Trametinib: First Global Approval Wright, Cameron J. M.; McCormack, Paul L.
Drugs (New York, N.Y.),
07/2013, Letnik:
73, Številka:
11
Journal Article
Recenzirano
Trametinib is an orally bioavailable mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor with antineoplastic activity. The compound specifically binds to MEK1 and MEK2, resulting in ...inhibition of growth factor-mediated cell signalling and cellular proliferation in various cancers. Originally developed by Japan Tobacco, GlaxoSmithKline has licensed exclusive worldwide rights to the compound and conducted development in a number of different cancer types. Trametinib, as a monotherapy, has been approved in the US for the treatment of unresectable or metastatic malignant melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. The compound, as a monotherapy, has also been submitted for regulatory review in the EU for BRAF mutation-positive malignant melanoma, and is in phase III development in Europe, Argentina, Canada and Oceania. Phase II development is underway for pancreatic cancer, non-small cell lung cancer and relapsed or refractory leukaemias. GlaxoSmithKline is also developing trametinib for use in combination with dabrafenib in BRAF V600 mutation-positive metastatic cutaneous melanoma; the combination is at the preregistration stage in the EU and a phase III clinical programme is underway worldwide. Phase II development for this combination is also underway in colorectal cancer. Several phase I trials have also been initiated to evaluate trametinib in combination with other drugs for the treatment of various solid tumours and haematological malignancies. A paediatric oral solution formulation has been assessed against the oral tablet formulation in a phase I trial. This article summarizes the milestones in the development of trametinib leading to this first approval for unresectable or metastatic BRAF mutation-positive malignant melanoma.
Background Open esophagectomy results in significant morbidity and mortality. Minimally invasive esophagectomy (MIE) has become increasingly popular at specialized centers with the aim of improving ...perioperative outcomes. Numerous single-institution studies suggest MIE may offer lower short-term morbidity. The two approaches are compared using a large, multiinstitutional database. Methods The Society of Thoracic Surgeons (STS) National Database (v2.081) was queried for all resections performed for esophageal cancer between 2008 and 2011 (n = 3,780). Minimally invasive approaches included both transhiatal (n = 214) and Ivor Lewis (n = 600), and these were compared directly with open transhiatal (n = 1,065) and Ivor Lewis (n = 1,291) procedures, respectively. Thirty-day outcomes were examined using nonparametric statistical testing. Results Both open and MIE groups were similar in terms of preoperative risk factors. Morbidity and all-cause mortality were equivalent at 62.2% and 3.8%. MIE was associated with longer median procedure times (443.0 versus 312.0 minutes; p < 0.001), but a shorter median length of hospital stay (9.0 versus 10.0 days; p < 0.001). Patients who underwent MIE had higher rates of reoperation (9.9% versus 4.4%; p < 0.001) and empyema (4.1% versus 1.8%; p < 0.001). Open technique led to an increased rate of wound infections (6.3% versus 2.3%; p < 0.001), postoperative transfusion (18.7% versus 14.1%; p = 0.002), and ileus (4.5% versus 2.2%; p = 0.002). Propensity score-matched analysis confirmed these findings. High- and low-volume centers had similar outcomes. Conclusions Early results from the STS National Database indicate that MIE is safe, with comparable rates of morbidity and mortality as open technique. Longer procedure times and a higher rate of reoperation following MIE may reflect a learning curve.
The European Society of Thoracic Surgery (ESTS) and the Society of Thoracic Surgeons (STS) general thoracic surgery databases collect thoracic surgical data from Europe and North America, ...respectively. Their objectives are similar: to measure processes and outcomes so as to improve the quality of thoracic surgical care. Future collaboration between the two databases and their integration could generate significant new knowledge. However, important discrepancies exist in terminology and definitions between the two databases. The objective of this collaboration between the ESTS and STS is to identify important differences between databases and harmonize terminology and definitions to facilitate future endeavors.
Background The Society of Thoracic Surgeons (STS) creates risk-adjustment models for common cardiothoracic operations for quality improvement purposes. Our aim was to update the lung cancer resection ...risk model utilizing the STS General Thoracic Surgery Database (GTSD) with a larger and more contemporary cohort. Methods We queried the STS GTSD for all surgical resections of lung cancers from January 1, 2012, through December 31, 2014. Logistic regression was used to create three risk models for adverse events: operative mortality, major morbidity, and composite mortality and major morbidity. Results In all, 27,844 lung cancer resections were performed at 231 centers; 62% (n = 17,153) were performed by thoracoscopy. The mortality rate was 1.4% (n = 401), major morbidity rate was 9.1% (n = 2,545), and the composite rate was 9.5% (n = 2,654). Predictors of mortality included age, being male, forced expiratory volume in 1 second, body mass index, cerebrovascular disease, steroids, coronary artery disease, peripheral vascular disease, renal dysfunction, Zubrod score, American Society of Anesthesiologists rating, thoracotomy approach, induction therapy, reoperation, tumor stage, and greater extent of resection (all p < 0.05). For major morbidity and the composite measure, cigarette smoking becomes a risk factor whereas stage, renal dysfunction, congestive heart failure, and cerebrovascular disease lose significance. Conclusions Operative mortality and complication rates are low for lung cancer resection among surgeons participating in the GTSD. Risk factors from the prior lung cancer resection model are refined, and new risk factors such as prior thoracic surgery are identified. The GTSD risk models continue to evolve as more centers report and data are audited for quality assurance.
Background The aim of this study is to create models for perioperative risk of lung cancer resection using the STS GTDB (Society of Thoracic Surgeons General Thoracic Database). Methods The STS GTDB ...was queried for all patients treated with resection for primary lung cancer between January 1, 2002 and June 30, 2008. Three separate multivariable risk models were constructed (mortality, major morbidity, and composite mortality or major morbidity). Results There were 18,800 lung cancer resections performed at 111 participating centers. Perioperative mortality was 413 of 18,800 (2.2%). Composite major morbidity or mortality occurred in 1,612 patients (8.6%). Predictors of mortality include the following: pneumonectomy ( p < 0.001), bilobectomy ( p < 0.001), American Society of Anesthesiology rating ( p < 0.018), Zubrod performance status ( p < 0.001), renal dysfunction ( p = 0.001), induction chemoradiation therapy ( p = 0.01), steroids ( p = 0.002), age ( p < 0.001), urgent procedures ( p = 0.015), male gender ( p = 0.013), forced expiratory volume in one second ( p < 0.001), and body mass index ( p = 0.015). Conclusions Thoracic surgeons participating in the STS GTDB perform lung cancer resections with a low mortality and morbidity. The risk-adjustment models created have excellent performance characteristics and identify important predictors of mortality and major morbidity for lung cancer resections. These models may be used to inform clinical decisions and to compare risk-adjusted outcomes for quality improvement purposes.
Navigating the lung for hidden treasure Wright, Cameron D.
The Journal of thoracic and cardiovascular surgery,
10/2018, Letnik:
156, Številka:
4
Journal Article
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