1.Rapid and dramatic response to alectinib in an ALK rearranged non-small-cell lung cancer patient who are critically ill.
Yoshida T1, Hida T, Yatabe Y. Anticancer Drugs. 2016 Mar 2. [Epub ahead of print]
Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have shown promising clinical activity in the treatment of non-small-cell lung cancer (NSCLC) that harbors ALK rearrangement. The next-generation ALK-TKI, alectinib, has been reported to have potent efficacy in ALK-positive NSCLC patients including on mutations that confer resistance to crizotinib, which was the first ALK-TKI approved for ALK-positive NSCLC. The efficacy and safety of ALK-TKIs, including crizotinib and alectinib, as the first-line treatment in critically ill patients is unclear. We report one ALK-positive NSCLC patient with poor performance status (PS) and disseminated intravascular coagulation because of respiratory failure and multiple metastases, and experienced the rapid and dramatic response to alectinib without adverse events that can lead to discontinuation and dose reduction of the drug. After a couple of months of treatment with alectinib, radiological review indicated a complete response.
2.Visualizing spatial distribution of alectinib in murine brain using quantitative mass spectrometry imaging.
Aikawa H1, Hayashi M1,2, Ryu S2, Yamashita M2, Ohtsuka N3, Nishidate M2,4,5, Fujiwara Y6, Hamada A1,2,5. Sci Rep. 2016 Mar 30;6:23749. doi: 10.1038/srep23749.
In the development of anticancer drugs, drug concentration measurements in the target tissue have been thought to be crucial for predicting drug efficacy and safety. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is commonly used for determination of average drug concentrations; however, complete loss of spatial information in the target tissue occurs. Mass spectrometry imaging (MSI) has been recently applied as an innovative tool for detection of molecular distribution of pharmacological agents in heterogeneous targets. This study examined the intra-brain transitivity of alectinib, a novel anaplastic lymphoma kinase inhibitor, using a combination of matrix-assisted laser desorption ionization-MSI and LC-MS/MS techniques. We first analyzed the pharmacokinetic profiles in FVB mice and then examined the effect of the multidrug resistance protein-1 (MDR1) using Mdr1a/b knockout mice including quantitative distribution of alectinib in the brain.
3.Elucidation of Resistance Mechanisms to Second-Generation ALK Inhibitors Alectinib and Ceritinib in Non-Small Cell Lung Cancer Cells.
Dong X1, Fernandez-Salas E2, Li E3, Wang S4. Neoplasia. 2016 Mar;18(3):162-71. doi: 10.1016/j.neo.2016.02.001.
Crizotinib is the first anaplastic lymphoma kinase (ALK) inhibitor to have been approved for the treatment of non-small cell lung cancer (NSCLC) harboring an ALK fusion gene, but it has been found that, in the clinic, patients develop resistance to it. Alectinib and ceritinib are second-generation ALK inhibitors which show remarkable clinical responses in both crizotinib-naive and crizotinib-resistant NSCLC patients harboring an ALK fusion gene. Despite their impressive activity, clinical resistance to alectinib and ceritinib has also emerged. In the current study, we elucidated the resistance mechanisms to these second-generation ALK inhibitors in the H3122 NSCLC cell line harboring the EML4-ALK variant 1 fusion in vitro. Prolonged treatment of the parental H3122 cells with alectinib and ceritinib led to two cell lines which are 10 times less sensitive to alectinib and ceritinib than the parental H3122 cell line. Although mutations of ALK in its kinase domain are a common resistance mechanism for crizotinib, we did not detect any ALK mutation in these resistant cell lines.
4.Dramatic response to alectinib in a patient of ALK-rearranged lung cancer with poor performance status.
Tanaka H1, Taima K2, Morimoto T2, Nakamura K2, Tanaka Y2, Itoga M3, Takanashi S4, Okumura K2. BMC Res Notes. 2016 Mar 17;9(1):173. doi: 10.1186/s13104-016-1983-9.
BACKGROUND: Lung cancers with anaplastic lymphoma kinase rearrangements are highly sensitive to anaplastic lymphoma kinase tyrosine kinase inhibition, underscoring the notion that such cancers are addicted to anaplastic lymphoma kinase activity. Several anaplastic lymphoma kinase inhibitors have been identified and are being evaluated in clinical trials. However patients with poor performance status (3 or 4) were not involved in these clinical trials, it has been unclear to use anaplastic lymphoma kinase-tyrosine kinase inhibitors for these patients. Here, we report an anaplastic lymphoma kinase-positive non small cell lung cancer patient with performance status 4, who was successfully treated with alectinib.
