Temsirolimus: a safety and efficacy review

Introduction: The vascular endothelial growth factor (VEGF) pathway and the mammalian Target of Rapamycin (mTOR) represent the most frequently exploited targets in renal cell carcinoma (RCC). Temsirolimus is an inhibitor of mTOR, and is a unique ester derivative of sirolimus, a macrocyclic lactone, with improved pharmaceutical properties, including stability and solubility. Temsirolimus binds to the cytoplasmic protein FKBP-12, and the complex binds and inhibits mTOR.

Areas covered: This review summarizes the clinical findings and safety of temsirolimus in RCC patients.

Expert opinion: A Phase III clinical trial has demonstrated that temsirolimus has statistically significant advantages over treatment with IFN-α in RCC patients with poor prognosis, in terms of OS (overall survival), PFS (progression-free survival), and tumor response. Median OS was improved 49% compared to IFN-α, and median PFS was approximately doubled. It is now considered the standard for RCC patients with poor prognostic features. The possibility that this agent is useful in metastatic non-clear cell carcinoma patients has also been suggested by a subset analysis of the pivotal Phase III trial. Studies in untreated favorable and intermediate risk clear cell and refractory mRCC patients are required.     

Tivozanib: current status and future directions in the treatment of solid tumors

Introduction: Tivozanib is a novel tyrosine kinase inhibitor (TKI) which inhibits vascular endothelial growth factor (VEGF) receptors-1, -2, and -3 at nanomolar concentrations.

Areas covered: A comprehensive MEDLINE and American Society of Clinical Oncology abstract search was performed to gather all relevant clinical and translational data related to tivozanib. We discuss pre-clinical studies associated with tivozanib, and the results of a Phase I assessment in advanced solid tumors. We highlight combination studies with tivozanib, including pairings of tivozanib with cytotoxic therapy in patients with colorectal cancer and breast cancer. A randomized discontinuation Phase II study and a randomized Phase III study assessing the activity of tivozanib in metastatic renal cell carcinoma (mRCC) are described in detail.

Expert opinion: Tivozanib will face the challenge of entering an already crowded therapeutic space in mRCC—emerging combination studies and biomarker assessments may distinguish this agent among other VEGF-TKIs. The current review will outline the development pathway of tivozanib to date, and offer lessons learned and future opportunities.     

IMA901: a peptide vaccine in renal cell carcinoma

Introduction: Immunotherapy has always been a promising therapeutic approach in metastatic renal cell carcinoma (mRCC) with frequently observed long-term responders. Since then, immunotherapy emerged from rather unspecific approaches to a specific stimulation of the immune system by tumor-associated antigens (TAAs) in therapeutic vaccination trials. Current vaccine trials are mainly based on the unspecific stimulation of antigen-presenting cells (APCs) by tumor cell lysates with not clearly defined TAAs.

Areas covered: IMA901 is a novel synthetic off-the-shelf vaccine consisting of 10 different tumor-associated peptides (TUMAPs), which has entered a Phase III trial. The preceding Phase I and II trials demonstrated a clear association of a clinical benefit in mRCC patients with an immunological response to the administered TUMAPs.

Expert opinion: IMA901 is a first-in-class drug, which is administered together with GM-CSF and single-dose cyclophosphamide. This triumvirate of vaccine, a local and a systemic immunomodulator showed an improved clinical benefit in mRCC patients. This interplay effectively activated cytotoxic T cells. Future strategies will lead to improved local immunomodulators to boost the activation of APCs, systemic immunomodulators to suppress Tregs and myeloid-derived suppressor cells (MDSCs) and antigens of higher cancer specificity and immunogenicity, together with an optimal schedule and dosage of the vaccine.     

Safety and tolerability of pazopanib in the treatment of renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) is still a challenging disease. Over the last 6 years, the use of novel targeted therapies interfering with vascularization and inhibition of other downstream pathways has revolutionized the therapy of this disease, leading to an improvement of patient outcomes. In particular, dysregulation of the vascular endothelial growth factor (VEGF) pathway and VEGF protein overexpression have proved important, as they result in increased tumor angiogenesis and RCC growth and development.

Areas covered: This review briefly discusses the mechanisms of action and clinical applications of pazopanib. It mainly outlines the safety and tolerability of pazopanib for locally advanced/metastatic RCC. Phase III pazopanib safety data are also indirectly compared with other standard, antiangiogenic receptor tyrosine kinase inhibitors currently used in the management of RCC.

Expert opinion: Pazopanib is a new drug available in the oncology portfolio to treat patients with predominantly clear-cell RCC. The toxicity profile of pazopanib is comparable, but in some ways distinct, from other antiangiogenic drugs used in the treatment of RCC. Long-term data about late side effects of this treatment are awaited.     

BIBF 1120/nintedanib: a new triple angiokinase inhibitor-directed therapy in patients with non-small cell lung cancer

Introduction: Several new targeted agents with anti-angiogenic properties have been developed recently, including vandetanib, sunitinib, sorafenib, bevacizumab and others. Tumor development, progression, metastasis are strongly linked to angiogenesis. Targeted agents like bevacizumab, a monoclonal antibody which targets VEGF, have been fully developed in several solid tumors. These new agents strongly advocate that targeting angiogenesis is one of the best approaches for cancer therapy.

Areas covered: Those agents that target additional pro-angiogenic intracellular signaling pathways beyond VEGF signaling have also the potential to contribute to anticancer therapies. The authors present here nintedanib (BIBF 1120), a triple angiokinase inhibitor. It targets not only VEGFRs, but also FGFR and PDGFR. All the available clinical information regarding Phase I – II trials and the toxicity and efficacy of BIBF 1120 both as single agent and in combination with cytotoxic agents in non-small cell lung cancer (NSCLC) is reviewed and discussed here.

Expert opinion: Up till now, Phase I and II trials with nintedanib showed an improvement for survival of advanced NSCLC patients. Tolerability profile seems to be acceptable in these clinical trials. However, Phase III trials are mandatory to translate these findings into clinical practice. The research for predictive biomarkers could improve the success of these anti-angiogenic agents.     

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.     

The potential role of sunitinib targeting melanomas

Introduction: Metastatic melanoma – independently of its cutaneous, uveal or mucosal origin – represents an exceptionally aggressive tumor with poor prognosis. Molecular and genetics investigations permitted to identify several important driver mutations: BRAF, NRAS, c-Kit, GNA11 and GNAQ. Additionally, hypervascular and immunlogenic characteristics of metastatic melanoma make in this tumor a unique therapeutic target. In this regard, the antiangiogenic, antiproliferative and immunomodulator properties of sunitinib make it an attractive drug to explore in melanoma.

Areas covered: In this article, the currently available data on sunitinib in terms of its pharmacokinetics and mechanisms of action is summarized. The reader will also be updated on current clinical experience using this drug in the treatment of cutaneous, mucosal and uveal melanomas. Special attention is placed on the scientific rationales behind its development in melanoma including the potentiality to broadly attack receptor-tyrosine kinases as well as its remarkable but certainly still unexplored immunomodulatory qualities.

Expert opinion: Given its wide spectrum of actions and the encouraging results obtained from the limited clinical experience, sunitinib remains as a promising drug, especially for mucosal and uveal melanoma, that deserves further exploration in properly designed clinical trials.     

A review of iniparib in ovarian cancer

Introduction: Patients with metastatic ovarian cancer continue to experience high recurrence rates and significant morbidity from standard treatments. There is a great need for efficacious tumor-specific agents in ovarian cancer. Iniparib (BSI-201) is a targeted drug currently under investigation.

Areas covered: The authors identified the mechanistic and clinical data available on the role of iniparib in ovarian cancer. Iniparib was initially thought to act via the poly-ADP ribose polymerase 1 (PARP-1) pathway, but recent studies have shown only nonspecific interactions between the drug and PARP proteins. Although iniparib is only active in cancer cells, the exact mechanism of action remains unclear. Iniparib was well tolerated at all dose levels in Phase I studies of solid organ malignancies. Preliminary data from Phase II studies of iniparib for the treatment of platinum-sensitive and platinum-resistant recurrent ovarian cancer show improvement in survival compared to historic controls. There are currently no Phase III studies.

Expert opinion: Iniparib shows promise in early clinical trials; however, understanding the pathways of cytotoxicity will be crucial as cancer therapy becomes increasingly individualized.     

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.     

Management of NSCLC: focus on crizotinib

Introduction: Presence of Anaplastic lymphoma kinase (ALK) translocations identifies a distinct subgroup of NSCLC with different prognosis and therapeutic opportunities. In cancer cells, ALK gene fusion acts as oncogenic driver, representing an attractive therapeutic target in NSCLC.

Areas covered: For the purpose of this review article, data from preclinical and clinical trials with crizotinib were collected and analyzed.

Expert opinion: Available data demonstrated that crizotinib is the best option we can offer today to ALK-positive NSCLC not previously exposed to ALK inhibitors, irrespective of line of therapy. In two large Phase III trials, crizotinib demonstrated to improve response rate and progression-free survival when compared to standard chemotherapy, both in first- and second-line treatment. Furthermore, results from pivotal Phase I and II studies indicated that crizotinib was active even in heavily pretreated populations. In addition, crizotinib displayed a favorable toxicity profile with a broad spectrum of adverse events, most of which is easily to manage and rarely require dose reduction or interruption. Unfortunately, almost all patients became refractory to crizotinib due to emergence of acquired resistance. The optimal management of these patients has not yet been defined. Novel ALK inhibitors are under investigation.     

Efficacy of S-1 in non-small cell lung cancer

Introduction: S-1 is an oral fluoropyrimidine derivative, including three pharmacological compounds: tegafur, gimeracil and oteracil, in a molar ratio of 1: 0.4: 1.

Areas covered: This review addresses the clinical evidence of S-1 in NSCLC in various clinical settings. Currently, S-1 for NSCLC is approved only in Japan. Prospective studies of S-1 as front-line and second-line chemotherapy with or without other agents and concurrent chemoradiotherapy are mainly reviewed. Only two Phase III clinical trials were published or presented for advanced NSCLC. S-1 and cisplatin is an active first-line chemotherapy regimen for advanced NSCLC and S-1 and carboplatin is noninferior to a carboplatin and paclitaexel regimen. The combination of S-1 and a platinum agent is active against NSCLC, regardless of tumor histology.

Expert opinion: It is becoming possible to design effective regimens with S-1 against NSCLC in various clinical settings considering the ethnic differences in pharmacokinetics and a greater understanding of the underlying molecular pathways or biomarkers of NSCLC. Further Phase III studies with S-1 for both early and advanced NSCLC are warranted worldwide.     

Nintedanib for the treatment of non-small-cell lung cancer

Introduction: In NSCLC, increased microvessel count, often used as a measure of angiogenesis, has been correlated with poor prognosis and associated with advanced disease and inferior outcomes. In the clinical development of antiangiogenic therapies, two approaches have been used; the first has been to inhibit ligand binding and receptor activation using targeted antibodies, whereas the second has been to inhibit receptor activation using tyrosine kinase inhibitors that target VEGF receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and/or fibroblast growth factor receptor (FGFR). Nintedanib is a triple angiokinase inhibitor that simultaneously acts on VEGFR, PDGFR and FGFR. It has shown significant antiangiogenic and antineoplastic activities in vitro, in preventing tumor growth and overcoming drug resistance.

Areas covered: Medline search was used with the following keywords: non-small-cell lung cancer and nintedanib or BIBF 1120, ASCO abstracts 2013 with nintedanib, and Phase I and Phase II abstracts lung cancer and nintedanib.

Expert opinion: Recent Phase III trials have shown promising efficacy results of nintedanib in NSCLC; however, many questions still need to be answered before it is put into routine use.     

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.     

Dapagliflozin: a review on efficacy,clinical effectiveness and safety

Introduction: The prevalence of type 2 diabetes mellitus has reached epidemic proportions. Progressive deterioration in glycaemic control and the current limitations of existing therapies such as weight gain and hypoglycaemia led us to welcome the first of a new class of drugs. Sodium-glucose co-transporter 2 (SGLT2) inhibitors represent a novel mode of therapy independent of insulin secretion or action. By blocking glucose reabsorption in the kidney they lead to an increase in urinary glucose excretion with reduction in plasma glucose levels.

Areas covered: In this article, we will review inhibition of SGLT2 as a novel strategy for the treatment of type 2 diabetes mellitus with dapagliflozin. PubMed and MEDLINE were searched for literature published up to July 2012, for efficacy, clinical effectiveness and safety reports of dapagliflozin.

Expert opinion: Improvement in glycaemic control with a low risk of hypoglycaemia, concomitant weight loss and the potential of lowering of blood pressure make SGLT2 inhibition an attractive approach using dapagliflozin therapy. Many SGLT2 inhibitors are undergoing Phase III clinical trials and more are in Phase I and II 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.     

Retigabine/Ezogabine,a KCNQ/KV7 channel opener: pharmacological and clinical data

Introduction: Epilepsy is a serious and common chronic neurological disease with an urgent need for novel treatment options, because 30% of all epilepsy patients do not respond to currently available drugs. Retigabine/Ezogabine (RTG) is a third-generation antiepileptic drug (AED) with a novel mechanism of action. It enhances the activity of voltage-gated K_V7 potassium channels.

Areas covered: The mechanism of action of RTG is reported in this paper, along with its pharmacodynamics and pharmacokinetics, based on a literature search from 1995 to 2011. Assessment of clinical efficacy and safety was performed using the published data of one Phase II and two Phase III clinical trials (RESTORE 1 and 2).

Expert opinion: RTG is an efficacious AED with a unique mechanism of action. It offers a new treatment option which could be particularly interesting for patients who are resistant to currently available AEDs. However, future investigations will show if such a "rational drug therapy" will be truly advantageous. RTG seems to have a low interaction profile, but its interactions with lamotrigine in particular should be further explored. Side effects are common and mainly related to the central nervous system, but also affect peripheral organs, such as the bladder, due its relaxing effect on smooth muscle. Slow titration could be an option to reduce such side effects.     

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.