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.     

Vandetanib for the treatment of lung cancer

Introduction: VEGF and EGFR are validated pathways for targeted therapy in non-small cell lung cancer (NSCLC). Once considered to be separate targets, VEGF and EGFR are now shown to have interconnected downstream pathways, potentiating the effectiveness of their dual signaling inhibition in cancer therapy. Molecules such as vandetanib that inhibit VEGFR and EGFR have also been reported to inhibit other receptors, including RET and additional kinases, and may be beneficial in treating patients with solid tumors.

Areas covered: This review covers the significance of targeting VEGF and EGFR in the treatment of NSCLC and the rationale behind their dual inhibition. Clinical trials that evaluate the use of vandetanib in the setting of refractory NSCLC are also explored.

Expert opinion: Vandetanib is currently not approved in the setting of NSCLC. However, its approval for medullary thyroid cancer makes it promising for identifying markers and potentially a NSCLC patient population who will benefit from the treatment.     

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.     

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.     

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.     

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.     

Oral vinorelbine in the treatment of non-small-cell lung cancer

Introduction: Originally formulated as an intravenous (i.v.) agent, vinorelbine is also currently available as an oral chemotherapeutic agent. Oral vinorelbine has demonstrated significant activity in different settings for NSCLC, including adjuvant treatment for resected disease, concurrent chemoradiation for locally advanced NSCLC and palliative chemotherapy for recurrent/metastatic NSCLC, as part of combination schedules or as a single-agent treatment.

Areas covered: The authors explored the available data describing the use of oral vinorelbine in NSCLC. PubMed articles and abstracts presented at international conferences were analysed, and relevant trials were reported and discussed. Specific settings, including the treatment of elderly and unfit patients and metronomic schedules including oral vinorelbine, were evaluated. Available pharmacoeconomic data were also assessed.

Expert opinion: Oral vinorelbine is an appealing agent, particularly as part of combination regimens containing platinum derivatives, although it can have a role as a single-agent treatment as well. Its safety profile is generally favourable and its route of administration is generally preferred by patients receiving chemotherapy. Compared to i.v. vinorelbine and other antineoplastic agents, oral vinorelbine has been reported to be advantageous in terms of cost savings.     

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.     

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.     

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.     

Nilotinib for treatment of gastrointestinal stromal tumors: out of the equation?

Introduction: Imatinib, a selective tyrosine kinase inhibitor (TKI), is currently the standard treatment for unresectable and metastatic gastrointestinal stromal tumors (GISTs). However, the disease control time by imatinib is limited due to intolerance or resistance. Nilotinib, a second-generation TKI, is expected to show enhanced clinical efficacy against advanced GIST.

Areas covered: PubMed and ClincalTrial.gov were searched to identify clinical trials of nilotinib for GIST. The key words used were GIST and nilotinib and/or AMN107. This review summarizes the clinical trials of nilotinib for advanced GIST and outlines current understanding of the clinical usefulness of nilotinib in GIST therapy.

Expert opinion: Clinical trials of nilotinib for advanced GIST were readily advanced from a Phase I study to Phase III studies. Unfortunately, the clinical utility of nilotinib was not demonstrated by the randomized control trials either in patients with imatinib-resistant GIST or in patients who used nilotinib as the first-line treatment. On the basis of the trial results, nilotinib is not recommended for GIST therapy generally. Nevertheless, a comparable number of patients showed significant response with different side-effect profiles from imatinib. Thus, this new TKI may still merit attention as an important alternative to imatinib in advanced GIST patients who are intolerant to imatinib.     

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.     

Antiarrhythmic properties of ranolazine – from bench to bedside

Introduction: Pharmacological management of cardiac arrhythmias is limited by the reduced availability of safe and effective antiarrhythmic agents.

Areas covered: Ranolazine is an agent currently used for the treatment of angina, which inhibits transmembrane ionic currents involved in several phases of the action potential in both the atrial and the ventricular cells. Due to its mechanism of action, ranolazine has been shown to exhibit antiarrhythmic properties that have been validated in the experimental models. This article recapitulates the mechanism of antiarrhythmic action of ranolazine, the existing clinical data, and the ongoing relevant clinical trials.

Expert opinion: The combination of the antiischemic properties of ranolazine with its antiarrhythmic potency and minimal proarrhythmia provides a promising background that could expand its therapeutic role in the management of atrial fibrillation and ventricular tachyarrhythmias. Data derived from adequately powered randomized clinical trials will determine whether the door to a new indication will open for ranolazine in the near future.     

Importance of potent P2Y12 receptor blockade in acute myocardial infarction: focus on prasugrel

Introduction: Angiogenesis plays a crucial role in the proliferation and in the metastatic spread of tumour cells. Several agents with anti-angiogenic activity have been tested in advanced non-small-cell lung cancer (NSCLC) patients. Motesanib (AMG 706) is a promising anti-angiogenic multi-targeted tyrosine kinase inhibitor (TKI), which has been investigated as a monotherapy or in combination with chemotherapy, in several types of cancer.

Areas covered: We have reviewed the literature, and we have presented the results of clinical trials that have investigated the administration of motesanib in advanced NSCLC patients.

Expert opinion: Encouraging results have been described with the administration of motesanib as first-line treatment in combination with carboplatin and paclitaxel in Asian patients with non-squamous advanced NSCLC. Further studies are needed in order to identify the predictive biomarkers of response and to select patients who may benefit from this anti-angiogenic treatment.     

Vemurafenib for the treatment of melanoma

Introduction: Metastatic melanoma is an aggressive disease resistant to chemotherapy. Recent clinical trials have reported improved survival for two novel agents; ipilimumab, a humanized, IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and vemurafenib, a BRAF (v-raf murine sarcoma viral oncogene homolog B1) inhibitor targeting an activating mutation in the serine-threonine-protein kinase BRAF gene.

Areas covered: The authors reviewed preclinical and clinical data examining the safety of vemurafenib in melanoma. MEDLINE and EMBASE were searched using the medical subject heading ‘vemurafenib' and the following text terms: melanoma, BRAF inhibition, vemurafenib. This review provides the reader with an overview of current data examining the efficacy and safety of vemurafenib in metastatic melanoma.

Expert opinion: Vemurafenib is an oral agent licensed for patients with BRAF V600E mutation-positive inoperable and metastatic melanoma. The most common adverse effects observed in Phase III clinical trials were dermatological events, arthralgia and fatigue. Specific dermatological toxicities included development of cutaneous squamous cell cancers and keratoacanthomas. Prolongation of the QT interval was also reported. Regular dermatological assessments and electrocardiograms are recommended. Ongoing trials are examining vemurafenib in both the adjuvant setting and metastatic setting in combination with ipilimumab and MEK inhibitors (mitogen-activated protein kinase/extracellular signal-regulated kinase). Understanding and overcoming mechanisms of resistance to BRAF inhibitors is the focus of ongoing research.     

Bazedoxifene + conjugated estrogens in HT for the prevention of osteoporosis and treatment of vasomotor symptoms associated with the menopause

Introduction: The recent concept that estrogen agonist–antagonists, often referred to as selective estrogen receptor modulators, can be combined with an estrogen has led to the development of a novel form of menopausal therapy called Tissue-Selective Estrogen Complex (TSEC). This paper reviews the TSEC bazedoxifene and conjugated equine estrogens (BZA/CE).

Areas covered: This review is based on clinical trials and a PubMed search. The pharmacokinetics and pharmacodynamics of BZA in BZA plus CE are reviewed. This review outlines the effects of this particular TSEC, which maintains or increases bone mineral density in women at high risk for osteoporosis, and has clinical qualities of a promising new menopausal therapy. The potential adverse effects of BZA/CE combinations are summarized.

Expert opinion: A TSEC that contains CE and BZA that has both estrogen agonist and antagonist effects has reached clinical development. Phase III clinical trials show this TSEC relieves hot flashes, improves vulvo-vaginal atrophy and its symptoms, does not stimulate the endometrium, and prevents bone loss. In the trials so far it appears to have a good safety and tolerability profile. The optimum combination of BZA/CE combination is 20 mg BZA with CE 0.45 and 0.625 mg daily.     

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.     

Desvenlafaxine for the treatment of major depressive disorder

Introduction: Major depressive disorder (MDD) is a chronic and debilitating condition often characterized by inadequate treatment. Notwithstanding the availability of more than a dozen first-line agents across disparate classes (e.g., selective serotonin reuptake inhibitors), the majority of individuals with MDD do not achieve and sustain a recovered state. A substantial percentage of MDD patients require a treatment change due to poor efficacy or tolerability.

Areas covered: This review focuses on recent (≤ 5 years) literature describing the pharmacokinetics, efficacy, and tolerability of desvenlafaxine, one of the more recently approved antidepressant drugs. Published papers identified via PubMed search and congress presentations were included. Results from short-term, placebo-controlled, MDD trials and randomized withdrawal trials, as well as post hoc analyses in patient subgroups, are reviewed.

Expert opinion: Desvenlafaxine has been shown to be an effective antidepressant with a favorable safety and tolerability profile in the general MDD population and in important patient subgroups. It has several notable differences from other serotonin-norepinephrine reuptake inhibitors, and those differences suggest populations in which it may have the most clinical benefit.