Emerging drugs in cutaneous T-cell lymphomas

Cutaneous T-cell lymphomas are a heterogeneous group of rare lympho-proliferative disorders. In most cases, they are characterised by the accumulation of clonal CD4⁺ lymphocytes in the skin. Extracutaneous involvement is present in late stages only. Unfortunately, only few drugs are registered for these disfiguring diseases. Skin-directed therapies using topical formulations are the preferred first-line modalities for cutaneous lesions in early stages. In this field there are interesting developments using topical retinoids and gene therapy products, such as adeno-IFN-γ. Systemic treatment uses biologicals, such as fusion molecules, monoclonal antibodies and immune response modifiers (IFNs, retinoids), and well-tolerated antiproliferative drugs, such as histone deacetylase inhibitors or liposomal doxorubicin.     

Forodesine in the treatment of cutaneous T-cell lymphoma

Introduction: Cutaneous T-cell lymphoma (CTCL) is characterized by the accumulation of neoplastic CD4+ T lymphocytes in the skin. Given the lack of curative treatments for CTCL, there is a significant need for new, superior therapies. Forodesine is a transition-state analogue that inhibits purine nucleoside phosphorylase. Because it selectively targets T lymphocytes, it represents a drug of interest for the treatment of CTCL.

Areas covered: Phase I/II dose-ranging studies of intravenous (IV) and oral forodesine demonstrated its activity, safety, and tolerability for refractory CTCL. Response rates were 31% and 27%, respectively. No dose-limiting toxicities were observed. These studies were followed by a phase II trial of oral forodesine 200 mg daily. This oral formulation showed only partial activity, with a response rate of 11%, likely attributable to underdosing. Common adverse events in these trials included infection, fatigue, peripheral edema, nausea, pruritus, headache, and insomnia.

Expert opinion: IV and oral formulations of forodesine have demonstrated partial activity and an acceptable safety profile in patients with refractory CTCL. A higher oral dose, or sequential therapy consisting of IV forodesine followed by maintenance oral forodesine, may be more effective. With proper dosing, forodesine may emerge as a safe and effective treatment for refractory CTCL.     

Bexarotene in cutaneous T-cell lymphoma: third retrospective study of long-term cohort and review of the literature

Background: Bexarotene was approved for cutaneous T-cell lymphoma (CTCL) in 1999. Apart from the two first clinical trials published ten years ago, very few data were published on the long-term use of bexarotene in CTCL patients.

Objectives: We performed a retrospective review of CTCL patients treated with bexarotene at a single skin Cancer department between 2002 and 2012. We aimed to determine retrospectively the long-term tolerability and outcome of bexarotene in a cohort of CTCL patients and to compare these results with data from the literature.

Results: Thirty-two patients were included (18 men/14 women); 20 patients had a mycosis fungoïdes and 12 a Sézary syndrome. The longest bexarotene treatment duration observed was 65.2 months and 10 patients were treated for more than 24 months. A clinical response was reported in 60% of all patients and in 75% of patients with Sézary syndrome. Most common drug-related adverse events were hypothyroidism (94%), hypertriglyceridemia (78%) and hypercholesterolemia (44%). Most events (84%) were mild to moderate.

Conclusions: This study with a very long observation time confirms that bexarotene is well tolerated by CTCL patients during long-term use. It is effective in early and advanced stages of CTCL.     

IPH4102, a monoclonal antibody directed against the immune receptor molecule KIR3DL2, for the treatment of cutaneous T-cell lymphoma

Introduction: Therapeutic options for mycosis fungoides and Sézary syndrome include a variety of immunomodulatory, epigenetic, and cytotoxic options; however, none has been demonstrated to be efficacious for all patients, or to deliver deep and durable responses to the majority of patients. In this review, we examine the monoclonal antibody, IPH4102, a novel agent for the treatment of cutaneous T-cell lymphoma.

Areas covered: In this review, we examine data demonstrating the tissue specificity of KIR3DL2 receptor, which is highly expressed on the malignant cells in cutaneous T-cell lymphoma, including mycosis fungoides and Sézary syndrome. This specificity has led to the development of the agent IPH4102. Preclinical data showing efficacy of IPH4102 in vivo are outlined, as well as the results from Phase I clinical trials, which suggest that the agent is both efficacious and well-tolerated. Larger scale clinical trials are to follow.

Expert Opinion: We examine the putative benefit of IPH4102 in comparison to established agents already in the clinic, highlighting its efficacy and relative safety. We also examine possible directions that may better define the role of IPH4102 in the treatment of T-cell lymphoma in the future.     

Emerging antibodies for the treatment of pancreatic cancer

Introduction: Pancreatic ductal adenocarcinoma cancer (PDAC) is the fourth leading cause of cancer death worldwide. Recently, two chemotherapy regimens have proven to improve median overall survival in comparison with gemcitabine. Based on better understanding of tumor molecular biology and of the role of tumor microenvironment, monoclonal antibodies (mAbs) could be an interesting and new type of targeted treatment of PDAC.

Areas covered: Preclinical and clinical trials have evaluated the efficacy of several mAbs in pancreatic cancer treatment. This review will underline the most important targeted pathways by mAbs involved in this disease, including EGFR, HER-2, IGF-1 R, VEGF/VEGFR, NOTCH, WNT and immune checkpoints.

Expert opinion: Despite the promising results of preclinical and phase I trials, the addition of mAbs to standard chemotherapy or in association with other target agents seems not to confirm these results in the following phase II and III trials in pancreatic cancer patients. However, an improved patient selection before treatment based on molecular characteristics in association with reliable predictive biomarkers can identified more efficacious treatment approaches, minimizing toxicity profile of these drugs.     

Investigational drugs for the treatment of cervical cancer

Introduction: Cervical cancer (CC) is currently the fourth most common malignant disease of women worldwide. Although the incidence and the mortality rates have been decreasing with screening detection and new treatment strategies, a significant number of metastatic or recurrent disease is still diagnosed. For those patients not amenable to curative treatments, such as surgery and radiation, palliative chemotherapy remains the standard of care. As chemotherapy regimens have limited activity, research is focalized on investigating novel pharmacologic strategies.

Areas covered: This paper aims to give a complete and updated overview on investigated therapies for the treatment of CC. The authors review the results of clinical studies and highlight the ongoing trials.

Expert opinion: Agents targeting various molecular pathways including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), poly ADP-ribose polymerase (PARP), epigenetics and other biological mechanisms represent interesting investigational opportunities. Amongst such drugs, bevacizumab, an anti-VEGF monoclonal antibody, was the first targeted drug recently approved by the FDA for the treatment of patients with metastatic, recurrent, or persistent CC. Another interesting experimental approach is represented by immunotherapy, which is leading to promising results with to the development of therapeutic vaccines and immune checkpoints inhibitors.     

Advances in emerging drugs for the treatment of neuroblastoma

Introduction: Neuroblastoma is the most common solid extracranial tumor of childhood. Outcome for children with high-risk neuroblastoma remains suboptimal. More than half of children diagnosed with high-risk neuroblastoma either do not respond to conventional therapies or relapse after treatment with dismal prognosis.

Areas covered: This paper presents a short review of the state of the art in the current treatment of high-risk neuroblastoma. An updated review of new targeted therapies in this group of patients is also presented.

Expert opinion: In order to improve prognosis for high-risk patients there is an urgent need to better understand spatial and temporal heterogeneity and obtain new predictive preclinical models in neuroblastoma. Combination strategies with conventional chemotherapy and/or other targeted therapies may overcome current ALK inhibitors resistance. Improvement of international and transatlantic cooperation to speed clinical trials accrual is needed.     

A drug safety evaluation of mogamulizumab for the treatment of cutaneous T-Cell lymphoma

Introduction: Cutaneous T-cell lymphomas (CTCL) are rare non-Hodgkin lymphomas of skin-homing T-cells that initially or mainly manifest cutaneously. Treatment of CTCL is challenging given the disease states’ varying presentation and prognosis. Systemic treatment options often lack comparative evidence and have relatively low response rates and short duration of response. The recent Food and Drug Administration (FDA) approval of mogamulizumab in adult patients with relapsed or refractory (R/R) CTCL after at least one prior line of therapy provided a new treatment option to patients with advanced disease.

Areas covered: The authors discuss basic information about CTCL and mogamulizumab’s mechanism of action. Then, the authors discuss the agent’s efficacy. Finally, the authors evaluate the safety of mogamulizumab in comparison to other agents available in CTCL.

Expert opinion: Mogamulizumab has been shown to be an effective and well tolerated therapy for patients with relapsed and refractory MF/SS with excellent activity in the circulating component of the disease.     

Current and emerging treatment options in the management of advanced ovarian cancer

Introduction: Epithelial ovarian cancer is the most lethal gynecologic malignancy. Recent advances in understanding the biology and its molecular and histological diversity have led to mechanism based therapeutic strategies such as poly-ADP-ribose polymerase inhibitors (PARP) targeting homologous recombination deficient tumor cells and anti-angiogenic therapies. Clinical trial designs in ovarian cancer have to evolve to incorporate assessment of the genomic complexity and identify predictive biomarkers to improve precision of treatment and outcome.

Areas covered: This review summarizes present-day strategies used in the management of ovarian cancer and novel promising therapeutic approaches in development. The article is based on English peer-reviewed articles located on MEDLINE and related abstracts presented at major international meetings.

Expert opinion: Two types of molecular targeted therapies, anti-angiogenics and PARP inhibitors, have been shown to be active in randomized clinical trials and approved by regulatory agencies. Management of ovarian cancer is poised to change with the continued advancement of precision medicine that is founded upon improved understanding of disease biology; separation into histologically and molecularly defined subgroups; and the incorporation of this new knowledge into early phase drug development and novel clinical trial design.     

Emerging drugs for urothelial (bladder) cancer

Introduction: Metastatic urothelial carcinoma has been associated with poor prognosis and a median survival of approximately 12–14 months with standard therapy. Treatment options for decades have been limited to platinum based chemotherapy as first line with few therapeutic options available to the majority who will ultimately progress beyond platinum.

Areas covered: This review focuses on the various targeted, antiangiogenic, chemotherapeutic and immunotherapeutic agents currently being developed for the treatment of urothelial carcinoma.

Expert opinion: Incorporation of systemic immunotherapy into the treatment of urothelial carcinoma has already fundamentally changed the treatment of this disease. The landscape is rapidly changing and it is likely that immunotherapy will be incorporated into therapy in earlier disease states and in novel combinations. Outcomes in urothelial carcinoma have improved and likely to improve further with ongoing and future clinical research that is discussed in this review.     

Emerging drugs for migraine treatment: an update

ABSTRACT

Introduction: Migraine is a very frequent and disabling neurological disorder. The current treatment options are old, generally poorly tolerated and not migraine-specific, reflecting the low priority of migraine research and highlighting the vast unmet need in its management.

Areas covered: Advancement in the understanding of migraine pathophysiological mechanisms and identification of novel potentially meaningful targets have resulted in a multitude of emerging acute and preventive treatments. Here we review the known putative migraine pathophysiological mechanisms in order to understand the rationale of the most promising novel treatments targeting the Calcitonin-Gene-Related Peptide receptor and ligand and the 5 hydroxytryptamine (5-HT)1F receptor. Key findings on the phase II and phase III clinical trials on these treatments will be summarized. Furthermore, a critical analysis on failed trials of potentially meaningful targets such the nitric oxide and the orexinergic pathways will be conducted. Future perspective will be outlined.

Expert opinion: The recent approval of Erenumab and Fremanezumab is a major milestone in the therapy of migraine since the approval of triptans. Several more studies are needed to fully understand the clinical potential, long-term safety and cost-effectiveness of these therapies. This paramount achievement should stimulate the development of further research in the migraine field.     

Experimental and investigational drugs for the treatment of anal cancer

ABSTRACT

Introduction: Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy, but its incidence rates have been increasing in the last decade. Studies have demonstrated that up to 47% of patients with locally advanced disease have high-risk features for treatment failure. The potential high rates of recurrence after standard chemoradiotherapy for locally advanced disease and the lack of established care for metastatic disease have created an urgent need for the evaluation of new drugs that will ultimately improve the efficacy of treatment.

Areas covered: This review presents results of recent phase-I and -II clinical trials which evaluate novel therapeutic modalities. The review also describes the findings of comprehensive genomic profiling studies which provide insights for promising therapeutics.

Expert opinion: HPV vaccination is underutilized in the United States and as a result, HPV-associated malignancies are likely to continue for several decades; however, pivotal breakthroughs may create a foundation for distinctive treatment approaches for other HPV-associated malignancies for which no other standard of care exists     

Tivantinib for the treatment of hepatocellular carcinoma

Introduction: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with a poor prognosis due to late diagnosis in the majority of cases. Physicians are frequently confronted with patients who are not eligible for curative or locoregional treatments any more. In this scenario, the multi-tyrosine kinase inhibitor sorafenib remains the only systemic first-line treatment option providing modest survival benefit compared to placebo with significant but for most patients acceptable adverse effects.

Areas covered: Tivantinib was the first antiproliferative agent to be been applied in a phase III trial based on receptor overexpression analyses after disease progression on sorafenib. While phase I and II trials with tivantinib in second line showed encouraging results, a recent press release announced that the METIV-HCC phase III study of tivantinib in HCC did not meet its primary endpoint of improving overall survival.

Expert commentary: Evidence for antiangiogenetic therapy inducing tumor hypoxia leading to overexpression of proliferative genes, including cMET, underlines the potential of tivantinib as second-line treatment. However, as the mechanism of action of tivantinib through cMET inhibition has recently been questioned by several groups, identification of alternative proliferative markers or targets is mandatory.     

Optimal drugs for second-line treatment of patients with small-cell lung cancer

Introduction: Despite the high response rate to chemotherapy, there have been few advances in the treatment of small-cell lung cancer (SCLC) in the last decades. The state-of-the-art second-line therapy and future research developments in relapsed SCLC are reviewed.

Areas covered: There are no optimal drugs for second-line treatment of recurrent SCLC but only agents registered for this use. Topotecan remains the standard-of-care for the treatment of second-line platinum-sensitive SCLC patients worldwide, while amrubicin is another option, but registered only in Japan. To date, no targeted agents reporting interesting results in second-line SCLC treatment are available. The next-generation DNA sequencing should discover somatic gene alterations and their roles in SCLC to help in selecting patients who could benefit from a targeted agent. Two immunotherapeutics, ipilimumab and nivolumab, have shown promising preliminary results and are being investigated in ongoing trials.

Expert opinion: Second-line treatment is not an option for most SCLC patients. Given the evidence up to now, the potentials for immuno-oncology in SCLC are high. The hope is that these expectations are met, and that all drugs being developed will offer new and improved treatment options for SCLC patients.     

An update on drugs for the treatment of menopausal symptoms

Introduction: Vasomotor symptoms (VMS) and the genitourinary syndrome of menopause (GSM) are recognized as the most frequent and bothersome symptoms associated with menopause. There are different treatments for both groups of symptoms, being necessary to individualize them.

Areas covered: There are different therapies for VMS including hormonal treatments with estrogen, with and without progestins; the new alternative, tissue-selective estrogen complex (TSEC), tibolone, phytoestrogens and only progestins. Evidence also shows efficacy with selective serotonin reuptake inhibitors. Other nonhormonal alternatives exist as second-line treatments, all with not conclusive results. The GSM can be treated with nonhormonal treatments such as vaginal lubricants and moisturizers, other alternatives as vaginal laser needs to have more evidence. On the other hand, there is the possibility to use the hormonal treatments with systemic or local estrogen, which are the most effective treatment, the TSEC and the newest selective estrogen receptor modulator (SERM), ospemifene. Therapies with testosterone and dehydroepiandrosterone (DHEA) are still under study. The GSM can be treated with nonhormonal treatments such as vaginal lubricants and moisturizers, and other alternatives as vaginal laser need to have more evidence. On the other hand, there is the possibility to use the hormonal treatments with systemic or local estrogen, which are the most effective treatment, the TSEC and the newest SERM, ospemifene. Therapies with testosterone and DHEA are still under study.

Expert opinion: The increasing numbers of therapies for menopausal symptoms open up new options, but we must individualize treatments. New possibilities arise in patients who did not have them and which can improve compliance and is also important to design strategies using combined or sequential treatments.     

基于Markov模型的肺动脉高压靶向治疗药物的成本-效果分析

目的：评价中国医疗环境下肺动脉高压一线靶向治疗药物的成本-效果。方法：从支付者角度,根据肺动脉高压的自然转归和现有的医疗成本构建Markov模型。结果指标包括人均总成本、总质量调整生命年和增量成本-效果比,应用一元敏感度和概率敏感度分析验证模型稳定性。结果：基线分析结果显示：在整个生命周期的模拟过程中安立生坦、马昔腾坦、波生坦、他达拉非、西地那非和姑息治疗的人均医疗成本分别为363 406.14,481 387.69,323 264.71,167 531.23,41 700.08和24 507.12元,人均可获得5.61,6.14,5.23,5.88,4.64和2.33个质量调整生命年,姑息治疗作为对照组的增量成本-效果比分别为103 410.74,120 034.97,103 079.80,40 351.36和7 438.14元/质量调整生命年,小于预设的意愿支付阈值,敏感度分析显示结果稳定。结论：在中国肺动脉高压患者使用安立生坦、马昔腾坦、波生坦、他达拉非和西地那非具有成本-效果性。     

The discovery and development of romidepsin for the treatment of T-cell lymphoma

Introduction: Romidepsin is a potent and selective inhibitor of histone deacetylases (HDCAi). It is also the only bicyclic inhibitor to undergo clinical assessment and is considered a promising drug for the treatment of T-cell lymphomas. The cellular action of romidepsin results in enhanced histone acetylation, as well as the acetylation of other nuclear or cytoplasmic proteins, influencing cell cycle, apoptosis, and angiogenesis. In phase II studies involving patients with relapsed or refractory of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), romidepsin produced overall response rates (ORR) of 34–35% and 25–38%, with complete response (CR) rates of 6% and 15–18%, respectively.

Areas covered: This review summarizes the development of romidepsin, the mechanisms behind its antineoplastic action and its pharmacology. It also covers its pharmacokinetic and pharmacodynamic properties, as well as the preclinical and clinical data on its activity in T-cell lymphoma.

Expert opinion: Since there are only few effective therapies available for T-cell lymphomas, romidepsin is a valuable option for relapsed/refractory patients with both CTCL and PTCL. It’s also generally well tolerated, and gives potentially durable responses for patients with advanced and symptomatic disease. Combinations of romidepsin with other antineoplastic agents may also further improve drug response and outcomes in T-cell lymphoma.     

Emerging drugs in the treatment of pancreatic cancer

Background: Pancreatic cancer is the fourth leading cause of cancer-related death in the US. However, there is a growing belief that novel biological agents could improve survival of patients with this cancer. Gemcitabine-based chemotherapy remains the cornerstone treatment for advanced pancreatic cancers. So far, the current targeted agents that have been used in combination with gemcitabine have failed to improve clinical outcomes. This failure may stem from the heterogeneous molecular pathogenesis of pancreatic cancers, which involves several oncogenic pathways and defined genetic mutations. Objective: The aims of this review are: i) to define the existing treatments available at present for patients with pancreatic cancers in the neo-adjuvant, adjuvant, locally advanced and metastatic settings; ii) to highlight the molecular heterogeneity of the cancers and the rationale for targeting specific oncogenic pathways; iii) to give an overview of targeted agents that may potentially have an impact in the treatment of pancreatic cancers. Conclusions: Molecular pathogenesis of pancreatic cancer involves several pathways and defined genetic mutations. Targeting these complex molecular pathways with a combination of novel biological and chemotherapeutic agents could potentially improve patient outcome.     

Anti-CD44 mAb for the treatment of B-cell chronic lymphocytic leukemia and other hematological malignancies: evaluation of WO2013063498

Introduction: The CD44 transmembrane glycoprotein family mediates cellular responses to the microenvironment through binding of hyaluronic acid (HA) and other proteins of the extracellular matrix. These interactions start intracellular signaling cascades that foster tumor growth, survival and spread.

Areas covered: The patent concerns the use of a humanized anti-CD44 mAb (RG7356) to treat patients with aggressive forms of chronic lymphocytic leukemia (CLL). The RG7356 humanized antibody was designed to bind the constant region of CD44, preventing binding with HA. The interruption of this circuit in vitro is followed by the induction of caspase-dependent apoptosis in leukemic cells. In agreement with a functional association between CD44 and zeta-associated protein of 70 kDa (ZAP-70) in activating intracellular signaling, the strongest effects were observed in ZAP-70⁺ CLL cells, generally associated to a poor prognosis. Furthermore, these effects were confirmed using in vivo models, where CLL cells were xenografted in immunocompromised mice.

Expert opinion: In summary, these studies suggest that this new humanized mAb may provide additional clinical benefit to CLL patients receiving current standard treatments, specifically to those with a more aggressive disease.