Diagnosis of Metastatic ALK-Rearranged NSCLC

Corey J. Langer, MD: This is a 51-year-old female never-smoker who presents with fatigue, chest pain, and low-back discomfort and is discovered to have a 4.5 cm right-upper-lobe mass with hilar adenopathy on a chest X-ray and confirmed on a CT scan. A diagnostic biopsy shows adenocarcinoma, and molecular testing, which at this point is standard in non—small cell, reveals FISH positivity forALKtranslocation.

They’ve done the proper workup. In this day and age, this would include FISH testing for bothALKandROS1and mutation testing, ideally next-generation sequencing. So, we look not just forEGFRbutBRAF,HER2,c-MET, etc. And PD-L1 testing in this patient, in fact, was negative, which is not uncommon—ALK-positive/PD-L1-negative,EGFR-positive/PD-L1-negative. The patient undergoes a PET scan that confirms lumbar spine metastases, which explain her low-back discomfort and also confirm stage 4 status. Otherwise, this patient would have stage 3 disease and would probably be best treated with a combined modality approach. But with bone involvement, local advanced-type strategy makes no sense. So, the patient is started on crizotinib, which is the “standard” agent in this setting.

In the past 5 to 10 years, the standard approach for patients with lung cancer, specifically adenocarcinoma of the lung, is to interrogate the tumor on a molecular basis. Originally, we were looking forEGFRmutation. That’s now expanded. We look forEGFRmutation, we look forALKorROS1translocations, and we’ve added other mutations or other molecular aberrations to that list, includingBRAF,HER2,c-MET, etc. So, the best approach, particularly in a patient who’s not terribly symptomatic and who has the luxury of time of at least waiting for these tests to come back, is to simultaneously do next-generation sequencing for an array of mutation markers, to do FISH specifically forALK,ROS1, and, to some extent,RET. And now in the face of an approval for immunotherapy up front, specifically pembrolizumab—which has shown superiority to chemotherapy—for individuals with PD-L1 expression 50% or higher, PD-L1 testing is also part of the mix. Now, that’s an IHC test, so we have a mix of tests that we’re doing: next-generation sequencing, FISH, and IHC for PD-L1. So, it’s incumbent on the clinician to make sure we have sufficient tissue to do all these tests, and that’s sometimes the biggest challenge.

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