1.Proactive management strategies for potential gastrointestinal adverse reactions with ceritinib in patients with advanced ALK-positive non-small-cell lung cancer.
Schaefer ES1, Baik C2. Cancer Manag Res. 2016 Mar 24;8:33-8. doi: 10.2147/CMAR.S96471. eCollection 2016.
Anaplastic lymphoma kinase (ALK) gene fusions occur in 3%-7% of non-small-cell lung cancer (NSCLC) cases. Ceritinib, a once-daily, oral ALK inhibitor, has activity against crizotinib-resistant and crizotinib-naïve NSCLC, including brain metastases. Ceritinib (Zykadia™) was granted accelerated approval by the US Food and Drug Administration in 2014 for treating crizotinib-resistant ALK-positive NSCLC. Adverse events (AEs), particularly gastrointestinal (GI) AEs, are commonly experienced at the recommended dose of 750 mg/d and ∼38% of patients require dose interruption or reduction for GI AEs. This case study details our experience with the use of proactive GI AE management regimens in patients treated with ceritinib (750 mg/d) across two study sites. Proactive Regimens A and B were implemented in patients with metastatic ALK-positive NSCLC treated with ceritinib to manage drug-related GI AEs. Regimen A comprised ondansetron and diphenoxylate/atropine or loperamide, taken 30 minutes prior to ceritinib dose.
2.Successful treatment with ceritinib after crizotinib induced hepatitis.
Sassier M1, Mennecier B2, Gschwend A2, Rein M3, Coquerel A4, Humbert X5, Alexandre J4, Fedrizzi S4, Gervais R6. Lung Cancer. 2016 May;95:15-6. doi: 10.1016/j.lungcan.2016.02.008. Epub 2016 Feb 23.
We report two cases of acute hepatitis induced by crizotinib in patients with ALK-rearranged non-small cell lung cancer (NSCLC) who were treated after by a second generation of ALK inhibitor without any incident. These cases suggest that ceritinib could be used as an alternative agent when crizotinib is responsible for hepatitis.
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.
