ALK+ NSCLC: Brigatinib Indication and ALTA Trial

Jonathan W. Reiss, MD, MS:This patient was switched to brigatinib from crizotinib based upon progressive disease on crizotinib. And that decision was based upon the ALTA trial, for which brigatinib was FDA approved. And that trial treated patients who progressed on crizotinib with brigatinib. And what it found was a good overall response rate of about 54% and a progression-free survival rate of about 12.9 months. Clinical trials with brigatinib after crizotinib have shown a median progression-free survival of anywhere between 12 and 16 months. And that is numerically a very good number. It also gets good blood—brain barrier penetration, which makes a lot of sense for this patient who has these asymptomatic brain metastases. And so, I think it makes sense to choose brigatinib as a treatment for this patient. Alectinib could also be considered as well.

Brigatinib is a next-generation ALK inhibitor that does have some unique features in terms of the spectrum of mutations it may have activity against. In preclinical models, brigatinib has more coverage forALK-resistance mutations and several other ALK inhibitors. So, it gets several more of theALK-dependent resistance mechanisms than alectinib when looking at in vitro data. It does not seem to get the G1202R mutation, which is often refractory to alectinib or brigatinib, where lorlatinib may have activity against that particular mutation that has been seen in clinical trials.

Now it’s unknown in patients who’ve had first-line alectinib what the response rate is with brigatinib after alectinib. I think that’s an area of active investigation. You would expect, based upon the preclinical data, that some mutations may be more sensitive than others to brigatinib when patients had progressed on alectinib. But certainly, after crizotinib, there’s a clear indication for treating this patient with a next-generation ALK inhibitor such as brigatinib.

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