Chemotherapy, monoclonal antibodies, tyrosine-kinase inhibitors (TKIs) for molecularly selected NSCLCs, such as epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-rearranged diseases, and immune checkpoint inhibitors are all systemic treatments that have shown activity against NSCLC-derived CNS metastases.
Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases.
We report a case of systemic T-cell anaplastic large cell lymphoma CD30+ ALK- with CNS involvement at the time of diagnosis and unusual MRI characteristics resembling acute disseminated encephalomyelitis.
Expert commentary: The recent data supports that EGFR-TKIs and ALK inhibitors are clinically relevant for first-line treatment to prevent and treat CNS metastases in molecularly selected NSCLC patients.
Moreover, ongoing clinical trials with novel-generation ALK inhibitors will produce more evidences on the best approach in the growing number of ALK-positive NSCLCs with CNS involvement.
IMPLICATIONS FOR PRACTICE: Despite the advancement of second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs), the emergence of resistance and progression of central nervous system metastases remain clinically significant problems in ALK-positive non-small cell lung cancer.
We enrolled patients in phase 2 into five cohorts: ALK inhibitor-naive ALK-rearranged NSCLC (cohort 1), crizotinib-treated ALK-rearranged NSCLC (cohort 2), EGFR<sup>T790M</sup>-positive NSCLC and resistance to one previous EGFR tyrosine kinase inhibitor (cohort 3), other cancers with abnormalities in brigatinib targets (cohort 4), and crizotinib-naive or crizotinib-treated ALK-rearranged NSCLC with active, measurable, intracranial CNS metastases (cohort 5).
Management of Central Nervous System Metastases in Patients With Advanced Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer During Crizotinib Treatment.
Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases.
In a phase 1 study, activity was seen in patients with ALK-positive non-small-cell lung cancer, most of whom had CNS metastases and progression after ALK-directed therapy.
It is generally believed that the incidence of CNS metastasis is lower in ROS1+ NSCLC than ALK+ NSCLC as ROS1 fusions are regarded as a less powerful driver mutation than ALK fusions in ALK+ NSCLC based on the longer progression-free survival of ROS1+ NSCLC patients than ALK+ NSCLC patients treated with crizotinib.
Alectinib appears to avert the progression of CNS metastases in patients with ALK-positive NSCLC and baseline CNS metastases, and to prevent the development of new CNS lesions in patients without baseline CNS disease.
We also discuss emerging controversies in treatment of patients with ALK-positive lung cancer, including the choice of first-line ALK inhibitor and the role of tyrosine kinase inhibitors in the treatment of central nervous system metastases.
Our findings suggest that ALK-tyrosine kinase inhibitor therapy should be continued in patients showing a long-term complete response, unless intolerable toxicities are present, and that rechallenge treatment with alectinib may represent a therapeutic option for central nervous system metastases.