Mutation Testing at Progression of ALK-Rearranged NSCLC

Corey J. Langer, MD: Mutation testing has become a major area of focus. Patients who are treated with second- and third-generation agents will unfortunately, inevitably, develop resistance. And there seems to be a whole array of new mutations that can appear. In fact, for the most part, patients withALK-translocated disease at the time of diagnosis have noALKmutations. It’s only with the pressure of exposure to treatment that these mutations emerge, not typically in individuals who have been treated with crizotinib, because, frankly, it’s not a terribly good ALK inhibitor. But it’s seen much more commonly in individuals who have received ceritinib, alectinib, or brigatinib.

The problem here is we don’t really know how to handle these new mutations. We do not know per se which of the new agents work best with which specific mutation. This is really an emerging paradigm that needs to be developed further, and there are researchers such as Ross Camidge and Christine Lovly who are looking at this specifically. There’s a clear unmet need in research inALK-positive non—small cell. It’s further identification ofALKmutations, both their incidence and the appropriate therapies, that should be directed against each individual mutation.

Liquid biopsies are a useful adjunct to tumor testing. Frequently, individuals may decline repeat biopsies, the tumor is relatively inaccessible, or there have been complications with repeated tissue biopsies. So, liquid biopsies now can identify a whole array of circulating tumor-free DNA. And if there’s an abnormality in that DNA, includingALKmutations, that can, at least theoretically, be identified just with a blood draw, which is obviously a lot more convenient than setting an individual up for a tissue biopsy. It’s still in the early stages of development. We have found probably the greatest benefit for liquid biopsies in individuals withEGFRmutations where we’re looking specifically forT790. Its role in the management of patients withALK-positive disease is still emerging; it’s still evolving.

Transcript edited for clarity.

August 2016

• A 51-year-old female presents to her physician with symptoms of fatigue, intermittent chest pain, and lower back pain
• PMH: hypertension managed on a calcium channel blocker; osteoarthritis
• No history of smoking
• CT of the chest showed a 4.5-cm mass in the upper right lobe and enlarged hilar lymph nodes
• Bronchoscopy and transbronchial lung biopsy were performed:
  • Pathology revealed a grade 2 adenocarcinoma, consistent with a lung primary tumor
  • Molecular testing:
    • FISH: positive forALKtranslocation
    • NGS: negative forEGFR, ROS1, RET, BRAF, KRAS
    • IHC: PD-L1 expression in 0% of cells
  • Staging with PET/CT showed¹⁸F-FDG uptake in the lung mass, hilar nodes, and lumbar spine (L4/L5)
  • Brain MRI, negative for intracranial metastases
• 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

June 2017

• After 9 months on crizotinib, the patient reported worsening fatigue and back pain
• CT showed increased size of the pulmonary mass and bone lesions
• Brain MRI showed disseminated small lesions
• Crizotinib was discontinued and the patient was started on brigatinib