ceritinib and Bone-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

Targeted therapies are a standard of care for first-line treatment of Anaplastic lymphoma kinase (ALK)-rearranged non small cell lung cancer (NSCLC). Giving the rapid pace of drug discovery and development in this area, reporting of adverse effects of ALK inhibitors is crucial. Here, we report a case of osteitis induced by an ALK inhibitor mimicking bone metastasis, a previously undescribed side effect of crizotinib.. A 31-year-old woman with stage IV ALK-rearranged NSCLC presented with back pain after 3 months of crizotinib treatment. Diagnostic work-up showed osteitis on the 4th and 5th thoracic vertebrae, anterior soft tissue infiltration and epiduritis, without any sign of infection. Spinal cord decompression, histological removal and osteosynthesis were performed. Histologic examination showed necrosis with abundant peripheral neutrophils, no microorganism nor malignant cell. Symptoms and Computarized Tomography-abnormalities rapidly diseappeared after crizotinib withdrawal and did not recur after ceritinib onset.. This is the first report of crizotinib-induced osteitis. Crizotinib differs from other ALK inhibitors as it targets other kinases as well, which may have been responsible for the osteitis. Crizotinib can induce rapidly extensive osteitis, which can mimic tumor progression.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Bone Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Osteitis; Protein Kinase Inhibitors; Pyrimidines; Sulfones; Tomography, X-Ray Computed

Topics: Anaplastic Lymphoma Kinase; Bone Neoplasms; Carcinoma, Non-Small-Cell Lung; Disease Progression; Gene Rearrangement; Humans; Lung Neoplasms; Male; Middle Aged; Osteoblasts; Prognosis; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones; Tomography, X-Ray Computed