ribociclib and Carcinoma--Non-Small-Cell-Lung

Preclinical data show that the combination of an ALK inhibitor (ALKi) with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) may act synergistically to overcome drug resistance mechanisms. Here, we assessed the safety, tolerability, and preliminary clinical activity of ceritinib, an ALKi in combination with ribociclib, a CDK4/6i, in patients with ALK-rearranged non-small cell lung cancer (NSCLC).. This was a multicenter, open-label, phase Ib/II dose-escalation study to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) for ceritinib plus ribociclib therapy.. Twenty-seven adult patients with ALK-rearranged advanced NSCLC with an ECOG PS ≤ 2 were enrolled into five cohorts to receive various dose combinations of ceritinib (range, 300-450 mg/day) and ribociclib (range, 100-300 mg/day). Median age of patients was 57 years. MTDs were not reached in this study. Enrollment into phase Ib was terminated early and phase II was not opened due to changes in the ALK-rearranged NSCLC treatment landscape. Ceritinib 300 mg/day and ribociclib 200 mg/day (3-weeks-on/1-week-off schedule) was identified as the RP2D. Among the 27 evaluable patients, the overall response rate (ORR) was 37.0% (95% CI, 19.4-57.6) and median progression-free survival (mPFS) was 21.5 months (95% CI, 5.5-25.0). At RP2D, the ORR was 50.0%, disease control rate was 75%, and mPFS was 24.8 months (95% CI, 5.5-25.1). Safety profile of the combination therapy was consistent with single-agent safety data.. Combination of ceritinib and ribociclib showed clinical activity with a manageable safety profile in patients with advanced ALK-rearranged NSCLC.

Topics: Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Middle Aged; Protein Kinase Inhibitors; Purines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones

Newly designed 4 - aminoquinazoline derivatives (5a-f, 6a, b, 7, 8, 9, 10a-c, 11a, b, 12a, b and 13a, b) have been synthesized and evaluated for their potential multitarget anticancer activities, apoptotic and anti-proliferative effects. Thereupon, in vitro cytotoxic activities of all the synthesized compounds were screened against NCI 60 human cancer cell lines (nine subpanels) at NCI, USA. Successfully, 2-morpholino-N-(quinazolin-4-yl) acetohydrazide 5e was granted an NSC code, owing to its significant potency and broad spectrum of activity against various cancer cell lines; leukemia K-562, non-small cell lung cancer NCI-H522 cells, colon cancer SW-620, melanoma LOX IMVI, MALME-3M, renal cancer RXF 393, ACHN and breast cancer MDA-MB231/ATCC (GI% = 99.6, 161, 126.03, 90.22, 174.47, 139.7, 191 and 97, respectively). Compound 5e showed the best inhibitory activity (GI

Topics: Antineoplastic Agents; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; ErbB Receptors; Female; Humans; Kidney Neoplasms; Lapatinib; Lung Neoplasms; Melanoma; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Cyclin-Dependent Kinase 9; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Isothiocyanates; Lung Neoplasms; Molecular Structure; Protein Kinase Inhibitors; Structure-Activity Relationship; Sulfoxides; Tumor Cells, Cultured