Options for Upfront Treatment of ALK-Rearranged NSCLC

Corey J. Langer, MD: Patients withALK-rearranged non—small cell phenotypically look very similar to patients with anEGFRmutation. By and large, they almost always have adenocarcinoma, a preponderance of never-smokers and remote former minimal smokers. Beyond that, the oncogenic driver that governs the behavior of the tumor is very different.EGFR-mutant tumors are highly sensitive to EGFR TKIs, such as gefitinib, erlotinib, and afatinib. Those drugs do not work inALK-rearranged tumors.

The first agent, approved roughly 5 or 6 years ago, was crizotinib, which actually was developed as a MET inhibitor. It was only incidentally discovered to be an ALK inhibitor. And that agent has stood the test of time and has shown superiority both in terms of response rate and progression-free survival compared with standard second-line chemotherapy. A little bit more recently, in one of the profile trials, single-agent crizotinib was clearly superior to a platinum/pemetrexed-based regimen in the frontline setting. At least until very recently, it has been the standard of care.

More recently, we’ve seen the emergence of second- and third-generation ALK TKIs, drugs that are developed specifically againstALK. Ceritinib was one of the first to be looked at in the second- and third-line settings and actually salvaged patients whose disease had responded and then progressed on crizotinib with progression-free intervals lasting 6, 7, 8, or 9 months. More recently, it has been compared with chemotherapy in the frontline setting and has shown a clear advantage—median progression-free survival of 16 months or more compared with the standard 7 or 8 months. So, it, too, now has a formal approval in the frontline setting.

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