Ramucirumab for the treatment of gastric or gastro-esophageal junction cancer

ABSTRACT

Introduction: Gastric cancer remains one of the most lethal malignancy, accounting for an estimated 783,000 deaths worldwide in 2018. Although there are several approved drugs for the treatment of gastric cancer, the survival of patients with advanced disease remains dismal. Ramucirumab, a vascular endothelial growth factor receptor-2 inhibitor, is an important new targeted drug approved for gastric and gastroesophageal adenocarcinoma (GEJ) in second-line setting.

Areas covered: In this article, we have reviewed the role of ramucirumab in the management of gastric and GEJ adenocarcinoma. A comprehensive review of various clinical trials is presented that support the use of ramucirumab in gastric cancer.

Expert opinion: In our opinion, ramucirumab should be considered as a standard of care option, either alone or with paclitaxel, after progression on first-line therapy for advanced or metastatic disease. The results of large, randomized phase III clinical trials show benefit of ramucirumab on median overall survival (OS). However, the benefit is limited, with only about two months OS benefit of using ramucirumab with paclitaxel compared to paclitaxel alone. Novel combination therapies, such as ramucirumab with other targeted agents and immune checkpoint inhibitors in ongoing clinical trials, may provide important information to further improve the patient outcomes.     

Sequential Therapy With JX-594, A Targeted Oncolytic Poxvirus, Followed by Sorafenib in Hepatocellular Carcinoma: Preclinical and Clinical Demonstration of Combination Efficacy

JX-594 is a targeted and granulocyte-macrophage colony stimulating factor (GM-CSF) expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In a phase 1 trial, JX-594 injection into hepatocellular carcinoma (HCC) was well-tolerated and associated with viral replication, decreased tumor perfusion, and tumor necrosis. We hypothesized that JX-594 and sorafenib, a small molecule inhibitor of B-raf and vascular endothelial growth factor receptor (VEGFR) approved for HCC, would have clinical benefit in combination given their demonstrated efficacy in HCC patients and their complementary mechanisms-of-action. HCC cell lines were uniformly sensitive to JX-594. Anti-raf kinase effects of concurrent sorafenib inhibited JX-594 replication in vitro, whereas sequential therapy was superior to either agent alone in murine tumor models. We therefore explored pilot safety and efficacy of JX-594 followed by sorafenib in three HCC patients. In all three patients, sequential treatment was (i) well-tolerated, (ii) associated with significantly decreased tumor perfusion, and (iii) associated with objective tumor responses (Choi criteria; up to 100% necrosis). HCC historical control patients on sorafenib alone at the same institutions had no objective tumor responses (0 of 15). Treatment of HCC with JX-594 followed by sorafenib has antitumoral activity, and JX-594 may sensitize tumors to subsequent therapy with VEGF/VEGFR inhibitors.     

Systemic therapy of hepatocellular carcinoma: Are we making progress?

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer deaths. Surgical resection, with or without transplantation, can result in long-term survival. However, surgery can only be performed in about 15% of patients with HCC and the 5-year survival rate is only approximately 33%–50% after potentially curative resection. Percutaneous ethanol injection, radiofrequency ablation, and transarterial chemoembolization are invasive techniques that have shown efficacy in reducing tumor bulk. Similarly, systemic chemotherapy may induce tumor responses, but a survival benefit has not been clearly demonstrated. In addition, the lack of efficacy of antiandrogens, tamoxifen, and single-agent interferon has now been confirmed. Sorafenib is a multikinase inhibitor with antiangiogenic, proapoptotic, and Raf kinase inhibitory activity. In a large, multicenter, randomized, phase 3 trial there was a significant improvement in both time to disease progression and overall survival with sorafenib compared with placebo. Sorafenib is the first agent to demonstrate a consistent improvement in overall survival for patients with advanced HCC. Further studies are required to determine the role of other molecular-targeted therapies, either alone or in combination with sorafenib in patients with advanced HCC. Further studies are also required to determine the role of sorafenib in combination with locoregional therapies (eg, transarterial chemoembolization), and the role of sorafenib as adjuvant therapy following surgery.     

Nursing considerations with pazopanib therapy: focus on metastatic renal cell carcinoma

The rapid evolution of targeted therapies has had a dramatic impact on multiple domains in oncology, particularly metastatic renal cell carcinoma (RCC). Four agents antagonizing vascular endothelial growth factor-mediated signaling have been approved for the treatment of metastatic RCC, including the monoclonal antibody bevacizumab and the small molecular inhibitors sunitinib, sorafenib, and pazopanib. Pazopanib was approved in 2009 for this disease on the basis of a phase III clinical trial demonstrating a superior progression-free survival compared to placebo in 435 patients with either treatment-naive or cytokine-refractory disease. The trial offered insight related to the toxicity profile associated with this agent. The most common clinical adverse events are diarrhea, hypertension, nausea, anorexia, and vomiting. With respect to laboratory adverse events, hepatotoxicity represents a specific concern with pazopanib. Oncology nurses play a critical role in counseling patients regarding the toxicity profile and management of adverse events in pazopanib treatment.     

The potential combinational immunotherapiesfor treatment of hepatocellular carcinoma

The treatment choices available for hepatocellular carcinoma (HCC) are limited and unsatisfactory. Recent improvements in our understanding of the mechanism involving immune checkpoints, including programmed cell death protein 1 (PD1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and also progress in the development of medicines make immunotherapy a promising approach to the treatment of numerous cancers, especially HCC. However, around 40% of patients still suffer from a progressive disease when treated with a monotherapy. Several clinical trials applying a combination therapy including immune checkpoint inhibitors have demonstrated the durable antitumor activity of these approaches in HCC patients. These clinical trials were done with the intent of evaluating the safety of these combination therapies, as well as whether they help improve the overall survival of patients. This study reviewed the recent progress in the use of combination therapies including immunotherapy in treating patients with HCC.     

Encouraging specific biomarkers-based therapeutic strategies for hepatocellular carcinoma

The prevention, early discovery and effective treatment of patients with hepatocellular carcinoma (HCC) remain a global medical challenge. At present, HCC is still mainly treated by surgery, supplemented by vascular embolization, radio frequency, radiotherapy, chemotherapy and biotherapy. The application of multikinase inhibitor sorafenib, chimeric antigen receptor T cells, or PD-1/PD-L1 inhibitors can prolong the median survival of HCC patients. However, the treatment efficacy is still unsatisfactory due to HCC metastasis and postoperative recurrence. During the process of hepatocyte malignant transformation, HCC tissues can express and secrete many types of specific biomarkers, or oncogenic antigen molecules into blood, for example, alpha-fetoprotein, glypican-3, Wnt3a (one of the key signaling molecules in the Wnt/β-catenin pathway), insulin-like growth factor (IGF)-II or IGF-I receptor, vascular endothelial growth factor, secretory clusterin and so on. In addition, combining immunotherapy with non-coding RNAs might improve anti-cancer efficacy. These biomarkers not only contribute to HCC diagnosis or prognosis, but may also become molecular targets for HCC therapy under developing or clinical trials. This article reviews the progress in emerging biomarkers in basic research or clinical trials for HCC immunotherapy.     

Overview of anti-VEGF therapy and angiogenesis. Part 1: Angiogenesis inhibition in solid tumor malignancies

Several new agents that target the vascular endothelial growth factor (VEGF) pathway and inhibit angiogenesis are emerging as promising therapies in multiple cancer types. Bevacizumab, a humanized monoclonal antibody to VEGF-A, is currently approved in combination with intravenous 5-fluorouracil-containing regimens for the first-line treatment of metastatic colorectal cancer and recently demonstrated clinically important results in combination with chemotherapy in patients with non-small cell lung cancer and metastatic breast cancer. Other anti-VEGF agents that have shown benefit in various cancer types will be discussed in this monograph. Despite the often striking results observed with anti-VEGF agents, several unanswered questions remain, such as the optimal duration of therapy and patient selection criteria. These other issues, including the biologic rationale for anti-VEGF therapy, as well as recent clinical trial data with anti-VEGF agents in colorectal, pancreatic, lung, kidney, and brease cancers, are discussed.     

晚期胆管癌的药物治疗现状

胆管癌发病率低，恶性程度高，预后差。吉西他滨联合顺铂是晚期胆管癌的标准一线治疗，其疗效并不突出；同时，胆管癌缺乏标准二线治疗，亟需探索新的治疗方法。抗表皮生长因子受体、血管内皮生长因子、人类表皮生长因子受体-2等分子靶向治疗在化疗基础上均无突破，但靶向成纤维细胞生长因子受体2基因融合、IDH1/2基因突变等新靶点的治疗展现出前景。免疫检查点抑制剂、细胞因子、过继细胞治疗、肿瘤疫苗等免疫治疗也正在胆管癌中进行尝试。本文将对晚期胆管癌的药物治疗现状进行综述。     

Delivery of siRNA Using CXCR4-targeted Nanoparticles Modulates Tumor Microenvironment and Achieves a Potent Antitumor Response in Liver Cancer

Antiangiogenic therapy has recently emerged as a highly promising therapeutic strategy for treating hepatocellular carcinoma (HCC). However, the only clinically approved systemic antiangiogenic agent for advanced HCC is sorafenib, which exerts considerable toxicity. Moreover, acquired resistance to antiangiogenic therapy often develops and restricts the therapeutic efficacy of this treatment. Hence, in this study, we develop a CXCR4-targeted lipid-based nanoparticle (NP) formulation to specifically deliver vascular endothelial growth factor (VEGF) siRNA as an antiangiogenic substance into HCC. AMD3100, a CXCR4 antagonist, is added into NPs to serve as both a targeting moiety and a sensitizer to antiangiogenic therapy. We demonstrate that AMD-modified NPs (AMD-NPs) can efficiently deliver VEGF siRNAs into HCC and downregulate VEGF expression in vitro and in vivo. Despite the upregulation of the SDF1α/CXCR4 axis upon the induction of hypoxia after antiangiogenic therapy, CXCR4 inhibition by AMD-NPs in combination with either conventional sorafenib treatment or VEGF siRNA prevents the infiltration of tumor-associated macrophages. These dual treatments also induce synergistic antiangiogenic effects and suppress local and distant tumor growth in HCC. In conclusion, the tumor-targeted multifunctional AMD-NPs that co-deliver VEGF siRNA and AMD3100 provide an effective approach for overcoming tumor evasion of antiangiogenic therapy, leading to delayed tumor progression in HCC.     

Everolimus in the treatment of renal cell carcinoma and neuroendocrine tumors

Renal cell carcinoma (RCC) and neuroendocrine tumors (NET) are uncommon malignancies, highly resistant to chemotherapy, that have emerged as attractive platforms for evaluating novel targeted regimens. Everolimus is an oral rapamycin derivative within the mammalian target of rapamycin class of agents. Preclinical series have shown that everolimus exhibits anticancer effects in RCC and NET cell lines. A phase 3 placebo-controlled study in advanced clear-cell RCC, known as RECORD-1 (for “REnal Cell cancer treatment with Oral RAD001 given Daily”), documented that everolimus stabilizes tumor progression, prolongs progression-free survival and has acceptable tolerability in patients previously treated with the multikinase inhibitors sunitinib and/or sorafenib. Everolimus has been granted regulatory approval for use in sunitinib-pretreated and/or sorafenib-pretreated advanced RCC and incorporated into clinical practice guidelines, and the RECORD-1 safety data are being used to develop recommendations for managing clinically important adverse events in everolimus-treated patients. Ongoing clinical trials are evaluating everolimus as earlier RCC therapy (first-line for advanced disease and as neoadjuvant therapy), in non-clear-cell tumors, and in combination with various other approved or investigational targeted therapies for RCC. Regarding advanced NET, recently published phase 2 data support the ability of everolimus to improve disease control in patients with advanced NET as monotherapy or in combination with somatostatin analogue therapy, octreotide long-acting release (LAR). Forthcoming data from phase 3 placebo-controlled trials of everolimus, one focused on monotherapy for pancreatic NET and the other on combination use with octreotide LAR for patients with advanced NET and a history of carcinoid syndrome, will provide insight into its future place in NET therapy. The results of a number of ongoing phase 3 evaluations of everolimus will determine its broader applicability in treating breast cancer (in combination with chemotherapy and hormonal therapy), several advanced gastrointestinal cancers, hepatocellular carcinoma, and lymphoma (in the adjuvant setting), as well as the various lesions associated with the tuberous sclerosis complex tumor suppressor gene.     

Clinical roundtable monograph. Integrating recent data in managing adverse events in the treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer-related morbidity and mortality worldwide. In the United States, HCC is the main cause of death in patients with cirrhosis, and the incidence of this malignancy is on the rise. Because HCC is associated with a particularly poor prognosis, emphasis is placed on surveillance of high-risk patients. Early detection allows a greater chance of diagnosing HCC before it has spread, thus increasing the chances that the patient can be potentially cured with surgical techniques such as resection and transplantation. However, most cases of HCC are not diagnosed until at least some of the cancer has spread or multiple nodules exist. For these patients, treatment options include percutaneous and transarterial ablation, as well as systemic chemotherapy. Systemic therapy is now considered the standard of care for patients with advanced tumors. Traditional treatment was based on cytotoxic chemotherapeutic agents, such as doxorubicin. This approach was associated with minimal benefit and a high rate of toxicity. Recently, targeted agents have proven more effective and safer in this setting. The oral multikinase inhibitor sorafenib is now approved for the treatment of unresectable HCC and is currently the only approved agent for advanced HCC. In order to maximize the benefit of sorafenib and other investigational agents for patients with advanced disease, effective interventions have been designed to mitigate their associated adverse events, such as hand-foot skin reactions and hypertension.     

Emerging strategies in the treatment of advanced hepatocellular carcinoma: the role of targeted therapies

Hepatocellular cancer (HCC) is the fifth most common cause of cancer worldwide and its incidence is increasing as a result of the dissemination of hepatitis B and C virus infection. Surgical resection and liver transplantation are considered the only cures for HCC, but benefit approximately 10-15% of patients. In addition, radiofrequency ablation may is potentially curative for patients' with small HCC. Some patients with unresectable disease confined to the liver may benefit from embolisation or chemoembolisation. In the presence of disease not amenable to loco-regional therapy, median survival is only a few months. Current systemic therapy with cytotoxic chemotherapy induces relatively few responses and has no clear survival benefit. Current interest is focussed on the potential role of targeted therapies based on the key aspects of molecular pathogenesis of HCC, most notably sorafenib, an oral multikinase inhibitor. Recent developments discussed in this article demonstrate the potential benefits of this drug which seems destined to become first-line therapy for advanced HCC.     

Assessment of the treatment response of HCC

Surgical hepatectomy or liver transplantation are considered as curative treatment modalities for hepatocellular carcinoma (HCC). However, many patients are not surgical candidates at the time of diagnosis. Great improvements in locoregional therapies including local ablative therapy [radiofrequency (RF) ablation or ethanol ablation] and transarterial techniques (transarterial embolization or transarterial radioembolization) have made possible local control of HCC. For unresectable HCC, a targeted therapy with sorafenib may improve survival. Unlike treatment of other oncologic tumor, the locoregional therapies are mainstay in the treatment of HCC. Therefore, the application of classical criteria such as the World Health Organization (WHO) guideline may not be suitable for accurate treatment response assessment of locoregional therapies or targeted therapy of HCC. An understanding of the imaging features of post-treatment imaging after various treatment modalities for HCC is crucial for treatment response assessment and for determining further therapy. In this article, we review the role of various imaging modalities in assessing treatment response of locoregional therapies and the targeted molecular therapy.     

Recent advances in immunotherapy for the treatment of prostate cancer

INTRODUCTION: Prostate cancer vaccines attempt to induce cancer-specific systemic immune responses and represent a new class of targeted therapies, many of which are non-toxic. Several vaccine technologies are in development. AREAS COVERED: An autologous antigen presenting cell vaccine loaded with prostate acid phosphatase conjugated with GM-CSF, sipuleucel-T confers a survival advantage in men with metastatic castration-resistant prostate cancer (CRPC) and is now FDA approved based on the IMPACT trial. A poxvirus-based vaccine, PROSTVAC-VF TRICOM targeting prostate-specific antigen (PSA), has demonstrated improved survival in a randomized Phase II trial of patients with metastatic CRPC. Novel T lymphocyte checkpoint inhibitors of cytotoxic T lymphocyte antigen 4 and programmed death-1 are also emerging. Recognition of improved survival without an earlier clinical signal of activity by conventional criteria has led to new guidelines to evaluate immunotherapeutic agents. The clinical benefit of combining vaccines with chemotherapy, radiotherapy and other immunotherapeutic and biologic agents is being evaluated in the context of disappointing results of combination GVAX vaccine and docetaxel chemotherapy. EXPERT OPINION: To build on the success of early phase trials, efforts must be made to optimize vaccine approaches and patient selection.     

Everolimus augments the effects of sorafenib in a syngeneic orthotopic model of hepatocellular carcinoma

Sorafenib targets the Raf/mitogen-activated protein kinase, VEGF, and platelet-derived growth factor pathways and prolongs survival patients in advanced hepatocellular carcinoma (HCC). Everolimus inhibits the mammalian target of rapamycin, a kinase overactive in HCC. To investigate whether the antitumor effects of these agents are additive, we compared a combined and sequential treatment regimen of everolimus and sorafenib with monotherapy. After hepatic implantation of Morris Hepatoma (MH) cells, rats were randomly allocated to everolimus (5 mg/kg, 2×/week), sorafenib (7.5 mg/kg/d), combined everolimus and sorafenib, sequential sorafenib (2 weeks) then everolimus (3 weeks), or control groups. MRI quantified tumor volumes. Erk1/2, 4E-BP1, and their phosphorylated forms were quantified by immunoblotting. Angiogenesis was assessed in vitro by aortic ring and tube formation assays, and in vivo with Vegf-a mRNA and vascular casts. After 35 days, tumor volumes were reduced by 60%, 85%, and 55%, relative to controls, in everolimus, the combination, and sequential groups, respectively (P < 0.01). Survival was longest in the combination group (P < 0.001). Phosphorylation of 4E-BP1 and Erk1/2 decreased after everolimus and sorafenib, respectively. Angiogenesis decreased after all treatments (P < 0.05), although sorafenib increased Vegf-a mRNA in liver tumors. Vessel sprouting was abundant in control tumors, lower after sorafenib, and absent after the combination. Intussusceptive angiogenic transluminal pillars failed to coalesce after the combination. Combined treatment with everolimus and sorafenib exerts a stronger antitumoral effect on MH tumors than monotherapy. Everolimus retains antitumoral properties when administered sequentially after sorafenib. This supports the clinical use of everolimus in HCC, both in combination with sorafenib or after sorafenib.     

Recent advances in the therapy of renal cancer

Metastatic clear cell renal cell cancer has traditionally been treated with cytokines (interferon or interleukin-2). Improved understanding of biology has engendered novel targeted therapeutic agents that have radically altered the outlook. Vascular endothelial growth factor, the related receptor and the mTOR signal transduction pathway have particularly been exploited. Sunitinib malate, sorafenib and temsirolimus have improved clinical outcomes compared with interferon in randomized trials. Other multitargeted tyrosine kinase inhibitors (lapatinib, axatinib and pazopanib) and antiangiogenic agents (bevacizumab and lenalidomide) have also demonstrated activity in early studies. Combinations of these agents are being evaluated. The future of the therapy of renal cancer appears promising owing to the efficacy of these novel agents. Clinical trials designed to further assess these and other agents need to be vigorously supported.     

Prospects for immunotherapy as a novel therapeutic strategy against hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a highly aggressive malignant disease, with a poor clinical prognosis. Many standard therapies are often considered for HCC treatment today; however, these conventional therapies often fail to achieve sufficiently effective clinical results. Today, HCC therapy is set to undergo a major revolution, owing to rapid developments in cancer immunotherapy, particularly immune checkpoint inhibitor therapy. Cancer immunotherapy is a novel and promising treatment strategy that differs significantly from conventional therapies in its approach to achieve antitumor effects. In fact, many cancer immunotherapies have been tested worldwide and shown to be effective against various types of cancer; HCC is no exception to this trend. For example, we identified a specific cancer antigen called glypican-3 (GPC3) and performed clinical trials of GPC3-targeted peptide vaccine immunotherapy in patients with HCC. Here, we present an overview of the immune mechanisms for development and progression of HCC, our GPC3-based immunotherapy, and immune checkpoint inhibitor therapy against HCC. Finally, we discuss the future prospects of cancer immunotherapy against HCC. We believe that this review and discussion of cancer immunotherapy against HCC could stimulate more interest in this promising strategy for cancer therapy and help in its further development.     

Lung cancer]

Since the late 1980s, lung cancer incidence in men has declined in Germany whereas in women there is still a rise. There is no approved screening program for lung cancer up to now and results from randomized trials like the National Lung Screening Trial are eagerly awaited. In stage II and IIIA non-small cell lung cancer (NSCLC), several positive trials have demonstrated the advantage of adjuvant chemotherapy which is now an established modality to improve cure rates. Epidermal growth factor receptor (EGFR) is commonly overexpressed in NSCLC. Erlotinib, an EGFR tyrosine kinase inhibitor, has been approved for relapsed advanced-stage NSCLC. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor, a primary mediator of angiogenesis that is commonly overexpressed in solid tumors including lung cancer. Bevacizumab, in combination with chemotherapy, has demonstrated improved outcomes in advanced NSCLC and is now approved for selected patients with advanced-stage NSCLC. Patient selection for therapeutic use of bevacizumab is crucial to optimize safety. Ongoing trials explore multitargeted agents such as sorafenib, sunitinib, and vandetanib.     

European Society for Medical Oncology 2006: meeting highlights on targeted therapies. Istanbul, Turkey, 29 September-3 October 2006

Considerable advances in our understanding of the complex cellular, molecular and genetic mechanisms underlying tumorigenesis over the last decade have contributed to the development of novel and improved targeted therapies in cancer intervention. These novel therapies interfere specifically with signaling pathways essential for tumor cell proliferation, survival and migration, they may be able to inhibit tumor growth and metastasis effectively, with fewer severe adverse events than seen with existing chemotherapeutic interventions, which have a narrow therapeutic index and are associated with severe toxic side effects. Among the most recent advances in anticancer treatments are therapies that target novel cellular entities, such as epidermal growth factor receptor and vascular endothelial growth factor. Monoclonal antibodies and protein tyrosine kinase inhibitors represent two classes among these promising new therapeutic interventions. During the European Society for Medical Oncology Congress 2006 (Istanbul, Turkey, 29 September-3 October) new and emerging biological therapies have represented a central argument of research. These highlights summarize the most interesting studies concerning molecular agents, such as panitumumab, lapatinib, sunitinib, sorafenib, erlotinib, bevacizumab and cetuximab, to provide a comprehensive overview of the important points and news about this area of research discussed during the meeting.