Drug safety evaluation of sorafenib for treatment of solid tumors: consequences for the risk assessment and management of cancer patients

Introduction: Sorafenib is a multi-tyrosine kinase inhibitor (TKI). Considerable clinical experience has been accumulated since its first Phase III clinical trial in metastatic renal cancer patients in 2007. The management of its early acute toxicity in fit patients is well known. The management of prolonged treatment becomes the new challenge.

Areas covered: Using sorafenib as a key word for PubMed search, we review preclinical and clinical data and discuss the pharmacokinetics and pharmacodynamics of sorafenib, its acute and cumulative toxicities and their consequences for patient management.

Expert opinion: The systematic multi-disciplinary risk assessment of cancer patients prior to TKI initiation reduces the risks of acute and late toxicity, especially drug–drug interactions and arterial risks. Sarcopenia is now identified as a major risk of severe toxicity. The very diverse clinical pictures of cumulative toxicity must be known. The monitoring of sorafenib systemic exposure is helpful especially in elderly patients. Moreover, at disease progression, it allows distinguishing between underexposure to sorafenib and truly acquired resistance to the drug. The optimal use of sorafenib should allow improving the reported results of flat-dose. Finally, most of this knowledge could be used for the development and optimal use of the other TKIs.     

Safety and tolerability of extended-release niacin with laropiprant

Introduction: Niacin is one of the oldest drugs used in the treatment of dyslipidemia. Previously its use has been limited because of excessive flushing. Now an agent laropiprant (LRP) has been developed, which blocks the flushing pathway. Therefore, it is time to collate available information to assess the safety and tolerability of combining niacin with LRP.

Areas covered: The authors searched PubMed and MEDLINE for literature published between January 2006 and July 2011, for safety and tolerability reports of extended-release niacin (ERN) with LRP.

Expert opinion: The addition of LRP to ERN, by reducing the side effect ‘flushing’, may enable lipidologists and physicians to use niacin more widely as part of lipid modification therapy, especially since the combination can be safely added to statins. However, it has to be accepted that the addition of LRP does not completely abolish flushing. The favorable safety profile supports the use of LRP to achieve higher therapeutic dosing of niacin.     

Sorafenib in locally advanced or metastatic breast cancer

Introduction: Sorafenib is an oral multikinase inhibitor with anti-angiogenic and anti-proliferative activity that is indicated for use in hepatocellular and renal cell carcinomas. Sorafenib is being developed in a number of solid tumors, including breast cancer (BC).

Areas covered: A series of four randomized, double-blind, placebo-controlled Phase IIb screening Trials were developed to Investigate the Efficacy of Sorafenib (TIES) when added to select chemotherapies for patients with HER2-negative advanced BC with a primary endpoint of progression-free survival (PFS). Results have been varied. SOLTI-0701 reported significant PFS benefit for sorafenib plus capecitabine as first- or second-line treatment, and AC01B07 reported a modest but significant PFS benefit when sorafenib was combined with gemcitabine or capecitabine for patients whose disease had progressed during or after bevacizumab. Sorafenib plus first-line paclitaxel did not significantly improve PFS (NU07B1 study), nor did its addition to first-line docetaxel and/or letrozole (FM-B07-01 study). A Phase III trial of sorafenib plus capecitabine has been initiated.

Expert opinion: Phase IIb data indicate a potential role for sorafenib in combination with select chemotherapies for HER2-negative advanced BC, but Phase III confirmatory trials are necessary. The variability in results across studies with sorafenib may be related to the chemotherapy combination and/or patient population.     

Sorafenib in melanoma

Introduction: Sorafenib is an orally available multi-kinase inhibitor that inhibits tumor proliferation by targeting multiple kinases including the vascular endothelial growth factor receptors VEGFR1, VEGFR2, VEGFR3 and the platelet-derived growth factor receptor PDGFR, and it targets tumor progression by inhibiting FLT3, C-Kit and BRAF. Since BRAF mutations are frequent in melanoma, sorafenib was investigated in various Phase I, II and III clinical trials. The drug is well tolerated with mild to moderate adverse effects, which are mostly limited to cutaneous toxicity, diarrhea and fatigue.

Areas covered: Systematic literature review of the randomized trials using PubMed was performed. Original articles were reviewed and citations from those were also considered. Additionally, clinical trial databases were examined to identify and summarize ongoing trials of sorafenib in melanoma patients.

Expert opinion: Sorafenib as a monotherapy or in combination with chemotherapy is of limited use. Combining it with dacarbazine doubled the response rate and the progression-free survival in metastatic melanoma patients. Unfortunately, these results have never been evaluated in large randomized Phase III clinical trials. According to the trials conducted so far a subpopulation of patients experience substantial benefit, therefore it is essential to identify biomarkers to select the subgroups of patients that are more likely to respond to sorafenib. Furthermore, other less frequent subtypes such as mucosal or ocular melanoma still constitute promising targets; academic institutions are currently launching investigator-initiated trials in these indications.     

MP-376 (Aeroquin) for chronic Pseudomonas aeruginosa infections

Introduction: The chronic airway infection with Pseudomonas aeruginosa (PA) is a risk factor for rapid disease progression in various chronic pulmonary diseases including cystic fibrosis or chronic obstructive pulmonary disease. Inhaled antibiotics are able to treat effectively such chronic airway infections, and MP-376 is currently in late-stage clinical development for such an indication.

Areas covered: Review of the existing preclinical and clinical data on MP-376, with a focus on the efficacy and safety of the compound on chronic airways infections due to PA.

Expert opinion: Chronic airways infection with PA represents a therapeutic challenge because of its own complex mechanisms of defense, because of the rapid development of antibiotic resistance and by the fact that systemic antibiotics are not always able to achieve appropriate concentrations at lung level. Inhaled antibiotics (tobramycin, aztreonam, etc.) represent optimal alternatives to their systemic homologs due to their better penetrability in the lungs and due to the lower systemic exposure. Inhaled levofloxacin which is currently investigated for chronic airways infection might be another possible antipseudomonal inhaled therapy.     

Macitentan for the treatment of pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a serious disease characterized by elevation of pulmonary artery pressures and right ventricular failure. It is a progressive disease with a poor 5-year survival despite recent advances in treatment. Endothelin plays an important role in the development and progression of the disease. Endothelin receptor blockers have been used to treat PAH since 2001. More recently, macitentan was approved for treatment of PAH.

Area covered: This review covers the preclinical and clinical data on macitentan.

Expert opinion: Macitentan is a more potent ERA and has been shown to delay progression of the disease. It does not appear to have any significant hepatotoxicity and has a convenient once-a-day dosing. In the large event driven trial, macitentan significantly reduced morbidity in patients with PAH. It was safe and well tolerated and the benefit was seen in treatment-naïve patients and those already receiving PAH therapy.     

Dasatinib for the treatment of Philadelphia chromosome-positive leukemias

Introduction: Dasatinib is a dual Abl/Src tyrosine kinase inhibitor (TKI), which was developed to treat patients with chronic myelogenous leukemia (CML), who had failed or were intolerant to therapy with imatinib.

Areas covered: In this article, we review preclinical and clinical studies with dasatinib for the therapy of Philadelphia (Ph)-positive leukemias.

Expert opinion: Dasatinib is very effective in the setting of CML resistance or intolerance to imatinib, particularly in patients in chronic phase (CP). Dasatinib is also effective against most BCR-ABL1 mutations that arise during therapy with imatinib. Further studies have confirmed activity of dasatinib as a single-agent, and combined with chemotherapy, for the treatment of patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+-ALL). More recently, randomized trials have demonstrated that dasatinib is superior to imatinib in the initial therapy of patients with CML, and the drug was approved by the FDA for this indication in 2011.     

Bleeding risk and safety profile related to the use of eptifibatide: a current review

Introduction: Eptifibatide is a glycoprotein IIb/IIIa inhibitor that blocks the final common pathway of platelet aggregation. Its major adverse effect is bleeding. Balancing its safety and efficacy is paramount for its appropriate usage.

Areas covered: The development of eptifibatide and its mechanism of action are explored. Clinical trials evaluating its efficacy and safety in a variety of clinical settings, as well as newer dosing regimens, are discussed. Readers will be able to understand the bleeding risks of eptifibatide in specific patient populations.

Expert opinion: The risk of bleeding with eptifibatide needs to be weighed against the potential benefits. Understanding which patients are at higher risk of bleeding will help the clinician make appropriate decisions.     

Asenapine review,part II: clinical efficacy,safety and tolerability

Introduction: Asenapine is a second-generation (atypical) antipsychotic currently marketed for the treatment of schizophrenia and bipolar mania/mixed episodes.

Areas covered: The purpose of this review is to describe the clinical profile of asenapine.

Expert opinion: Asenapine's efficacy in the treatment of schizophrenia and in the acute management of bipolar manic or mixed episodes, within the recommended therapeutic dose range of 5 – 10 mg twice a day, is evidenced by a broad clinical development program. Asenapine's overall tolerability profile is notable for the potential for sedation (time-limited) and, to a lesser extent, extrapyramidal symptoms/akathisia, dizziness, and oral hypoesthesia. Asenapine's effects on weight and metabolic variables appear modest, as are its effects on the ECG QTc interval and on prolactin.     

Quetiapine for the treatment of acute bipolar mania,mixed episodes and maintenance therapy

Introduction: Bipolar disorder is characterized by mood instability, which can be challenging to manage. First-line pharmacological approaches usually involve lithium, anticonvulsants and antipsychotics. Over the past fifteen years, several second-generation antipsychotics have demonstrated benefits for various phases of this disorder.

Areas covered: This article examines the pharmacodynamics and pharmacokinetics of quetiapine; its evidence base as an acute and maintenance monotherapy or adjunctive therapy for bipolar manic or mixed episodes is also discussed, along with the related issues of its safety and tolerability.

Expert opinion: In the context of bipolar disorder, quetiapine is the only agent approved as a monotherapy or adjunct therapy for acute manic/mixed episodes in adults and adolescents; as a monotherapy for acute depressive episodes in adults; and as an adjunctive maintenance therapy for bipolar I and II disorder in adults. In addition to its antipsychotic properties, this broad mood-stabilizing potential may simplify the management of select patients.     

Perifosine – a new option in treatment of acute myeloid leukemia?

Introduction: Perifosine is a novel targeted oral Akt inhibitor. In preclinical leukemia models, perifosine has an independent cytotoxic potential but also synergizes well with other rationally selected targeted agents. The evidence from clinical trials supporting the use of perifosine in the therapy of leukemias is limited. The optimal dose and schedule have yet to be defined. However, given its favorable toxicity profile and mechanism of action, the therapeutic potential of perifosine should be evaluated in well-designed clinical trials.

Areas covered: The role of the phosphatidylinositol-3 kinase (PI3K)/Akt zpathway in normal cells, cancer and leukemias is discussed. The mechanism of action of perifosine and the basic information on the development and chemical properties are summarized. The evidence from in vivo and in vitro studies is presented. The efficacy and side effect profile are summarized.

Expert opinion: The safety and tolerability profile of perifosine are satisfactory. The evidence from clinical trials in patients with leukemias is very limited. The preclinical data are encouraging. Perifosine has the potential to play a role in the treatment of leukemias in the future. Its role needs to be confirmed in clinical trials.     

Rifaximin for the treatment of irritable bowel syndrome

Introduction: Few therapeutic options are available for irritable bowel syndrome (IBS). Lubiprostone is approved by the FDA for IBS with constipation, and alosetron in IBS with diarrhea (IBS-D). It has been proposed that alterations in the bowel microflora may play a role in the pathophysiology of IBS, and that modulation of the microflora holds therapeutic potential. Rifaximin is a nonsystemic antibiotic that has shown efficacy in IBS.

Areas covered: This narrative review covers the treatment options available for IBS-D and focuses on rifaximin. Rifaximin pharmacodynamics, clinical pharmacology and results of clinical studies from proof of concept to the latest Phase III and retreatment studies in IBS are summarized. Challenges to rifaximin use, safety issues and regulatory data are also discussed.

Expert opinion: The evidence supports rifaximin as an emerging treatment for IBS. Strategies for appropriate patient selection need to be further developed, and continued efficacy of rifaximin over repeated treatment courses needs to be better characterized.     

Dalcetrapib,a cholesteryl ester transfer protein modulator

Introduction: Cholesteryl ester transfer protein (CETP) plays an important role in reverse cholesterol transport by transferring cholesteryl esters from high-density lipoprotein (HDL) to the apolipoprotein B-containing lipoproteins. Inhibition of CETP is a target to increase HDL-cholesterol and potentially reduce atherosclerosis. Dalcetrapib is an orally administered CETP inhibitor developed for the treatment of primary hypercholesterolaemia and mixed hyperlipidaemia.

Areas covered: Areas covered are: mode of action, preclinical development and clinical trials of dalcetrapib, a CETP modulator. The article provides an understanding of the pharmacokinetic and pharmacodynamic characteristics of dalcetrapib and insight into its clinical efficacy and safety. In clinical trials, dalcetrapib produced significant elevations in HDL-cholesterol when taken alone or in combination with statin with no effect on blood pressure or expression of genes involved in the renin–angiotensin–aldosterone system.

Expert opinion: Although dalcetrapib is the least potent CETP inhibitor, it does not impair the formation of CETP-induced pre-β HDL, which might be needed to increase reverse cholesterol transport. While dalcetrapib is well-tolerated and does not show major side effects, the recent interim results of the Phase III dal-OUTCOMES trial have shown the lack of a clinically meaningful benefit, and further testing of the drug has been halted.     

Latanoprost/timolol fixed combination for the treatment of glaucoma

Introduction: Glaucoma is a multifactorial optic neuropathy that can lead to progressive and irreversible loss of vision. Today there are > 60 million glaucoma patients worldwide, and this figure is rising due to aging. The aim of glaucoma therapy is to maintain the patient's visual function and quality of life by means of intraocular pressure (IOP) reduction, which currently constitutes the only evidence-based approach.

Areas covered: Briefly discussed are selected, recent evidence on antiglaucoma fixed combinations. Then the efficacy and safety of the latanoprost/timolol fixed combination is comprehensively reviewed.

Expert opinion: The latanoprost/timolol fixed combination can be a helpful stepwise therapeutic option in patients whose IOP is insufficiently controlled with monotherapy options. Future research is needed to better delineate the role and value of this medication in glaucoma therapy.     

Lenalidomide as a novel treatment of acute myeloid leukemia

Introduction: Lenalidomide is an oral immunomodulatory drug derived from thalidomide. This drug has been approved by the Food and Drug Administration for transfusion-dependent anemia due to low-risk myelodysplastic syndromes (MDS) associated with deletion 5q abnormality with or without additional cytogenetic abnormalities and multiple myeloma in combination with dexamethasone. Trials have been conducted for its use in higher-risk MDS and acute myeloid leukemia (AML).

Areas covered: The pharmacokinetic and mechanism of action are discussed and clinical studies of lenalidomide in AML are reported herein in detail. An overview of safety and tolerability is also presented.

Expert opinion: Lenalidomide has clinical activity in AML with manageable toxicity. The population that would benefit from lenalidomide and optimal dose needs to be better defined. Recent trials have focused on combining lenalidomide with other agents active in MDS and AML and promising data are emerging.     

Radium-223 dichloride for the treatment of metastatic prostate cancer

Introduction: Bone metastases are a frequent complication of many malignancies and are particularly common in metastatic prostate cancer, where they are associated with a high degree of morbidity. Until recently, treatments relied on palliative bone targeting measures with no proven survival-prolonging action or on systemic agents with general anti-prostate cancer activity but significant toxicities. Radium-223 dichloride is a bone-seeking, α-emitting, radionuclide that has recently been licensed in the US and Europe for the treatment of men with castration-resistant prostate cancer, bone metastases and no known visceral metastases. Radium-223 is the first bone-seeking radionuclide therapy proven to result in increased overall survival versus placebo.

Areas covered: The existing market of bone-targeted agents is reviewed before considering what radium-223 adds by examining its pharmacology, pharmacokinetics and clinical efficacy and safety data. Initial relevant papers were identified by searching PubMed using combinations of the terms, ‘Radium’, ‘Prostatic neoplasms’, ‘Bone’, ‘Neoplasm metastasis’.

Expert opinion: Consideration is given to further preclinical work needed into the mechanism of action of radium-223 and future clinical directions of the drug including combinations with other agents.     

MLN4924: a novel first-in-class inhibitor of NEDD8-activating enzyme for cancer therapy

Introduction: The small ubiquitin-like molecule NEDD8 has been identified as an essential regulator of the activity of the cullin-RING E3 ubiquitin ligases (CRLs), which control the turnover of multiple proteins with fundamental roles in cancer biology. The aberrant function of the NEDD8 cascade within the context of malignancy makes it an attractive target for the development of novel anticancer agents. MLN4924 is a first-in-class inhibitor of the proximal regulator of the NEDD8 system (NEDD8-activating enzyme, NAE) that has entered Phase-I trials for cancer therapy and has established that significant therapeutic benefit can be achieved by antagonizing NEDD8-mediated protein degradation.

Areas covered: This review provides a detailed overview of the NEDD8 system and discusses the mechanisms of action of MLN4924, a novel small molecule NAE inhibitor. Key findings from preclinical investigations of MLN4924 in a broad range of cancer models and preliminary findings from ongoing Phase-I clinical trials with MLN4924 are also discussed.

Expert opinion: Targeting protein NEDDylation represents an exciting new anticancer strategy with demonstrable therapeutic benefit. Ongoing and future studies focused on dissecting the functional status/regulation of the NEDD8 system in individual tumor types will facilitate the design of novel approaches that yield optimal therapeutic benefit.