Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR sensitizing mutation and EGFRT790M and has demonstrated efficacy in non-small cell lung cancer (NSCLC) central nervous system metastases.
Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases.
We report treatments and outcomes in patients with HER2-positive MBC and CNS metastasis from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs).
The third-generation EGFR-TKI osimertinib, initially approved as the second-line treatment for patients with T790-mutant NSCLC, demonstrated survival benefits in TKI-naïve EGFR-mutated patients, especially in patients with CNS metastasis.
Close monitoring and reasonable approaches such as CNS penetrating HER2 blockades combined with the current standard therapy could contribute to improving intracranial tumor control and quality of life in patients with CNS metastasis from HER2-enriched breast cancer.
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.
Management of Central Nervous System Metastases in Patients With Advanced Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer During Crizotinib Treatment.
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.
The EGFR mutational status in the cfDNA from paired CSF and plasma samples from LAC patients with CNS metastases, including 20 brain metastases (BM) and 15 leptomeningeal metastases (LM), was assessed by droplet digital polymerase chain reaction (ddPCR).
We conducted a phase I trial using an accelerated dose escalation design in patients with HER2-positive (HER2<sup>+</sup>) breast cancer with CNS metastasis.
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.
Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases.
Second-generation TKIs tended to be chosen over first-generation TKIs as frontline therapy in younger patients with uncommon EGFR mutations and without central nervous system metastases.
Patients with advanced NSCLC who received osimertinib after progression of early-generation EGFR-TKIs and CNS metastases on baseline brain scan were retrospectively collected.
Progression of Central Nervous System Metastases in Advanced Nonsmall Cell Lung Cancer Patients Effectively Treated with First-Generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor.
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.
Purpose In patients with epidermal growth factor receptor ( EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC), there is an unmet need for EGFR-tyrosine kinase inhibitors with improved CNS penetration and activity against CNS metastases, either at initial diagnosis or time of progression.
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.
This review explores the literature reporting the intracranial activity of EGFR TKIs, and finds that there is evidence for varying efficacy of the approved agents, erlotinib, gefitinib, afatinib, and osimertinib in patients with 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.