patients are going on clinical trials, but even without a clinical trial, understanding the mechanisms of resistance can help us choose the appropriate therapy. At this time, lorlatinib is the only approved agent post–third-generation ALK TKI and has broad coverage across resistance mechanisms. Brigatinib also has efficacy across most of the point mutations and alterations that occur as resistance mechanisms. In this case, the patient received brigatinib; there are few data utilizing other inhibitors post-brigatinib at this time. We also know that patients do well utilizing pemetrexed-based chemotherapy. This needs to be a part of the patient’s treatment course to provide the longest overall survival. We discussed that at some point, after receiving usually 2 TKIs, that pemetrexed-based chemotherapy will be part of their treatment regimen. For somebody with brain metastases, we often do continue the ALK TKI to maintain the brain penetrants.

Transcript edited for clarity.

Case: A 68-Year-Old Woman with ALK+ Non–Small Cell Lung Cancer

Initial presentation

  • A 68-year-old woman presented with fatigue, wheezing and decreased appetite
  • PMH: unremarkable
  • PE: wheezing on auscultation; ECOS PS 1

Clinical Workup

  • Labs: WNL 
  • Chest x-ray showed a left lower lobe mass
  • Chest/abdomen/pelvic CT scan confirmed a 6.8-cm left lower lobe lung mass and a suspicious liver lesion
  • PET scan showed activity in the left lower lobe mass and liver
  • MRI of the brain showed several subcentimeter lesions without edema
  • Bronchoscopy with transbronchial biopsy of the left lower lobe mass confirmed lung adenocarcinoma
  • Molecular testing: NGS revealed EML4/ALK fusion+, EGFR-, ROS1-, BRAF-, KRAS-, NTRK-, MET-, RET-, PD-L1 0% by IHC
  • Staging: IVB adenocarcinoma


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

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