Emerging drugs for renal cell carcinoma

Importance of the field: The treatment of metastatic renal cell carcinoma (RCC) has evolved significantly over the past 5 years and targeted therapy has become the standard of care. However, complete and lasting responses to these drugs are still uncommon. Currently, novel agents are being tested in clinical trials.

Areas covered in this review: We discuss approved targeted agents in RCC and emphasize on emerging therapies. We searched the US National Library of Medicine (PubMed) using the terms ‘renal cell carcinoma’, ‘targeted therapy’ and ‘novel agents’, from 1990 to the present. We also searched for abstracts from the meetings of the American Society of Clinical Oncology and Genitourinary Cancers Symposium from 2007 to the present.

What the reader will gain: This paper provides understanding of the approved treatments for advanced RCC as well as the novel agents and their targeted biological pathways.

Take home message: Despite dynamic and recent advances in the management of metastatic RCC much about the molecular biology of this tumor has yet to be delineated. Even more so, strategies of sequential treatment, combination of targeted drugs, mechanisms of resistance, optimal dosages and scheduling remain areas of potential development interest.     

Present and future therapeutic options for locally advanced and metastatic renal cell carcinoma

Introduction: Locally advanced or metastatic renal cell carcinoma (RCC) is notoriously chemo- and radioresistant, leaving immunotherapy as the only treatment option. In recent years, targeted therapies have offered significant increases in progression-free survival (PFS). Despite this, the majority of patients soon develops resistant disease and finally succumbs. The need to implement treatment strategies that improve overall survival while having an acceptable safety profile is imperative.

Areas covered: This review provides information on the efficacy of recently studied treatment strategies for advanced RCC. These include sequential and combination therapy of established drugs as well as data on agents in early clinical development. The Medline and ASCO database were searched for clinical trials on medical therapy of advanced RCC from 2004 until May 2010. Data on targeted therapies, including tyrosine kinase inhibitors, vascular endothelial growth factor inhibitors, mammalian target of rapamycin inhibitors, and antiepidermal growth factor receptor agents are summarized.

Expert opinion: Improvements in response rates and PFS in patients with advanced RCC have been observed with new treatment strategies. The benefit in overall survival is less clear and needs further evaluation. Toxicity represents a concern especially in combination regiments.     

Current investigational drugs in psoriasis

Introduction : The advent of biologic therapies has revolutionized the treatment of psoriasis. Increased understanding of immunogenetic pathways has allowed for the development of more selective targeted biologic therapies. Multiple new treatments are currently in development for the treatment of psoriasis. Preliminary data for many of these agents, particularly with regard to agents targeting the IL-23/Th17 pathway, are promising. Proven long-term safety, however, is an absolute necessity with newly developed drugs, and should, therefore, still be considered second-line agents to current established treatments with long-term safety data.

Areas covered : This review details the mechanisms of action of drugs currently in development or in clinical trials for the treatment of psoriasis, using clinical trial registries and associated publications. Readers will gain a comprehensive overview about the mechanism of action of emerging treatments targeting various immune pathways deeply involved in psoriasis. Pathogenesis, clinical efficacy and safety data for these treatments are discussed where available.

Expert opinion : Psoriasis remains a heavily undertreated systemic immune-mediated disease despite increased understanding of immunopathogenesis of the disease and advent of a multitude of novel therapeutic agents with potentially improved bioavailability and safety profiles. Limitations, however, remain in the realm of topical agents for treatment of mild to moderate psoriasis, which has seen little progress over the years. A concerted effort will need to be made among researchers, clinicians and patient advocacy groups to ensure new therapeutic agents are developed and gain proper exposure.     

Advancing therapies in metastatic castration-resistant prostate cancer

ABSTRACT

Introduction: Prostate cancer is the second most common cause of cancer worldwide and is the most frequently detected cancer in the European Union in men over 50 years of age. Androgen deprivation therapy remains the cornerstone of treatment for recurrent or metastatic disease. Unfortunately, nearly all patients will develop resistance to androgen blockade leading to castration-resistant prostate cancer (CRPC). Over the last 10 years, new treatments have dramatically improved overall survival of men with mCRPC. Current therapies are based on AR-axis inhibitors and taxane-based chemotherapies, as well as radiopharmaceuticals and Sipuleucel T.

Areas covered: The authors provide a review of the current field of systemic therapy in metastatic CRPC. This is followed by an in-depth analysis of recent developments in treatment, and the biological rationale behind these therapies.

Expert opinion: Since several trials with docetaxel or novel hormonal agents showed improvement in overall survival in metastatic castration-sensitive prostate cancer, as well as in non-metastatic castration-resistant patients, it is expected that a growing subgroup of patients will be exposed earlier to chemotherapy and to AR targeted agents. It becomes then fundamental to find novel strategies to overcome drug resistance and further improve survival.     

Axitinib: from preclinical development to future clinical perspectives in renal cell carcinoma

Introduction: Based on extensive preclinical data and abundant evidence for clinical activity, vascular endothelial growth factor receptor (VEGFR) inhibitors are currently standard of care for metastatic renal cell carcinoma (mRCC). Axitinib is one of the most selective molecules in the class of anti-angiogenic agents, which confers an optimal profile between its safety and anti-cancer activity spectrum.

Area covered: In this review, the authors discuss the different stages that lead to the approval of axitinib in the clinic as well as the current perspectives for its clinical use with other promising therapies in mRCC such as immune checkpoint inhibitors and vaccines.

Expert opinion: In 2015, axitinib has emerged as one of the major agents used in mRCC. Based on robust preclinical data, this highly specific VEGFR inhibitor continues to be evaluated in different indications, including the adjuvant setting but also sequential administration with other molecularly targeted agents or combinations with immune therapies.     

Emerging drugs targeting human epidermal growth factor receptor 2 (HER2) in the treatment of breast cancer

Introduction: Human epidermal growth factor 2 (HER2) overexpression is present in 20% of breast cancer patients. It is associated with more aggressive disease and worse clinical outcome. New drugs are thus needed. Approved and future treatments will be discussed in this review.

Areas covered: The monoclonal antibodies trastuzumab and pertuzumab, the tyrosine kinase inhibitor lapatinib and the antibody-drug conjugate trastuzmab emtansine are approved for HER2 positive breast cancer. The combination of trastuzumab, pertuzumab and docetaxel is currently the first-line treatment in the metastatic setting. New therapies are still needed due to frequent relapse and resistance. These include mammalian target of rapamycin inhibitors, heat shock protein 90 inhibitors, pan-HER2 tyrosine kinase inhibitors, antibody-drug conjugates, immunotherapy agents (antibodies and vaccines), radioimmunotherapy and HER2 specific affinity proteins. Possible developmental issues are the complexity of the molecular biology of the HER2 positive cancer cell, the occurrence of resistance, toxicity and the high cost.

Expert opinion: The determination of the right sequence of use of old and new therapies remains a challenging issue. The selection of patients who do or don’t benefit from potentially toxic chemotherapy is also difficult. Central nervous system metastases are a common problem in HER2 positive breast cancer that needs to be addressed in future trials.     

New targeted therapies for renal cell carcinoma

INTRODUCTION: The aim of treatment in metastatic renal cell carcinoma is palliation. In the last 5 years, multiple targeted agents have been developed which have resulted in prolongation of patients' lives, but complete responses remain rare. New therapies and approaches are required to further improve the prognosis for patients with this disease. AREAS COVERED: This review discusses the molecular targets in renal cell carcinoma relevant to the development of new treatments and describes the progress of novel therapies. The evidence is compiled from the PubMed database and proceedings of scientific meetings, searched up to December 2010. EXPERT OPINION: A multitude of experimental agents are in clinical development and offer theoretical advantages over those currently in use. It is hoped that these treatments will result in better long-term control of metastatic renal cell carcinoma, with improved side effect profiles, but curative treatment in this disease remains elusive until the mechanisms underlying response and resistance to therapy are elucidated. Progress in the field has been limited by inadequate tissue collection within clinical trials; current and future clinical trial design will incorporate a larger translational component in an attempt to establish predictive biomarkers.     

Immunomodulatory agents in myelofibrosis

Introduction: The treatment options for patients with myelofibrosis (MF) remain limited. Anemia, thrombocytopenia, extramedullary hematopoiesis, constitutional symptoms, and disease progression are the primary causes of morbidity and mortality. Traditional non-transplant therapies remain non-curative. Moreover, in the JAK2 inhibitor era, no single pharmacologic agent has been shown to improve all MF-related clinical manifestations. Immunomodulatory agents (IMiDs), such as thalidomide and lenalidomide, have been useful in the treatment of some MF patients while newer IMiDs such as pomalidomide are showing promise in MF.

Areas covered: This review focuses on the biologic rationales of IMiDs and the clinical results supporting their use in MF. It includes data on the new IMiD, pomalidomide and also explores the possible utility of combining IMiDs with other agents. A PubMed search of articles related to IMiDs and myelofibrosis were conducted. Relevant studies and clinical studies with sample size of > 15 were included.

Expert opinion: In the JAK2 inhibitor era, IMiDs are alternative treatments in managing splenomegaly and constitutional symptoms. They remain useful in the treatment of cytopenias. Pomalidomide's good anemia response may lead to its inclusion as one of the frontline anemia therapies in MF. Molecular biomarkers may allow us to identify patients who will respond to IMiDs.     

New therapies in soft tissue sarcoma

Importance of the field: Soft tissue sarcomas are rare mesenchymal tumors accounting for <?1% of all adult neoplasia. In the last decade, locally advanced and metastatic soft tissue sarcoma have been managed only through surgery, radiotherapy and standard chemotherapy (mainly based on anthracycline and ifosfamide). Despite the efforts, overall 5-year survival rate in patients with soft tissue sarcomas of all stages remains only 50 – 60%.

Areas covered in this review: In the present article, all the main new molecules under clinical evaluation for the treatment of soft tissue sarcoma are revised by describing the mechanism of action, the biological rationale of their use in sarcoma and by reporting the available data about safety and efficacy, up to 2009.

What the reader will gain: A brief summary of the standard treatments available at the moment and a complete analysis of the state of art about the development of new target therapies in the management of soft tissue sarcoma.

Take home message: The identification of new biological therapies that target soft tissue sarcoma tumorigenesis key points seems to offer a real opportunity of improving the prognosis of this often aggressive disease. In this sense, the best management for soft tissue sarcoma patients is in a clinical trial and participation in clinical trials should be encouraged.     

Emerging therapeutics in refractory renal cell carcinoma

Introduction: Metastatic renal cell carcinoma (mRCC) has seen the introduction of numerous new treatments over the past decade. However, the efficacy of these therapies has plateaued, and new treatment options are needed for the majority of patients with mRCC whose disease inevitably progresses through one or more standard therapies (‘refractory’ mRCC). Recently approved agents in this space have shown great promise.

Areas covered: This article reviews the evidence behind current management strategies for mRCC. After reviewing clinical trials that established current first-line therapies and agents used in the refractory setting, we address new ideas for the treatment of refractory disease including combination therapies and novel targeted agents. In particular, we focus on targeted immunotherapy in refractory mRCC. We conclude by considering future directions in combination treatments utilizing these novel agents.

Expert opinion: Numerous approaches have produced tangible benefits for the treatment of patients with mRCC. These include development of next generation VEGFR/TKIs, targeted immunotherapy agents, and the development of combined regimens. In particular, immunotherapy agents targeting the PD1/PD-L1 pathway have shown great promise with a robust survival advantage seen in patients treated with nivolumab. A tolerable side effect profile of immunotherapy agents makes them amenable for use in combination therapies and ongoing trials are addressing this question.     

Emerging drugs for the treatment of myelofibrosis

Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with significant disease burden composed of splenomegaly, constitutional symptoms and a reduced life expectancy. The advent of targeted treatments has provided new means by which to improve MF associated splenomegaly, symptoms, health-related quality of life and even mortality.

Areas covered: We discuss the spectrum of targeted treatments currently under investigation for MF. We furthermore compare their effects on improving anemia, reducing fibrosis and splenomegaly and enhancing symptom control.

Expert opinion: MF is a complex disorder, partly attributable to its heterogeneity. Although the severity of patient symptoms correlates with risk category, high symptom burden may also be observed in low-risk patients. Serial use of PRO tools allows clinicians to objectively evaluate the MF symptom burden, compare efficacy of therapies and adjust medications to improve symptom control. Novel targeted agents have proven superior to historic treatment regimens for symptom management. Promising treatment categories include JAK2 inhibitors, histone deacetylase inhibitors, hypomethylating agents, heat shock protein-90 inhibitors, hedgehog inhibitors, PI3-AKT-mTOR inhibitors, antifibrosing agents and telomerase inhibitors. The majority of therapies remain under investigation, either alone or in combination with other treatments. It is anticipated that these agents will be increasingly integrated into standard treatment algorithms for MF symptom management.     

Tyrosine kinase inhibitors to treat liver cancer

Importance of the field: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Although patients with early-stage disease have a good prognosis, there has been no effective therapy available for those with advanced disease. Despite the death risk of patients with advanced HCC being reduced with sorafenib therapy, many patients eventually turn out to be refractory to this therapy. Thus, treatment of HCC remains an urgent health concern.

Areas covered in this review: Recent improvement in understanding the pathophysiology of HCC at the molecular level has fostered the development of molecular targeted therapies that specifically block the disrupted pathways.

What the reader will gain: This review summarizes the preclinical and clinical data from 2004 to 2009 on the efficacy and safety of the emerging drug for the treatment of HCC, including small molecule inhibitors (erlotinib, sunitinib, sorafenib, vandetanib, cediranib, brivanib and dovitinib) and the rationale for combination therapies for patients with advanced HCC.

Take home message: Understanding the mechanisms of action, safety and efficacy of these new agents and new methods of combining these drugs may help prolong overall survival of patients with HCC and reduce disease recurrence after surgery or ablative therapies.     

Safety of available treatment options for renal cell carcinoma

ABSTRACT

Introduction: For many years, cytokines (high-dose interleukin (IL)-2 and interferon (IFN)) have been the unique available treatment options for metastatic renal cell carcinoma (mRCC) and they provided durable but modest responses at the cost of significant toxicities. To date, targeted therapies have replaced cytokine therapy due to higher response rates and more favorable toxicity profiles. The major classes of targeted therapy for mRCC include tyrosine kinase inhibitors, monoclonal antibody against vascular endothelial grow factors and inhibitors of the mammalian target of rapamycin. Thanks to these new strategies, the prognosis for the mRCC is shifting toward a chronic disease and the new challenges are the adequate treatment of adverse events (AEs) and the care for quality of life, which is crucial. Emerging immunotherapies targeting the programmed death-1 (PD-1) receptor and the programmed death ligand-1 (PD-L1) ligand have shown promising results in both efficacy and safety profiles.

Areas covered: Safety data published on available treatment options for renal cell carcinoma RCC are reviewed.

Expert opinion: Various toxicities are associated with targeted agents; these toxicities are generally well tolerated but careful monitoring and appropriate management are needed to optimize the use of these strategies.     

Treatment of head and neck cancer in the elderly

Introduction: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and the majority of patients present with advanced stage disease. Chemotherapy is an important component of head and neck cancer treatment regimens and has shown beneficial effects in locally advanced and recurrent/metastatic stages of disease. Approximately 25% of HNSCC patients are aged 70 and older, often associated with co-morbid medical conditions. Most clinical trials exclude patients of advanced chronological age such that valid information about the efficacy and safety of drugs and treatment regimens in elderly patients is not available.

Areas covered: Surgery, radiotherapy and particularly chemotherapy with the six FDA-approved chemotherapeutic agents for head and neck cancer treatment are discussed with a focus on age, performance status, comorbidities. New targeted therapies and the field of immune checkpoint inhibitors are evaluated in the context of elderly populations.

Expert opinion: Surgery, radiotherapy and administration of cytotoxic chemotherapeutic agents are largely safe and effective in elderly patients. Targeted therapies are mostly well tolerated. Clinical studies should be designed to include elderly patients (>70 years). Immune checkpoint inhibitor therapies may exert age-related effects, since substantial functional changes in T cell responses increase during the aging process.     

Emerging drugs for urothelial carcinoma

Introduction: Advanced urothelial carcinoma is associated with a poor prognosis. In the metastatic setting, the response rate to first-line, cisplatin-containing chemotherapy is high, but survival is poor. Second-line treatment options are limited. Advanced age at diagnosis and the presence of comorbidities often preclude treatment with cisplatin-containing regimens.

Areas covered: This review addresses the current therapy of urothelial carcinoma, the unmet needs in treatment and the status of drug development in this disease. The molecular targets identified and efforts to incorporate targeted agents into therapy will be addressed.

Expert opinion: There have been no major advances in the treatment of urothelial carcinoma in three decades. Despite high response rates in the first-line setting, survival is limited. Major impediments to improved outcomes include poor durability of response to first-line chemotherapy and lack of second-line treatments. Better understanding in tumor biology has identified multiple targets in urothelial carcinoma; however, such discoveries have yet to lead to the incorporation of targeted agents into the routine treatment of urothelial carcinoma. Multiple ongoing clinical trials are investigating the use of targeted agents in urothelial carcinoma. Continued efforts are underway to better understand the molecular drivers of disease and such efforts are likely to identify additional therapeutic targets.     

Protein kinase inhibitors in renal cell carcinoma

Introduction: Metastatic Renal Cell Carcinoma (mRCC) was historically treated with cytokine therapy with a poor outcome. In the last decade, new therapies targeting vascular endothelial growth factor (VEGF) or the mammalian target of rapamycin (m-TOR) pathways demonstrated efficacy in mRCC. Protein kinase inhibitors as well as monoclonal antibodies targeting these pathways have become the standard treatment of renal cell carcinoma (RCC) in the first-line setting and beyond.

Areas covered: This review describes the various Phase III trials concerning protein kinase inhibitors including anti-angiogenic tyrosine kinase inhibitors (TKIs) and m-TOR serine/threonine kinase inhibitors, which have demonstrated a benefit in the treatment of mRCC. It focuses on efficacy, safety and management.

Expert opinion: VEGF TKI and m-TOR inhibitors have significantly improved the outcome of mRCC and offer a gain in survival by sequential treatments for the majority of patients. But they induce a particular toxicity profile. An adequate management of each drug and its sequence in treatment is essential to optimise the outcome and preserve the quality of life (QoL) of patients with mRCC. In forthcoming years, pending results should indicate whether VEGF TKI are of interest in an adjuvant setting and if new drugs targeting will challenge the current standard guidelines in the metastatic setting.     

Emerging VEGF-receptor inhibitors for colorectal cancer

Introduction: Targeted agents have dramatically improved and enriched the therapeutical choices for patients with metastatic colorectal cancer (mCRC). By better understanding the role of the angiogenic pathway in colorectal cancer (CRC), new therapies have been developed. Bevacizumab, the first anti-angiogenetic agent approved for the treatment of mCRC provide a proof of concept since it has improved the progression-free survival and overall survival when combined with cytotoxic chemotherapy.

Areas covered: This review is focused on the most recent findings on the VEGF signaling pathway and new therapeutic drugs explored in clinical trials.

Expert opinion: Despite the advantage offered by bevacizumab, the median overall survival of mCRC patient exceeds 21 months; thus, investigational efforts are needed. Several antiangiogenic agents for the treatment of mCRC are being tested in preclinical and clinical Phase I/II trials. Unfortunately a discrete number of Phase III trials produced negative results. Recently aflibercept and regorafenib, two new antiangiogenic drugs, have been approved as the new-targeted agents for the treatment of mCRC, according to the positive findings from the VELOUR and the CORRECT studies. In order to maximize clinical impact it will be important to validate predictive biomarkers and best combination treatments to offer for mCRC patients; further research and intense investigation is still required.     

Pharmacotherapy for treating metastatic clear cell renal cell carcinoma

Introduction: Over the past decade metastatic renal cell carcinoma (RCC) treatment landscape has dramatically evolved from the era of cytokines-based immunotherapy (which benefited very few patients, at the expenses of high toxicities) to the present era of targeted agents and novel immunotherapeutics, greatly improving the prognosis of our patients.

Areas covered: Here we have reviewed the present status of the medical treatment of metastatic RCC. To do this, we interrogated the Medline database, as well as the proceedings of the main Oncological and Urological conferences for the relevant trials coducted so far.

Expert opinion: Despite all the advances made in these relatively few years, further improvements are needed, since none of the available agents proved able to cure even a sigle metastatic RCC patient. In particular, advances are awaited from the results of ongoing trial of combinations of different immune checkpoint inhibitors and of immune checkpoint inhibitors with anti-VEGF/VEGFRs agents. Furthermore, a better understanding of the molecular escape pathways used by the tumor to overcome VEGFR blockade or immune activation will hopefully bring soon to the clinic more active, tailored treatments, to be used in second line and beyond.     

Pharmacoeconomic and clinical implications of sequential therapy for metastatic renal cell carcinoma patients in Central and Eastern Europe

Introduction: The incidence and mortality rates of kidney cancer in the Central and Eastern European (CEE) region are among the highest in the world. Access to second and subsequent lines of metastatic renal cell carcinoma (mRCC) therapies is highly varied in the region. Despite the increasing body of evidence supporting the clinical benefit of multiple lines of treatment, access to treatment beyond first line is restricted in many of these countries.

Areas covered: The adoption of targeted therapies for the first-line treatment of mRCC in the region was slow and faced many obstacles. In order to evaluate the current status of treatment beyond the first-line setting in the CEE region, this review examines the availability and reimbursement of mRCC drugs and clinical practice in institutions that treat patients with mRCC.

Expert opinion: This review highlights the need to raise awareness among physicians, payers and regulators on clinical trial and cost-effectiveness data regarding the treatment of mRCC beyond the first line. The obstacles to mRCC drug access highlighted in this review need to be overcome to ensure that patients are receiving the best treatment available.