Value of Repeat Mutation Testing for ALK+ NSCLC

Jonathan W. Riess, MD, MS:At the time of progression, an important question is whether or not to doALKmutation testing to try to find the mechanism of resistance to an ALK TKI, and that’s something I generally do. So, with the standard of care now being alectinib in the first-line treatment, the next step can sometimes be driven by theALKresistance mechanism.

Now, the standard of care after progression on alectinib would generally be platinum-based chemotherapy. And immunotherapy, such as PD-1 antibodies, now pembrolizumab, nivolumab, and so forth have been studied in these patients and response rates are generally very low. So, that’s something I don’t consider until way later lines of therapy. The standard treatment, without having a resistance mutation, I would consider to be platinum-based chemotherapy.ALKresistance mutations can sometimes point in the direction of a clinical trial.

For example, one of the resistance mechanisms to alectinib is the G1202R mutation, and responses have been shown to lorlatinib and other further next-generation ALK inhibitors with those drugs. It’s unclear whether brigatinib and ceritinib and those drugs could be sensitive when there’s progression on alectinib. There’s a certain spectrum ofALKmutations that we know, based on the IC50 in cell culture, where certain ALK inhibitors may have more activity than others. By identifying what those mutations are, you could potentially match to another ALK TKI, either approved or in a clinical trial, to try to treat the patient. So, that’s something that I do. But the standard of care right now after progression on first-line alectinib remains platinum-based chemotherapy. But I would strongly consider for physicians who are treating these patients to seek out and help find clinical trials, such as lorlatinib and other next-generation ALK inhibitors, that may have activity against the spectrum of resistance mutations.

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