The accelerated path of ceritinib: Translating pre-clinical development into clinical efficacy

Abstract The discovery of anaplastic lymphoma kinase ( ALK )-rearranged non–small-cell lung cancer (NSCLC) in 2007 led to the development and subsequent approval of the ALK inhibitor crizotinib in 2011. However, despite its clinical efficacy, resistance to crizotinib invariably develops. There is now a next generation of ALK inhibitors, including two that have been approved—ceritinib and alectinib—and others that are in development—brigatinib, lorlatinib and X-396. Ceritinib and the other next-generation ALK inhibitors are more potent than crizotinib and can overcome tumor cell resistance mechanisms. Ceritinib gained US Food and Drug Administration approval in 2014 following accelerated review for the treatment of patients with ALK -positive ( ALK +) metastatic NSCLC who have progressed on or are intolerant to crizotinib. In pre-clinical studies, it demonstrated more potent inhibition of ALK than crizotinib in enzymatic assays, more durable responses in xenograft models and the ability to potently overcome crizotinib resistance mutations in vitro (including the gatekeeper mutation). There is also evidence for ceritinib penetration across the blood-brain barrier. In clinical trials, ceritinib has demonstrated durable responses and progression-free survival in ALK-inhibitor–pre-treated and –naive NSCLC patients, including high overall and intracranial response rates in those with central nervous system metastases. Selective gastrointestinal toxicity of ceritinib, such as diarrhea, nausea and vomiting is generally manageable with prophylactic medication and prompt dose reduction or interruption. Future progress in treating ALK + NSCLC will focus on determining the optimal sequencing of therapies and strategies to overcome acquired resistance, an ongoing challenge in treating ALK -mutation–driven tumors

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The Cost of Palliative Care for Hepatocellular Carcinoma in Hong Kong

Background: Hepatocellular carcinoma (HCC)is endemic in parts of Asia and Africa and most patients are not suitable for treatment with a curative approach. Little is known about the cost of palliative care for HCC. Objective: To determine: (i) patient-specific costs of palliative care of HCC; and (ii) individual factors that drive patient-specific costs and to develop a model of cost per case under alternative circumstances. Methods: 204 patients with inoperable HCC were prospectively tracked from first hospitalisation until death for health service utilisation. A societal perspective of cost was taken, including costs of formal and informal services incurred by payers, caregivers and patients. Observational data from a large Hong Kong cancer care programme were used. A regression analysis was performed using formal costs only, with the cost per observed day as the dependent variable. Results: The median survival was 95 days and the mean observation period was 153 days. The mean value per person for formal healthcare cost was 30 983 Hong Kong dollars [$HK] ($US3872, 1998 values). The distribution of cost values were positively skewed. The regression analysis showed that age, days of observation and survival were negatively related to cost per observed day, and the Child-Pugh grading of severity of liver cirrhosis was positively related to cost per observed day. A sensitivity analysis based on the regression equation indicated that nonsurvivorship doubles the cost per case, increased severity as measured by the Child-Pugh Index adds about 50% to the cost, and chemotherapy increases cost 2-fold. Conclusions: The relatively modest average cost per patient with HCC in Hong Kong reflects the short median survival and subsequently the limited use of inpatient care and chemotherapy.Antineoplastics, Cost analysis, Herbal medicines, Liver cancer, Pharmacoeconomics