Frontline Targeted Therapy in ALK+ NSCLC


Robert C. Doebele, MD, PhD:Following theALK-positive IHC [immunohistochemistry] test, this patient was initiated on first-line therapy with alectinib.

The patient experienced adverse effects, including fatigue, constipation, and nausea. These are all relatively typical for alectinib. All our tyrosine kinase inhibitors that are used to treatALK-positive disease do have some adverse effects, but in general, these are far better than most standard therapies, such as chemotherapy.

The FDA-approved options for first-line ALK inhibitor treatment in non—small cell lung cancer currently include crizotinib, ceritinib, and alectinib. Crizotinib was the first FDA-approved drug; later, ceritinib; following that, alectinib. Here, I agree with the choice of alectinib as first-line therapy. I think it’s clearly the most beneficial frontline therapy of the FDA-approved options. Crizotinib, we know, has an average PFS [progression-free survival] in the range of 10 to 12 months; ceritinib, in the range of 18 months; and alectinib has a PFS in the range of 2 to 3 years. And so we’re really talking about a significant improvement. Now, ceritinib was never compared directly with crizotinib. It was only compared with chemotherapy. But again, using that kind of cross-trial comparison of progression-free survival, alectinib seems to be the better choice. Alectinib was compared directly with crizotinib and was far superior in terms of time to progression.

Brigatinib is a potential new frontline option for patients withALK-positive disease. It’s not FDA approved, but it is recommended in the NCCN [National Comprehensive Cancer Network] Guidelines as a potential first-line therapy. Here again, we have a randomized trial, not of brigatinib versus alectinib but brigatinib versus crizotinib. And although the first results that were presented were relatively early, we’re seeing a very significant improvement in progression-free survival with brigatinib versus crizotinib, suggesting a similar magnitude of benefit. We don’t really know what that magnitude will be compared with alectinib, but it was quite significant, and I think it represents another potential first-line option for patients who are diagnosed withALK-positive lung adenocarcinoma.

Transcript edited for clarity.

Case: A 53-Year-Old Woman WithALK-Rearranged NSCLC

  • A 53-year-old woman presented with dyspnea, persistent cough with bloody sputum, and intermittent pain in right side of her chest
  • Relevant PMH:
    • Nonsmoker, had childhood exposure to second-hand smoke
    • No history or presence of pneumonia or bronchitis
    • No history of diabetes, cardiovascular disease, or renal disease
  • PE: lungs, clear; no palpable masses or visible lesions; patient is of average height and weight, appears physically fit
  • Diagnostic workup:
    • Chest X-Ray: revealed multiple small solid lesions in right lung
    • CT with contrast chest/abdomen/pelvis: several hyperattenuated tumors in right lung
    • Biopsy confirmed lung adenocarcinoma
    • Molecular testing:
      • Genetic testing;EGFR, BRAF, RET,KRAS, HER2wild-type,ROS1FISH
      • IHC;ALK-rearrangement
      • PD-L1 TPS; 20%
    • Brain MRI: revealed extensive CNS involvement
  • Treatment:
    • Started on alectinib; achieved partial response
    • Developed fatigue, grade 1 constipation, and nausea; continued treatment
    • Imaging at 12 months showed disease progression
    • Tumor testing of a lung lesions demonstrated MET FISH+
  • She was started on crizotinib
    • Imaging at 3 and 6 months showed a partial response
    • Developed grade 2 diarrhea and visual disturbance; continued treatment
    • Imaging at 10 months showed progression in the CNS lesions and the lung
    • Repeat biopsy of the lung lesions and genotyping showed ALK L1196M mutation
  • She was started on brigatinib at 90 mg once daily; she tolerated therapy well and after 1 week, dose was increased to 180 mg once daily
    • Achieved partial response, including in CNS metastases
    • Had fatigue, but was able to resume some exercise
    • Remains on treatment 16 months later
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