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.     

Molecular targeted therapy of advanced hepatocellular carcinoma beyond sorafenib

Importance of the field: With the recent advances in the knowledge of molecular biology of hepatocellular carcinoma (HCC), there have been encouraging developments in targeted therapy for advanced HCC.

Areas covered in this review: This review discusses the development of targeted therapy for advanced HCC patient since 2006. Among the newly identified targets, promising results have been shown in targeting the anti-angiogenic pathway. Pure anti-angiogenic agents such as bevacizumab and PTK 787 demonstrate modest activity in treating patients with advanced HCC. Sorafenib, a multi-targeted tyrosine kinase inhibitor with both anti-angiogenic and anti-proliferative effects, has been shown to prolong the overall survival of patients with advanced HCC in two Phase III randomized trials. Like sorafenib, other anti-angiogenic multi-targeted tyrosine kinase inhibitors, such as sunitinib, pazopanib, brivanib and linifanib, also show promising activity in various stages of clinical trials. Other on-going early-phase studies are exploring the activities of drugs targeting novel pathways, such as PI3K/AKT/m TOR, hepatocyte growth factor/mesenchymal epithelial transition factor and insulin-like growth factor.

What the reader will gain: After reading this review, the reader should have an in-depth understanding of the latest developments in the molecular targeted therapy of advanced HCC.

Take home message: The development of sorafenib in the treatment of advanced HCC proves the concept that molecular targeted therapies, especially anti-angiogenic agents, play a pivotal role in the treatment of this otherwise chemoresistant neoplasm. Future progress depends on further unraveling more molecular mechanisms of HCC for therapeutic intervention.     

Novel inhibitors in development for hepatocellular carcinoma

Importance of the field: The multikinase inhibitor sorafenib was the first agent to demonstrate a survival benefit for patients with locally advanced or metastatic hepatocellular carcinoma (HCC). Although sorafenib represents a landmark in the treatment of HCC and proved molecularly targeted therapy to be effective in this disease, it represents just the first step towards an improvement in systemic therapy. Since then, novel inhibitors have been evaluated in early clinical trials, showing potential activity.

Areas covered in this review: This article aims to review novel inhibitors emerging in the field of advanced HCC. An Internet-based search was performed to identify abstracts, clinical trials (www.clinicaltrials.gov, last accessed 30 November 2009), and original research and review articles.

What the reader will gain: Readers will gain a comprehensive survey of current molecularly targeted therapy approaches in advanced HCC. In addition, challenges such as the design of clinical trials, the assessment of radiological response, the role of combination therapy, and future developments in molecularly targeted therapy are discussed.

Take home message: Sorafenib is the standard of care in patients with advanced HCC. However, promising novel inhibitors are under investigation. Combined molecularly targeted therapies according to an individual genomic and proteomic profiling will probably lead to more personalised medicine in advanced HCC.     

Emerging targeted therapies for melanoma

Introduction: Melanoma is an aggressive cutaneous malignancy associated with poor response to traditional therapies. Recent regulatory approval for immune checkpoint inhibitors and agents targeting mutated BRAF has led to a tremendous expansion of effective treatment options for patients with advanced melanoma. Unfortunately, primary or acquired resistance develops in most patients, highlighting the need for additional therapies. Numerous genetic and other molecular features of this disease may provide effective targets for therapy development.

Areas covered: This article reviews available melanoma treatments, including immune and molecularly-targeted therapies. We then discuss agents in development, with a focus on targeted (rather than immune) therapies. In particular, we discuss agents that block mitogen-activated protein kinase (MAPK) signaling, as well as other emerging approaches such as antibody-drug conjugates, cell-cycle targeting, and novel genetically-informed clinical trials.

Expert opinion: Despite the incredible advances in melanoma therapeutics over the last several years, a clear need to develop more effective therapies remains. Molecularly-targeted therapy approaches will likely remain a cornerstone of melanoma treatment in parallel to immune therapy strategies.     

Hepatocellular carcinoma treatment: a comparative review of emerging growth factor receptor antagonists

Introduction: Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Over the last decade, sorafenib has been the only available therapeutic option for advanced HCC, although regorafenib recently showed a survival benefit compared with placebo in a second-line setting.

Areas covered: This review discusses key published and ongoing studies with targeted agents in HCC, molecular targets of HCC, the mechanism of resistance to sorafenib, and the role of biomarker-enriched clinical trials.

Expert opinion: The multiplicity of drivers and the existence of substantial molecular heterogeneity limit the benefits of targeted therapies in HCC. Based on molecular biology developments, a few biomarker-enriched clinical trials that target candidate driver genes are ongoing, and the outcomes of these are highly anticipated. Poor availability of tumor tissue and tumor heterogeneity in patients with HCC make liquid biopsy a very attractive option, although this technique remains to be validated.     

Pharmacotherapy of cervical cancer

Importance of the field: Cervical cancer (CC) remains an important health problem. It is the second most frequent malignancy in women worldwide, with one-third of patients dying from pharmacoresistant disease.

Areas covered in this review: We reviewed pharmacotherapy approaches in the medical and multidisciplinary management of CC and conducted a systematic search of Pubmed for clinical trials, reviews and meta-analysis published in the last 20 years. Abstracts of the American Society of Clinical Oncology, European Society of Gynecological Oncology and International Gynecologic Cancer Society were also searched, together with the US National Institutes of Health clinical trial database.

What the reader will gain: The state-of-the art of cytotoxic and biologically targeted therapies in early, locally advanced and metastatic/recurrent CC is discussed.

Take home message: Until recently, the role of pharmacotherapy in CC was restricted to palliation of advanced/metastatic or recurrent disease. During the past two decades, this reluctant attitude towards chemotherapy has been modified after a series of randomized trials demonstrated its beneficial contribution as an adjunct to radiotherapy or surgery in early and locally advanced CC. Moreover, new combinations of cytotoxics, together with novel molecular target agents, open new perspectives in the treatment of primary and recurrent CC.     

Novel therapeutic targets and predictive markers for hepatocellular carcinoma

Introduction: Following the approval of sorafenib as the first systemic agent for treatment of advanced hepatocellular carcinoma (HCC), there have been an increasing number of targeted treatments under testing for the cancer. However, most of the recently published drug trials in HCC failed to produce remarkable results. The researchers are actively pursuing novel therapeutic targets as well as predictive biomarker for treatment of HCC.

Areas covered: This review discusses a number of potential novel targets for drug development of HCC. Focus is put on the underlying rationale for therapeutic development of the target and the possibility of using a predictive biomarker to select patients for drug testing.

Expert opinion: Future direction of drug development will be discussed. Notably, a clinical trial on drug testing in HCC should be shifted from all-comers approach to selected populations based on underlying viral etiology and molecular targets. A study to evaluate predictive biomarker is crucial to the development of targeted agents for HCC. Design of clinical trials on HCC should introduce measures to encourage acquisition of tumor and plasma samples for biomarker development.     

Molecular targeted therapy in recurrent glioblastoma: current challenges and future directions

Introduction: The survival of patients with glioblastoma (GBM), which is the most common primary brain malignancy, remains poor with current treatment modalities. However, an enhanced understanding of gliomagenesis is supporting the development of targeted molecular therapies with the potential for improving clinical outcomes.

Areas covered: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) initiate key signaling pathways in GBM; however, trials with anti-EGFR agents have failed to show improved outcomes. Bevacizumab, a monoclonal antibody targeting VEGF, remains the only FDA-approved molecular drug in GBM; yet its use has only improved progression-free survival without any improvement in overall survival. We review the evidence supporting the continued evaluation of targeted molecular therapies in recurrent GBM. In addition, newer potential therapies targeting other signaling pathways, heat shock proteins and proteosomes, as well as the concept of targeting glioma stem cells are discussed.

Expert opinion: The complex genetic origin of GBM makes it challenging to identify molecular subsets that may benefit from specific targeted therapies. Pathway inhibition, via multisite kinase inhibitors or a carefully selected combination of molecular drugs with or without cytotoxic agents, is currently undergoing evaluation in clinical trials and may improve outcomes in these patients.     

Sorafenib in liver cancer

Introduction: With growing knowledge of the molecular pathway of carcinogenesis, targeted therapies have become the ‘blue ocean' of cancer treatment. sorafenib is an oral multikinase inhibitor that targets Raf/mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) (Raf/MEK/ERK) and several tyrosine kinases (VEGFR-2, VEGFR-3, PDGFR-β) that has shown efficacy in hepatocellular carcinoma (HCC).

Areas covered: An updated summary of the preclinical and clinical experience with sorafenib in HCC is presented in this paper. Data are based on abstracts from international conferences and journal articles found in a PubMed search of literature published up to December 2011.

Expert opinion: Based on favorable data from preclinical and clinical trials, sorafenib has been approved as a standard therapy in advanced HCC. However, further efforts to understand the additional roles of sorafenib in the treatment of HCC are still necessary. Data for sorafenib will guide the development of new drugs for the treatment of HCC.     

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.     

Novel approaches to the development of tyrosine kinase inhibitors and their role in the fight against cancer

Introduction: Protein tyrosine kinase inhibitors are currently one of the most important classes of cancer drugs and one of the most impressive approaches of targeted cancer therapy. Aberrant activation of tyrosine kinase pathways is among the most dysregulated molecular pathways in human cancers; therefore, a large number of tyrosine kinases may serve as valuable molecular targets. To date, several inhibitors of tyrosine kinases have been approved and there are hundreds more compounds that are in various stages of development. Because of the deregulation in human malignancies, the ABL1, SRC, the epidermal growth factor receptor and the vascular endothelial growth factor receptor kinases are among the protein kinases that are considered as prime molecular targets for selective inhibition.

Areas covered: This review focuses on most important small-molecule inhibitors that serve as a model for future development. They also provide a broad overview of some of the new approaches and challenges in the field.

Expert opinion: With the exception of a few malignancies seemingly driven by a limited number of genetic lesions, current targeted therapeutic approaches have shown only limited efficacy in advanced cancers. Consequently, more sophisticated strategies, such as identification of pathogenic ‘driver' mutations and optimization of personalized therapies are needed.     

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.     

Oral chemotherapy for the treatment of hepatocellular carcinoma

Introduction: Many clinical trials have been conducted with chemotherapies in patients with advanced hepatocellular carcinoma (HCC). However, few agents have shown efficacy. It is thought that the efficacy of some agents might have resulted from the heterogeneity of tumors, insufficient dosages due to liver cirrhosis, and post-therapy effects. In recent years, immune checkpoint inhibitors have shown promising clinical activity and safety in patients with advanced HCC.

Areas covered: The authors provide an overview of chemotherapies used for the treatment of HCC, including ongoing trials. The authors also provide their expert opinion on the subject area and provide their future perspectives.

Expert opinion: Based on favorable phase III clinical trial data, sorafenib and lenvatinib are considered promising agents for HCC as first-line systemic chemotherapy. Moreover, regorafenib and cabozantinib are useful second-line therapies after the failure of sorafenib. Furthermore, in early phase clinical trials, immune checkpoint inhibitors and the combinations of these inhibitors and molecular targeted agents have demonstrated promising activity. Therefore, better survival results are expected from future phase III clinical trials.     

Drug design strategies for the treatment of prostate cancer

Introduction: While metastatic prostate cancer remains an incurable tumor, remarkable progress has been made with novel drug design strategies for this incurable disease. Several new agents, including hormonal analogues, cytotoxic chemotherapy drugs, radionuclides and innovative targeted therapies, have recently been approved by the FDA for use in advanced and/or metastatic castrate-resistant prostate cancer. Furthermore, a growing number of new diagnostic or predictive genetic tests have also been incorporated into the management of this disease. Immunotherapy-based approaches have shown promise and have led to drug approvals. Other experimental approaches such as vascular targeting are in early translational clinical trials.

Areas covered: Herein, the authors outline select state-of-the-art approaches in the field. They also discuss the current challenges and future opportunities in the medical care of prostate cancer patients.

Expert opinion: An inherent challenge in the treatment of prostate cancer is to determine which patients need immediate aggressive treatment versus active surveillance. For patients needing aggressive treatment, integrating the sequence of therapeutic interventions, to provide the most benefit, remains a challenge that clinicians face. Recently, several genetic tests have been approved, facilitating early treatment decisions. Innovative targeted therapies are moving towards clinical applications, providing treatment options for tumors previously considered refractory to androgen ablation treatment.     

Cost implications of IV versus oral anti-angiogenesis therapies in patients with advanced renal cell carcinoma: retrospective claims database analysis*

ABSTRACT

Objective: Angiogenesis inhibitors (AI) are promising novel treatments for patients with renal cell carcinoma (RCC). However, IV therapy may impose infection risk from IV catheters, and will include increased costs due to administration and transportation costs. This study evaluated the incremental costs associated with IV administration of selected AI therapies (bevacizumab off-label) compared to oral therapies (sunitinib or sorafenib) for the treatment of RCC.

Methods: Patients with ≥2 RCC claims (ICD-9: 189.0, 198.0) were identified from a US commercial health insurance claims database from 1/2004 to 12/2007. Patients receiving bevacizumab (n?=?109) were matched 1:1 to patients receiving sorafenib or sunitinib, and observed from their first AI therapy claim until the last treatment date. AI, inpatient, outpatient and pharmacy costs were calculated on a per-patient per-month (PPPM) basis over the treatment period. Costs were compared between the IV AI group and each separate oral AI group using multivariate Tobit regressions for each category separately, adjusting for demographic and baseline clinical characteristics. This study assessed costs of treatment and did not evaluate the cost-effectiveness of AIs.

Results: Mean total medical costs were $13?351, $6998, and $8213 PPPM for bevacizumab, sorafenib, and sunitinib, respectively (p?<0.05 for equality). Adjusted incremental total cost for the bevacizumab group was $4951 PPPM compared to sorafenib and $4610 PPPM compared to sunitinib (both p?<?0.05). Bevacizumab patients incurred incremental PPPM outpatient services cost compared to sorafenib and sunitinib of $2772 and $2548, respectively (both p?<?0.05).

Conclusions: Assuming median progression-free survival of 8.5 months as shown for bevacizumab (Bukowski, et al., J Clin Oncol 2007), the incremental costs would be estimated at $39?188–42?080 per patient compared to those treated with sunitinib or sorafenib. Assuming similar efficacies, oral AI therapies may result in cost savings to patients and healthcare payers over IV therapies.     

BRAF kinase inhibitors for treatment of melanoma: developments from early-stage animal studies to Phase II clinical trials

Introduction: Approximately, 30.4–66.0% of cutaneous melanomas possess a mutation in the BRAF gene that activates downstream signaling through the mitogen-activated protein (MAP) kinase pathway; this provides an attractive target for the treatment of advanced melanoma. Although BRAF inhibitors rapidly suppress melanoma growth, median progression-free survival remains unsatisfactory. Recent clinical trials have investigated drugs that can optimally enhance and prolong the anti-melanoma effects of BRAF inhibitors.

Area covered: This review discusses the development of BRAF inhibitor-based combination therapies for BRAF-mutant advanced melanoma.

Expert opinion: Future strategies for the treatment of advanced melanoma include novel combination therapies using BRAF/MEK inhibitors and immune checkpoints inhibitors or histone deacetylase inhibitors. These combination therapies might enhance antitumor responses against melanoma, prolonging survival in advanced melanoma patients. Further clinical studies are needed to optimize these novel combination therapies.     

The challenge of targeted therapies for gastric cancer patients: the beginning of a long journey

Introduction: Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced disease remains dismal. Collaborative, high-quality research and advances in high-throughput technologies have contributed to elucidate molecular pathways underpinning disease progression and have stimulated many clinical studies testing target therapies in the advanced disease setting. Although progress has been made thanks to trastuzumab in HER2 positive tumours, antiangiogenic drugs have produced conflicting results and EGFR-inhibitors have failed to show major improvements.

Areas covered: While commenting on the results of many key Phase III randomized trials, the Authors discuss the most promising classes of novel targeted agents and present the current challenges toward a customized treatment.

Expert opinion: Palliative chemotherapy became the worldwide standard of care for patients with advanced gastric cancers, producing significant life prolongation and improvement of life quality. Nevertheless, long-term outcomes of those patients remain poor. Because of the encouraging advancement in novel targeted therapies, such a disappointing scenario is now evolving. While results serve as a springboard for future research, more comprehensive efforts are needed to clarify the biological mechanisms underpinning cancer progression and help clinicians to develop new effective treatments.     

Molecularly targeted therapy in hepatocellular carcinoma

With an annual incidence of over 660,000 deaths, hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally. This disease is often diagnosed at an advanced stage, when potentially curative therapies are not feasible. HCC is highly resistant to conventional systemic therapies and prognosis for advanced HCC patients remains poor. Given the clear need, clinical development of novel therapeutic agents in HCC has begun in earnest. Our recent knowledge of the molecular mechanisms responsible of tumor initiation and progression has identified several potential molecular targets in HCC. These targets are the receptor tyrosine kinase-activated pathways, which include the Raf/MEK/ERK, PI-3K/Akt/mTOR, and Jak/Stat. Sorafenib is the multikinase inhibitor that has shown modest survival benefits in advanced HCC in two randomized controlled trials, supporting the use of molecularly targeted therapies in treatment of HCC. A number of strategies including monoclonal antibodies and tyrosine kinase inhibitors such as erlotinib, sunitinib, vandetanib, cediranib, brivanib, foretinib, and dovitinib have been developed and tested in various phases of clinical trials. The successful development of these novel targeted agents in the future will be dependent on the selection of patient populations that are most likely to derive clinical benefit, optimization of the dose used and schedules, and investigation of combined therapies. This review describes evolving molecular targeted agents, their common adverse side effects, and its potential use in management of HCC.