NSCLC: Initial Impressions and Alternate ALK Therapy

Jonathan W. Riess, MD, MS:My initial impressions of this patient are that she has stage 4 non—small cell lung cancer, adenocarcinoma. PD-L1 expression was negative at 0%. Her next-generation sequencing panel was positive for anALKtranslocation, and this is very important. Patients who present withALK-positive lung cancer can often present in this way. They’re also more like to have effusions, like pleural effusions and pericardial effusions. The mainstay of treatment for these patients are ALK tyrosine kinase inhibitors. The patient was started on crizotinib, which was the initial ALK inhibitor that was approved to treat metastaticALK-rearranged non—small cell lung cancer, which has a median progression-free survival in clinical trials of about 9 to 10 months.

However, there are newer next-generation ALK inhibitors, including brigatinib and alectinib, that have been developed. And more recently, alectinib has been approved for first-line treatment ofALK-rearranged non—small cell lung cancer based on comparison between alectinib and crizotinib in the ALEX trial, with recently updated progression-free survival data that showed progression-free survival in excess of 30 months on average. So, that’s very exciting and a game changer for the treatment of these patients.

If I diagnosed this patient today, I would start the patient on alectinib as first-line therapy for her stage 4ALK-rearranged lung cancer, and that’s based upon 2 clinical large phase III clinical trials: the J-ALEX study conducted in Japan and the ALEX study conducted in the United States and Europe, which showed a progression-free survival benefit that was dramatic between alectinib and crizotinib. This was updated to show a median progression-free survival in the ALEX study of more than 30 months compared with about 10 months on crizotinib. So, a dramatic improvement. And that improvement’s driven mainly by its excellent blood—brain barrier penetration that can induce intracranial responses and actually help forestall the development of, and prevent, brain metastases. So, that’s one of the main differences between alectinib and crizotinib, and really helps underlie that benefit, so that’s very exciting.

And you can see that when the patient relapsed, she had intracranial metastatic disease. And you know that’s something that could be, more often than not, delayed or forestalled with alectinib.

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