Use of Brigatinib in ALK+ NSCLC & Future

Jonathan W. Riess, MD, MS:In terms of using brigatinib, brigatinib is approved after progressive disease or intolerance to crizotinib as second-line treatment. And for that, it’s shown to be effective with high response rates and a median progression-free survival ranging from about 12.9 to 16 months. It also has intracranial responses and excellent CNS activity where it can be used in patients who have asymptomatic brain metastases without resorting to whole brain radiation and other things that, after a certain amount of time can develop long-term toxicity, since these patients withALK-rearranged non—small cell lung cancer are living longer and longer with the development of brigatinib and other next-generation ALK inhibitors.

And now the standard has evolved where alectinib is approved for first-line use forALK-rearranged non—small cell lung cancer. And the standard of care upon progression on alectinib is generally platinum-based chemotherapy. There are some mutations that mediateALK-dependent resistance. There are several of them that are shared with alectinib and brigatinib, but looking at preclinical data, there are several that may be sensitive to brigatinib where that can be considered upon progression with alectinib.

However, that’s not FDA approved or standard. In particular, the G1202R mutation appears at least preclinically to have intermediate resistance to brigatinib, so other ALK inhibitors are in development looking at that as well. And I eagerly await reports of activity of brigatinib after alectinib and think that should be studied further in clinical trials, based upon the evolution of treatment ofALK-rearranged non—small cell lung cancer. And I eagerly await the results from the first-line brigatinib study to see how effective it is in the ALK inhibitor–naïve setting and to see if it can at least meet, if not exceed, the excellent progression-free survival, on average greater than 30 months, that we’re seeing with alectinib.

The expectations for this patient who initially received crizotinib for herALK-rearranged non—small cell lung cancer had an excellent response and then she developed progression. I would expect brigatinib to give a high probability of having a good response to treatment, including within the central nervous system, based upon data presented by Dr. Huber and colleagues that we discussed previously from the ASCO abstract.

I would also expect them to do well, with an on-average progression-free survival, or time for things to progress, between 12 and 16 months. Upon progression, some of the things I think about doing in addition to considering standard platinum-based chemotherapy would be if it’s oligoprogression, I consider radiation—focused radiation, continuing brigatinib, and/or biopsying the tumor. For example, looking for that G1202R mutation that you can match potentially to, like, a clinical trial, such as lorlatinib or other mechanisms of resistance, that may inform clinical trials and future treatments for the patient.

The future treatment ofALK-positive lung cancer I think is bright. We’ve made unprecedented advances in the treatment ofALK-rearranged lung cancer, as evidenced by the high response rates we’re observing with next-generation ALK inhibitors and the data that were presented with the exceptional median progression-free survival on alectinib. I hope in the future that we develop tolerable combination strategies to treat patients up front, to even make more strides in treatingALK-positive lung cancer, where we’ve already had great successes but we need to always do better.

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