Areas covered: Current data are presented on the efficacy and safety of BRAFi + MEKi combination therapy (dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib) from phase I, II, and III trials in the unresectable/locally advanced metastatic setting, as well as neoadjuvant and adjuvant applications. The theoretical basis, pre-clinical findings, clinical trial results and current ongoing clinical studies of combined BRAF/MEK inhibition with immunotherapy, also known as ‘triplet therapy,’ are also explored.
Expert opinion: Combination therapy with BRAF and MEK inhibitors dramatically improves response rates, progression-free survival and overall survival in patients with BRAF-mutant metastatic melanoma compared to historical treatments such as chemotherapy. Some serious adverse effects, including cutaneous squamous cell carcinoma, are attenuated with combination therapy, while less severe and reversible effects including pyrexia, left ventricular dysfunction, and ocular events can be more common with combination therapy. Existing data are insufficient to recommend triplet therapy, or a particular treatment sequence, with respect to BRAF and MEK inhibitors and immune therapies, though results from multiple ongoing trials are anticipated. 相似文献
Areas covered: In this review, the authors discuss the evidence for currently approved therapies for cutaneous melanoma, including adjuvant therapy, potential new biomarkers, and emerging treatments with early phase clinical trial data. The authors have searched both the PubMed and clinicaltrials.gov databases for published clinical trials and discuss selected landmark trials of current therapies and of investigational treatment strategies with early evidence for the treatment of melanoma.
Expert opinion: Significant efficacy has been demonstrated with both immune checkpoint inhibitors and targeted therapies in treating advanced melanoma. A multitude of novel therapies are in development and there is need for instructive biomarker assessment to identify patients likely to respond or be refractory to current therapies, to identify mechanisms of resistance and to direct further treatment options to patients based on individual disease biology. 相似文献
Areas covered: Encorafenib in combination with bimetinib offers a new approach that may offer benefits over existing BRAF/MEK inhibitor combinations.
Expert opinion: While other BRAF/MEK inhibitor combinations have achieved a median overall survival (OS) of 22 months, patients with advanced BRAF mutation-positive melanoma treated with encorafenib plus binimetinib achieved a median OS of 33.6 months in the phase III COLUMBUS trial. PFS also appears to be improved with encorafenib plus binimetinib. This improved efficacy may be related to the distinct pharmacokinetics of encorafenib, with prolonged binding to the target molecule providing greater BRAF inhibition and increased potency compared with other drugs in the same class. Increased specificity of encorafenib may also result in better tolerability with less off-target effects, including reduced occurrence of pyrexia and photosensitivity. Encorafenib plus binimetinib seems likely to emerge as a valuable therapeutic alternative to established BRAF/MEK inhibitor combinations. 相似文献
Areas covered: We summarize the recent clinical successes of CTLA-4 inhibitors and place a strong emphasis on those in early phase clinical trials, often in combination with other immune check-point inhibitors, i.e., programmed cell death protein 1 (PD-1) and BRAF/mitogen-activated protein kinase inhibitors.
Expert opinion: Recent phase I and phase II clinical trials confirm the efficacy of anti-CTLA-4 therapy for treatment of cancers such as renal cell carcinoma. These studies also indicated increased efficacy with combined immune checkpoint blockade with PD-1 or Ras/Raf/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) inhibitors. Researchers must search for new immune targets that may enable more effective and safe immune checkpoint blockade and cancer therapy. This goal may be achieved by next-generation combination therapies to overcome immune checkpoint therapy resistance. 相似文献
Areas covered: The role of PDE inhibitors in asthma treatment and the possible mechanism of action via their anti-inflammatory and/or bronchodilating effect are discussed.
Expert opinion: Novel PDE inhibitors exhibiting fewer adverse events may have a role as add-on therapies in asthma treatment in the future. More clinical trials are necessary to prove their efficacy and evaluate their safety profile before approval by regulatory bodies is granted. 相似文献
Areas covered: A literature search on ‘HDAC inhibitors’ and ‘multiple myeloma’ was carried out using PubMed and Google Scholar in the preparation of this overview on clinical efficacy and safety data.
Expert opinion: First-generation non-selective HDAC inhibitors have demonstrated minimal single-agent activity in refractory MM. Subsequently, combination therapy has proven an improvement in progression-free survival (PFS) but not response rates. The main concerns are associated with toxicities. Ongoing studies on new and more selective agents, i.e. Romidepsin or Ricolinostat, are promising in terms of better efficacy and less toxicity. 相似文献
Commonly used cytotoxics in these patients include paclitaxel, dacarbazine, platins, and temozolomide. The overall response rates of these agents are usually disappointing and short-lived.
Areas covered: Herein, the author provides a literature review of the role of nab-paclitaxel in metastatic melanoma including coverage of its pharmacokinetics, pharmacodynamics and efficacy.
Expert opinion: The role of chemotherapy in the treatment of metastatic melanoma is limited to patients who failed checkpoint inhibitors and, when applicable, targeted agents, and those not appropriate for clinical trials. nab-Paclitaxel has single agent activity in chemotherapy-naïve untreated metastatic melanoma which compares favorably to the activity of weekly paclitaxel or single agent dacarbazine. However, the activity in chemotherapy-pretreated patients is modest. Data on nab-paclitaxel in patients pretreated with targeted agents or check point inhibitors are lacking. Further advances are expected from new checkpoint inhibitors and targeted agents for the treatment of metastatic melanoma in addition to the optimal combination and sequencing of these agents. 相似文献
Areas covered: This article outlines the current knowledge of ncRNA involvement in BRAF-mutant melanomas and the development of resistance to targeted/immunotherapies. We also discuss how ncRNAs can be exploited for the development of therapeutic and diagnostic approaches.
Expert opinion: ncRNAs can be envisaged as powerful diagnostics and therapeutics. Despite progress in our knowledge about their deregulation in cancer, it is still difficult to derive universal and robust ncRNAs unique signatures of malignancy for diagnostic purposes, which need validation in large cohort of patients. Also, ncRNA specific targeting to melanoma cells in vivo requires the development of improved systemic delivery tools. In this regard, the development of stable nanodelivery particles seems to offer renewed hope for success in the clinic. 相似文献
Areas covered: Multitargeted kinase inhibitors are small molecule inhibitors with limited toxicity. This review will focus on early-stage investigations of multitargeted tyrosine kinase inhibitors (m-TKIs) (those that target at least two tyrosine kinases) for HNSCC. Preclinical and early trials investigating m-TKIs for various disease settings of HNSCC will be evaluated for efficacy, identification of significant biomarkers and potential for combination therapy.
Expert opinion: Few single agent m-TKIs have demonstrated efficacy in unselected HNSCC populations. The most promising clinical results have been obtained when m-TKIs are tested in combination with other therapies, including immunotherapy, or in mutation-defined subgroups of patients. The future success of m-TKIs will rely on identification, in preclinical models and clinical trials, of predictive biomarkers of response and mechanisms of innate and acquired resistance. 相似文献
Areas covered: This article reviews preclinical data, clinical studies that have evaluated the efficacy and safety profiles of buparlisib as a monotherapy or in combination with targeted therapy (including endocrine and anti-HER2 therapy) or cytotoxics. The authors cover completed and ongoing studies to evaluate the benefit vs risk profile of buparlisib.
Expert opinion: Targeting PI3K showed efficacy in BC. Buparlisib, a pan PI3K inhibitor, presents manageable but not negligible toxicity with an activity/toxicity ratio in favor of the use of emerging second generation, α–selective PI3K inhibitors for ongoing and future trials. 相似文献
Areas covered: The VEGFR pathway, its aberrant signaling, and the agents under development that inhibit VEGFR signaling are discussed. The mechanism(s), pharmacokinetics, pharmacodynamics, efficacy, and toxicity of these investigational agents are also reviewed.
Expert opinion: Management of metastatic RCC involves combination immunotherapy or administration of oral VEGFR inhibitors and largely depends on risk stratification. Emerging and investigational oral VEGFR inhibitors, given as monotherapy or in combination with immunotherapy, could augment current treatment approaches and may mitigate toxicities associated with VEGFR inhibition. 相似文献
Areas covered: This review summarizes the mechanisms of action, current role and future directions of microtubule targeting agents; we focus on investigational agents in phase I and II clinical trials.
Expert opinion: Chemotherapy maintains a pivotal role in the treatment of NSCLC. New generation agents that have the potential to overcome the mechanisms of resistance to the available drugs may provide new therapeutic opportunities. Predictive biomarkers derived from combination strategies and phase III studies are necessary going forward. 相似文献
Area covered: This review aims to provide a comprehensive overview of the different types of molecules patented as potent urease inhibitors from the year 2012 to 2018.
Expert opinion: Urease is an important target to treat urease-related bacterial infections manifesting as gastric ulcers, urinary tract infections, and kidney stones. Although many different molecules as inhibitors of urease have been reported, only a few have advanced to clinical trials. The development of new effective urease inhibitors demands new suitable lead molecules. This review covers the patents on urease inhibitors in recent years (2012–2018) with a hope to bring into focus the issue and need for availability of new urease inhibitors on the market. 相似文献
Areas covered: Patients receiving TNF-α inhibitors are at high risk of infections. An update is made on the risk of infection in patients receiving TNF-α inhibitors and the strategies for mitigating against the development of these serious adverse events.
Expert opinion: Infliximab than etanercept appears to be responsible for the increased risk of infections. Re-activation of latent tuberculosis infection and the overall risk of opportunistic infections should be considered before beginning a course of TNF-α inhibitors. A careful medical history, Mantoux test/quantiferon-TB Gold In-tube Test and chest-X-ray should always be performed before starting TNF-α inhibitors. Particular attention should be paid to risk factors for Pneumocystis jirovecii infection. Hepatitis B and C virological follow-up should be considered during TNF-α inhibitors treatment. Finally, appropriate vaccinations for influenza, S. pneumoniae, and HBV should be administered to decrease the risk of infection, and patients who are at high risk of herpes zoster reactivation would benefit from a second vaccination in adulthood. 相似文献
Areas covered: In this review, we present current information about the physiological role of the cohesin complex in normal and malignant cells and describe current therapeutic strategies that are being explored in cohesin-mutated cancers. We discuss a range of targets and strategies that should be explored to develop targeted therapies for patients with aberrant cohesin.
Expert opinion: Targeting of the cohesin complex is an underexplored area of drug development. There is a high frequency of cohesin mutations in multiple cancers, hence specific targeting strategies should be explored. Cohesins play a crucial role in cellular organization; therefore, we expect a narrow therapeutic window of direct inhibitors of cohesin components. Exploiting experimental approaches that correct dysfunctional cohesins and coupling them with current therapeutic strategies can provide novel, innovative and more effective treatment regimens. 相似文献
Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson’s disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed.
Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4–12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients.
Conclusions: Istradefylline improved gait disorders in Parkinson’s disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified.
Trial registration: UMIN-CTR (UMIN000020288). 相似文献
Areas covered: This review comprises a summary of patent applications (2013–2018) of SGLT2 inhibitors with focus on chemical structural advancement and therapeutic potentials in the management of diabetes and related disorders.
Expert opinion: SGLT2 inhibitors exert multiple metabolic benefits, including reduced glycated hemoglobin (HbA1c), improved glycemic control (fasting and postprandial), reduced body weight, reduced systolic and diastolic blood pressure and improved HDL cholesterol. Due to the virtue of no interference with insulin action and secretion, their efficacy remains the same even in presence of progressive β cell failure in type 2 diabetes. Additionally, few members of this class have been reported to exhibit cardioprotective, renoprotective, and anticancer activity. However, more study on the long-term outcomes in patients taking SGLT2 inhibitors is warranted. 相似文献
Methods: PubMed was searched (2010–2015) for articles involving the treatment and management of advanced STS. Key search terms included “soft tissue sarcoma”, “pazopanib”, “chemotherapy”, “doxorubicin”, “ifosfamide”, “trabectedin” and “gemcitabine”. Additionally, ClinicalTrials.gov was searched to identify ongoing studies evaluating pazopanib in STS. Reference citations within relevant articles revealed further sources of value.
Results: Standard treatment for advanced STS is single agent or combination systemic chemotherapy. The efficacy of these treatments varies widely, likely because of tumor heterogeneity and cellular mechanisms of chemoresistance, and adverse effects may be a limiting factor for combination therapy. Pazopanib, approved for the treatment of advanced STS in patients who received prior chemotherapy, has demonstrated clinical benefit in a variety of histologic types of advanced STS where the prognosis is often poor. While pazopanib has a favorable safety profile compared with commonly prescribed chemotherapies, it has several safety concerns and dose-limiting adverse effects. We share our best practice for managing adverse events to ensure patient tolerability.
Conclusions: Use of pazopanib increases the treatment options available to control advanced STS, with management of adverse events through close monitoring, patient education and treatment as necessary. 相似文献
Areas covered: This article first summarizes the results reported with RAAS inhibitors, mainstay of nephroprotection in T2DM with albuminuria. Second, it describes the positive results with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and, even more impressive, sodium-glucose cotransporter type 2 inhibitors (SGLT2is). Third, besides the potential of combined therapies, it briefly considers some new approaches currently in development.
Expert opinion: RAAS inhibitors exert renoprotective effects beyond their blood pressure lowering effects while SGLT2is, and possibly GLP-1RAs, exert nephroprotection independently of their glucose-lowering activity. These effects were demonstrated not only on surrogate endpoints such as albuminuria and estimated glomerular filtration rate decline, but also on hard endpoints, including progression to end-stage renal disease requiring replacement therapy. The underlying mechanisms are different and potentially complementary on glomerular hemodynamics, arguing for combined therapies. Nevertheless, there is still room for new emerging drugs to tackle CKD in T2DM. 相似文献