ALK+ NSCLC: PFS and Activity in CNS, Dosing, & Toxicity

Jonathan W. Riess, MD, MS:The PFS to brigatinib has ranged in clinical trials anywhere from about 12.9 to about 16 months, and that’s post progression on crizotinib. And cross trial comparisons between ALK TKIs, or any drug cross-trial comparison, can often be difficult to firmly interpret. But in terms of numerical superiority, it does seem to be a little bit better than alectinib, which was about 10 months, as well as ceritinib, which was a little bit less than that. So, I think that brigatinib did show numerically higher progression-free survival, but it is a cross-trial comparison where they’re not necessarily the same population. There can be some differences there, so you have to interpret with caution. But it certainly provides some justification for thinking about brigatinib in this type of case situation.

In patients treated with brigatinib in the ALTA study, the Huber and colleagues abstract looking at intracranial responses did show excellent activity justifying the use of brigatinib in patients with asymptomatic brain metastases. The overall response rate in the CNS was about 67%, which is superb, with a median progression-free survival of 18.4 months in patients who received brigatinib at the FDA-approved dose of 90 mg for 1 week followed by 180 mg daily.

For brigatinib dosing, titration, and administration, brigatinib is given initially at 90 mg once daily for 1 week followed by 180 mg once daily thereafter, with or without food. And the reason it starts at a lower 90-mg dose for the first week is because of early onset pulmonary events that were observed in about 9% of patients that occur on average between 2 and 3 days on brigatinib. When these events occur, brigatinib needs to be held until those symptoms resolve.

Toxicity management with brigatinib is something to consider, as with any medication. Several unique adverse events that occur with brigatinib have been noted. One is early-onset pulmonary toxicity that can look like interstitial lung disease but occurs much earlier than typically observed with interstitial lung disease. It’s why brigatinib is prescribed at 90 mg daily for the first week and then escalated to 180 mg daily if tolerated well. The mean time of onset of these early-onset pulmonary events is about 2 to 3 days and requires holding the drug. Other adverse events that have been noted include hypertension, myalgia is an elevation in CPK, bradycardia, and those should be managed as indicated in the package insert.

Transcript edited for clarity.

CASE:ALK+ Non—Small Cell Lung Cancer

March 2017

• A 69-year-old female never-smoker presented with dyspnea, cough and fatigue
• PMH: hypertension managed on losartan 100 mg
• Chest X-ray showed multiple bilateral lung nodules
• Brain MRI, negative for intracranial metastases
• Bronchoscopy was performed with a fine needle aspirate biopsy
  • Pathology revealed adenocarcinoma, consistent with a lung primary tumor
  • Molecular testing:
    • NGS: positive for ALK gene rearrangement
    • NGS: negative forEGFR, ROS1, RET, BRAF, KRAS
    • IHC: PD-L1 expression in 0% of cells
• The patient was started on therapy with crizotinib
• Follow-up imaging at 3 and 6 months showed marked regression of the lung mass, nodal spread, and bone lesions

January 2018

• After 10 months on crizotinib, the patient reported worsening fatigue, back pain, and dyspnea
• CT showed increased size of the pulmonary masses and bone lesions
• Brain MRI showed disseminated small lesions
• Crizotinib was discontinued and the patient was started on brigatinib