Drugs

Colleoni, Marco; Munzone, Elisabetta

doi: 10.1007/s40265-015-0433-7pmid: 26177891

Endocrine therapy is a key component of adjuvant treatment for premenopausal patients with endocrine-responsive tumors. It is commonly well tolerated, although side effects are a main concern in the selection of treatment options. Tamoxifen is still considered an adequate endocrine therapy in a large group of premenopausal patients (e.g. lower-risk patient, presence of co-morbidities, patient preference). Results of the SOFT and TEXT trials addressing new adjuvant endocrine treatment options in premenopausal patients were recently presented. Overall, in the SOFT study the premenopausal population did not benefit from the addition of ovarian function suppression (OFS). Nevertheless, for women at sufficient risk of recurrence to receive adjuvant chemotherapy and who maintained premenopausal estradiol, the addition of OFS to tamoxifen reduced the risk of recurrence. The magnitude of the effect was larger in younger patients. Moreover, in the SOFT and TEXT trials, adjuvant treatment with exemestane plus OFS, as compared with tamoxifen plus OFS, significantly improved disease-free survival, breast cancer-free interval and distant disease-free survival. However, premenopausal patients include heterogeneous subsets of women and tumors where costs and benefits of adjuvant endocrine therapy should be properly weighted. Issues specific for premenopausal patients, related to desire for pregnancy, family planning, safety, quality of life and subjective side effects, should be a priority in the therapeutic algorithm. Therefore, selecting the best-tolerated agent can enhance adherence to therapies and reduce the impact on quality of life and health status for these younger patients.

Bauer, Sebastian; Joensuu, Heikki

doi: 10.1007/s40265-015-0440-8pmid: 26187774

Imatinib is strongly positioned as the recommended first-line agent for most patients with advanced gastrointestinal stromal tumor (GIST) due to its good efficacy and tolerability. Imatinib-resistant advanced GIST continues to pose a therapeutic challenge, likely due to the frequent presence of multiple mutations that confer drug resistance. Sunitinib and regorafenib are approved as second- and third-line agents, respectively, for patients whose GIST does not respond to imatinib or who do not tolerate imatinib, and their use is supported by large randomized trials. ATP-mimetic tyrosine kinase inhibitors provide clinical benefit even in heavily pretreated GIST suggesting that oncogenic dependency on KIT frequently persists. Several potentially useful tyrosine kinase inhibitors with distinct inhibitory profiles against both KIT ATP-binding domain and activation loop mutations have not yet been fully evaluated. Agents that have been found promising in preclinical models and early clinical trials include small molecule KIT and PDGFRA mutation-specific inhibitors, heat shock protein inhibitors, histone deacetylase inhibitors, allosteric KIT inhibitors, KIT and PDGFRA signaling pathway inhibitors, and immunological approaches including antibody-drug conjugates. Concomitant or sequential administration of tyrosine kinase inhibitors with KIT signaling pathway inhibitors require further evaluation, as well as rotation of tyrosine kinase inhibitors as a means to suppress drug-resistant cell clones.

Califano, R.; Tariq, N.; Compton, S.; Fitzgerald, D.; Harwood, C.; Lal, R.; Lester, J.; McPhelim, J.; Mulatero, C.; Subramanian, S.; Thomas, A.; Thatcher, N.; Nicolson, M.

doi: 10.1007/s40265-015-0434-6

Fongemie, Justin; Felix-Getzik, Erika

doi: 10.1007/s40265-015-0435-5pmid: 26177892

Nebivolol is a highly selective β1-adrenergic receptor antagonist with a pharmacologic profile that differs from those of other drugs in its class. In addition to cardioselectivity mediated via β1 receptor blockade, nebivolol induces nitric oxide-mediated vasodilation by stimulating endothelial nitric oxide synthase via β3 agonism. This vasodilatory mechanism is distinct from those of other vasodilatory β-blockers (carvedilol, labetalol), which are mediated via α-adrenergic receptor blockade. Nebivolol is approved for the treatment of hypertension in the US, and for hypertension and heart failure in Europe. While β-blockers are not recommended within the current US guidelines as first-line therapy for treatment of essential hypertension, nebivolol has shown comparable efficacy to currently recommended therapies in lowering peripheral blood pressure in adults with hypertension with a very low rate of side effects. Nebivolol also has beneficial effects on central blood pressure compared with other β-blockers. Clinical data also suggest that nebivolol may be useful in patients who have experienced erectile dysfunction while on other β-blockers. Here we review the pharmacological profile of nebivolol, the clinical evidence supporting its use in hypertension as monotherapy, add-on, and combination therapy, and the data demonstrating its positive effects on heart failure and endothelial dysfunction.

Filozof, Claudia; Goldstein, Barry; Williams, Richard; Sanyal, Arun

doi: 10.1007/s40265-015-0437-3pmid: 26201461

The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing world-wide in parallel to the increase of the obesity epidemic. Insulin resistance (IR) and the accumulation of triglyceride-derived toxic lipid metabolites play a key role in its pathogenesis. Multiple biomarkers are being evaluated for the non-invasive diagnosis of NASH. However, a percutaneous liver biopsy is still the gold standard method; the minimal diagnostic criteria include the presence of >5 % macrovesicular steatosis, inflammation, and liver cell ballooning. Several pharmaceutical agents have been evaluated for the treatment of NASH; however, no single therapy has been approved so far. Due to the increasing prevalence and the health burden, there is a high need to develop therapeutic strategies for patients with NASH targeting both those with early-stage disease as well as those with advanced liver fibrosis. There are unique challenges in the design of studies for these target populations. Collaborative efforts of health authorities, medical disease experts, and the pharmaceutical industry are ongoing to align options for a registrational pathway. Several companies pursuing different mechanisms of action are nearing the end of phase II with their candidates. This manuscript reviews those compounds with a variety of mode of actions that have been evaluated and/or are currently being tested with the goal of achieving a NAFLD/NASH indication.

Deeks, Emma

doi: 10.1007/s40265-015-0439-1pmid: 26220911

Apremilast (Otezla®) is an oral phosphodiesterase 4 inhibitor indicated for the twice-daily treatment of adults with psoriasis and psoriatic arthritis (PsA). Its use in these patient populations has been assessed in two phase III clinical trial programmes (ESTEEM and PALACE). At 16 weeks in the two ESTEEM trials, apremilast reduced the severity and extent of moderate to severe plaque psoriasis, including nail, scalp and palmoplantar manifestations, versus placebo in adults, with these benefits generally being sustained over 52 weeks of treatment. Similarly, in three PALACE trials (PALACE 1–3), apremilast improved the signs and symptoms of PsA relative to placebo at 16 weeks in adults with active disease despite treatment with conventional synthetic and/or biologic disease-modifying anti-rheumatic drugs. These PsA benefits were generally sustained for up to 104 weeks of treatment; skin involvement, enthesitis and dactylitis also improved with the drug. Apremilast was generally well tolerated, with the most common adverse events being diarrhoea and nausea in the first year of treatment (usually occurring in the first 2 weeks after the first dose and resolving within 4 weeks) and nasopharyngitis and upper respiratory tract infection with continued treatment. Although further longer-term and comparative efficacy and tolerability data would be beneficial, the current clinical data indicate that apremilast is an effective and well tolerated option for the management of psoriasis and PsA in adults.

Dhillon, Sohita

doi: 10.1007/s40265-015-0441-7pmid: 26201462

Collagenase Clostridium Histolyticum (CCH) (Xiaflex®, Xiapex®) intralesional injection is a mixture of class I (AUX-I) and class II (AUX-II) clostridial collagenases. It is indicated for the treatment of adult men with Peyronie’s disease with a palpable plaque and curvature deformity of ≥30° at the start of therapy. This article reviews the efficacy and tolerability of CCH in this indication and briefly summarizes its pharmacology. CCH treatment significantly improved penile curvature deformity and reduced patient-reported bother associated with Peyronie’s disease in the 52-week, double-blind, phase III IMPRESS I and II studies. Treatment benefit with CCH was also seen in 36-week, open-label studies, providing further support for its efficacy. CCH was generally well tolerated in patients with Peyronie’s disease, with most treatment-related adverse events being of mild or moderate severity. Serious treatment-related adverse events (penile haematoma or corporal ruptures) were reported in <1 % of CCH recipients in clinical studies. Although further studies assessing the long-term effects of CCH intralesional injection are needed, current evidence indicates that this is a minimally invasive, effective and generally well tolerated treatment option for patients with Peyronie’s disease.

Scott, Lesley

doi: 10.1007/s40265-015-0442-6pmid: 26220912

An improved understanding of cancer genetics and immune regulatory pathways, including those associated with evasion of immune surveillance by tumours, has culminated in the development of several targeted therapies. One such strategy that acts to negate evasion of immune surveillance by tumours is inhibition of the programmed cell death receptor-1 (PD-1) checkpoint pathway. Intravenous nivolumab (Opdivo®), a PD-1 checkpoint inhibitor, is approved or in pre-registration in various countries for use in adult patients with advanced melanoma, with the recommended monotherapy dosage being a 60-min infusion of 3 mg/kg once every 2 weeks. In well-designed multinational trials, as monotherapy or in combination with ipilimumab (a cytotoxic T-lymphocyte antigen 4 checkpoint inhibitor), nivolumab significantly improved clinical outcomes and had a manageable tolerability profile in adult patients with advanced melanoma with or without BRAF mutations. Nivolumab monotherapy was associated with a higher objective response rate (ORR) than chemotherapy in treatment-experienced patients and a higher ORR and prolonged progression-free survival (PFS) and overall survival than dacarbazine in treatment-naive patients. In combination with ipilimumab, nivolumab was associated with an improved ORR and prolonged PFS compared with ipilimumab monotherapy in treatment-naive patients. In addition, nivolumab monotherapy significantly prolonged PFS and improved ORRs compared with ipilimumab monotherapy. The optimal combination regimen for immune checkpoint inhibitors remains to be fully elucidated, with various combination regimens and different sequences of individual immunotherapies currently being investigated in ongoing clinical trials. Given the significant improvements in outcomes associated with nivolumab in clinical trials, nivolumab monotherapy or combination therapy is a valuable first-line or subsequent treatment option for adult patients with unresectable or metastatic melanoma, irrespective of BRAF mutation status.

Keating, Gillian

doi: 10.1007/s40265-015-0445-3pmid: 26201463

Cangrelor (Kengrexal®, Kengreal™) is an intravenously administered P2Y12 receptor inhibitor. It is direct-acting and reversible, with a very rapid onset and offset of action. The randomized, double-blind, multinational, phase III CHAMPION PHOENIX trial compared the efficacy of intravenous cangrelor with that of oral clopidogrel in patients requiring percutaneous coronary intervention (PCI) for stable angina pectoris, a non-ST-segment elevation acute coronary syndrome or ST-segment elevation myocardial infarction (MI). The primary composite efficacy endpoint of death from any cause, MI, ischaemia-drive revascularization or stent thrombosis in the 48 h following randomization occurred in significantly fewer cangrelor than clopidogrel recipients. The rate of severe or life-threatening non-coronary artery bypass graft-related, GUSTO-defined bleeding at 48 h did not significantly differ between cangrelor and clopidogrel recipients. In conclusion, intravenous cangrelor is an important new option for use in patients undergoing PCI who have not been treated with oral P2Y12 inhibitors.

Syed, Yahiya; McKeage, Kate

doi: 10.1007/s40265-015-0444-4pmid: 26220913

Aflibercept is a recombinant fusion protein that acts as a soluble decoy receptor for vascular endothelial growth factor (VEGF), a key regulator of angiogenesis. It binds to all isoforms of VEGF-A as well as VEGF-B and placental growth factor, and, thus, prevents them from binding to and activating their cognate receptors. In the USA and EU, intravenously administered aflibercept in combination with an infusion of leucovorin, fluorouracil and irinotecan (FOLFIRI) is approved for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed after treatment with an oxaliplatin-containing regimen. The efficacy of aflibercept in this indication was assessed in a multinational, pivotal phase 3 trial (VELOUR), in which the approved regimen of aflibercept 4 mg/kg every 2 weeks plus FOLFIRI significantly prolonged median overall survival by 1.44 months compared with FOLFIRI alone (primary endpoint). The addition of aflibercept also significantly prolonged progression-free survival and significantly increased the objective response rate compared with FOLFIRI alone. Addition of aflibercept to FOLFIRI was associated with anti-VEGF-related adverse events and an increased incidence of FOLFIRI-related adverse events, but the tolerability of the combination was generally acceptable in this pre-treated population. The most common grade 3 or 4 adverse events with aflibercept plus FOLFIRI included neutropenia, diarrhoea and hypertension. In conclusion, aflibercept plus FOLFIRI is a useful treatment option for patients with metastatic colorectal cancer previously treated with an oxaliplatin-containing regimen, with or without bevacizumab.