ceritinib and Liver-Neoplasms

In an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted.. Here, we report efficacy and updated safety data from primary efficacy analysis of the ASCEND-8 study. Key secondary endpoints were overall response rate and duration of response, assessed by blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors 1.1.. In total, 306 patients were randomized to ceritinib 450-mg fed (n = 108) or 600-mg fed (n = 87) or 750-mg fasted (n = 111), of which 304 patients were included in safety analysis and 198 treatment-naive patients (ALK receptor tyrosine kinase [ALK]-positive by immunohistochemistry) were included in the efficacy analysis (450-mg fed [n = 73], 600-mg fed [n = 51], and 750-mg fasted [n = 74]). The BIRC-assessed overall response rate was 78.1% (95% confidence interval [CI]: 66.9-86.9), 72.5% (95% CI: 58.3-84.1), and 75.7% (95% CI: 64.3-84.9), respectively; and the median duration of response (months) by BIRC was not estimable (NE) (95% CI: 11.2-NE), 20.7 (95% CI: 15.8-NE), and 15.4 (95% CI: 8.3-NE), respectively. Based on the safety analysis (n = 304), the 450-mg fed arm showed the highest median relative dose intensity (100% versus 78.5% versus 83.7%), lowest proportion of patients with dose reductions (24.1% versus 65.1% versus 60.9%), and lowest proportion of patients with gastrointestinal toxicities (75.9% versus 82.6% versus 91.8%).. Ceritinib at a dose of 450 mg with food compared to 750-mg fasted showed consistent efficacy and less gastrointestinal toxicity.

Topics: Adult; Aged; Aged, 80 and over; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Bone Neoplasms; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Fasting; Female; Follow-Up Studies; Food; Gene Rearrangement; Humans; Liver Neoplasms; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Prognosis; Pyrimidines; Response Evaluation Criteria in Solid Tumors; Sulfones; Young Adult

In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT01970865.).

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Binding Sites; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lactams; Lactams, Macrocyclic; Liver Failure; Liver Neoplasms; Lung Neoplasms; Middle Aged; Molecular Structure; Mutation; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Our study was to examine the roles of crizotinib and ceritinib in hepatocellular carcinoma (HCC) cells and explore the possible mechanisms. MTT assay was employed to examine the proliferation of five HCC cell lines treated with various concentrations of crizotinib or ceritinib. HepG2 and HCCLM3 cells were incubated with 2 nmol/l ceritinib for 1 week, followed by crystal violet staining and cell counting. Protein amounts of t-ALK, p-ALK, t-AKT, p-AKT, t-ERK, p-ERK, Mcl-1, survivin, and XIAP in HepG2 cells under different culture conditions were evaluated by western blot. HepG2 and HCCLM3 cells were treated with vehicle or ceritinib and measured by flow cytometry apoptosis analysis with Annexin-V/propidium iodide staining. MTT assay showed that both crizotinib and ceritinib suppressed the proliferation of various human HCC cells. Crystal violet staining analysis also indicated that ceritinib effectively inhibited human HCC cell proliferation. Western blot analysis indicated that both crizotinib and ceritinib inhibited ALK, AKT, and ERK phosphorylations. In addition, ceritinib reduced antiapoptotic gene expressions in HepG2 cells. Flow cytometry analysis indicated that ceritinib induced HepG2 and HCCLM3 cells apoptosis. ALK inhibitor exhibited antitumor effects by inhibiting ALK activation, repressing AKT and ERK pathways, and suppressing antiapoptotic gene expressions, which subsequently promoted apoptosis and suppressed HCC cell proliferations.

Topics: Anaplastic Lymphoma Kinase; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Crizotinib; Extracellular Signal-Regulated MAP Kinases; Hep G2 Cells; Humans; Liver Neoplasms; Myeloid Cell Leukemia Sequence 1 Protein; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidines; Sulfones; Survivin; X-Linked Inhibitor of Apoptosis Protein