Beyond bevacizumab: antiangiogenic agents

Angiogenesis is a rational target for the treatment of patients with non-small-cell lung cancer (NSCLC). In the E4599 trial, the vascular endothelial growth factor (VEGF)-targeted antibody bevacizumab combined with carboplatin/paclitaxel improved both progression-free survival (PFS) and overall survival (OS) compared with chemotherapy alone. However responses to bevacizumab are usually transient and resistance inevitably develops. Thus other targets should be considered for future antiangiogenic strategies. A number of antiangiogenic agents with a variety of targets are in clinical development for NSCLC. Several multitargeted receptor tyrosine kinase inhibitors (TKIs) such as sorafenib, cediranib, and BIBF 1120, with activity against vascular endothelial growth factor receptor (VEGFR) and other proangiogenic pathways (eg, fibroblast growth factor [FGF] and platelet-derived growth factor [PDGF] pathways) are in clinical development for NSCLC. Many of these TKIs have shown clinical activity in early trials, both alone and in combination with chemotherapy. Other promising agents in development include inhibitors of the angiopoietin/TIE2 pathway, integrin-targeted agents, vascular disrupting agents, and delta-like ligand-4/Notch pathway inhibitors.     

Antiangiogenic agents for the treatment of nonsmall cell lung cancer: characterizing the molecular basis for serious adverse events

Novel agents to reduce angiogenesis by targeting vascular endothelial growth factor and other proangiogenic signaling pathways are being developed for advanced nonsmall cell lung cancer. Antibody-based therapies (e.g., aflibercept) and multitargeted tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, and BIBF 1120) are being evaluated in phase III clinical trials. Some antiangiogenic agents have demonstrated distinct profiles in producing a variety of nonhematologic toxicities, including bleeding/hemorrhage, venous and arterial thromboembolic events, gastrointestinal perforation, hypertension, and proteinuria. Elucidating the molecular basis of these toxicities may lead to clinical benefits by improving patient selection and allowing for the development of effective prevention and management strategies.     

Combination of antiangiogenic therapy with other anticancer therapies: results, challenges, and open questions.

Angiogenesis is necessary for tumor growth. Drug discovery efforts have identified several potential therapeutic targets on endothelial cells and selective inhibitors capable of slowing tumor growth or producing tumor regression by blocking angiogenesis in in vivo tumor models. Certain antiangiogenic therapeutics increase the activity of cytotoxic anticancer treatments in preclinical models. More than 75 antiangiogenic compounds have entered clinical trials. Most of the early clinical testing was conducted in patients with advanced disease resistant to standard therapies. Several phase III trials have been undertaken to compare the efficacy of standard chemotherapy versus the same in combination with an experimental angiogenesis inhibitor. Preliminary results of the clinical studies suggest that single-agent antiangiogenic therapy is poorly active in advanced tumors. Although some of the results of combination trials are controversial, recent positive outcomes with an antivascular endothelial growth factor antibody combined with chemotherapy as front-line therapy of metastatic colorectal cancer have renewed enthusiasm for this therapeutic strategy. This article presents an overview of experimental and clinical studies of combined therapy with antiangiogenic agents and highlights the challenges related to the appropriate strategies for selection of the patients, study design, and choice of proper end points for preclinical and clinical studies using these agents.     

Antiangiogenesis Therapy in Breast Cancer

Increased expression of the vascular endothelial growth factor (VEGF) is a poor prognostic factor in breast cancer, indicating that antiangiogenic therapies may improve outcomes. Novel antiangiogenic agents targeting the proangiogenic VEGF ligand and receptor tyrosine kinase inhibitors have been developed. Of these, bevacizumab, a humanized monoclonal antibody directed against VEGF, is very promising in breast cancer. A large phase 3 clinical trial demonstrated a statistically significant improvement in progression-free survival with the addition of bevacizumab to paclitaxel as first-line treatment of advanced breast cancer, establishing the benefit of antiangiogenic therapy in breast cancer. Additional studies of bevacizumab in the metastatic, adjuvant, and neoadjuvant settings are underway. Ongoing trials are also evaluating the efficacy of multitargeted tyrosine kinase inhibitors in advanced breast cancer. This article reviews the results of the key trials evaluating antiangiogenic agents in breast cancer with particular emphasis on bevacizumab and future directions of antiangiogenic therapy.     

Emerging antiangiogenic agents in lung cancer

The success of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab in numerous tumor types including non-small-cell lung cancer (NSCLC) has spurred the development of additional novel antiangiogenic agents with distinct mechanisms of action. These include the small-molecule receptor tyrosine kinase (TK) inhibitors ZD6474, sorafenib, sunitinib malate, and AG-013736, all of which inhibit VEGF receptor TK activity. Because of the structural similarity of the different receptor TKs, these receptor TK inhibitors inhibit multiple receptors in addition to VEGF receptor. Vascular endothelial growth factor Trap, a novel, high-affinity molecule with specificity to the VEGF molecule, was generated as a fusion molecule of the VEGF receptor extracellular domain and the Fc portion of immunoglobulin (Ig) G1. Data from phase I/II trials have indicated the clinical feasibility of these agents, which are currently being investigated in phase II/III trials.     

Targeted therapy of colorectal cancer: clinical experience with bevacizumab

Advanced colorectal cancer remains an urgent health concern, despite improvements in systemic chemotherapy. Targeted therapeutics promise effective tumor therapy with minimal side effects. Angiogenesis (the formation of new blood vessels) is essential for tumor growth and metastasis and may be an ideal target in the search for new antineoplastic agents. Vascular endothelial growth factor is one of the best characterized of the proangiogenic growth factors that regulate angiogenesis and is a logical target in colorectal cancer therapy. Bevacizumab (Avastin; Genentech Inc.; South San Francisco, CA), a humanized murine monoclonal antibody directed at vascular endothelial growth factor, is being evaluated in the treatment of various types of cancer. It has shown promising efficacy in phase II clinical trials in patients with metastatic colorectal cancer. Addition of bevacizumab at a dose of 5 mg/kg to chemotherapy (5-fluorouracil plus leucovorin) resulted in a higher objective response rate (40% versus 17%), longer time to disease progression (9.0 versus 5.2 months), and longer median survival time (21.5 versus 13.8 months). Hypertension and thrombosis were the principal safety concerns, but were manageable. Further phase II/III studies of bevacizumab, administered with 5-fluorouracil plus leucovorin, with or without irinotecan and/or oxaliplatin, in colorectal cancer, are under way.     

Update on antiangiogenic treatment of advanced non-small cell lung cancer (NSCLC)

Bevacizumab is a monoclonal antibody that specifically inhibits vascular endothelial growth factor, and is the first antiangiogenic agent to be approved for first-line treatment of advanced non-small cell lung cancer (NSCLC). Evidence from two large phase III trials demonstrates that bevacizumab combined with chemotherapy improves outcomes for patients with non-squamous NSCLC. In patients with adenocarcinoma without epidermal growth factor receptor (EGFR) mutation, a median overall survival of 18.0 months is achieved. Several post-registration phase IV studies have confirmed bevacizumab’s efficacy and tolerability profile and have clarified the eligibility criteria. Clinical research is still ongoing to define the role of bevacizumab in different settings, such as single-agent bevacizumab for continuation maintenance therapy in advanced disease, treatment beyond disease progression, adjuvant therapy in early-stage NSCLC, or bevacizumab in combination with other targeted agents. A number of antiangiogenic tyrosine kinase inhibitors (TKI) have also been investigated in phase II and III trials. None of these drugs has proven significant clinical benefit in unselected patient populations. This article reviews the extensive information from randomized trials and large observational studies for bevacizumab in advanced NSCLC, and shortly describes the current clinical development of antiangiogenic monoclonal antibodies, TKIs and related compounds.     

Targeting angiogenesis for the treatment of sarcoma

PURPOSE OF REVIEW: More therapeutic options are needed for bone and soft tissue sarcomas, especially for patients with metastatic disease. Recent randomized clinical trials conducted in colon, breast and lung cancer have shown the anti-vascular endothelial growth factor agent, bevacizumab, alone or in combination with chemotherapy, improves response and survival. Preclinical studies have demonstrated the anti-tumor effects of varied anti-angiogenic agents in sarcoma cell lines and tumor models. RECENT FINDINGS: Preclinical studies in sarcomas have evaluated the role of targeted agents including platelet-derived growth factor, matrix metalloproteinases, urokinase receptor and varied small-molecule tyrosine kinase inhibitors. Novel angiogenesis inhibitors are being studied in the treatment of sarcoma, including monoclonal antibodies against vascular endothelial growth factor, cis- and trans-retinoic acids, thalidomide, and tyrosine kinase inhibitors. Phase I, II and III clinical trials continue to evaluate these agents alone, in combinations together and combined with standard chemotherapy. We review herein the preclinical rationale and clinical trial results of anti-angiogenesis therapy in the treatment of soft tissue and bone sarcoma. SUMMARY: Preclinical mechanistic study and clinical trials are continuing in order to evaluate the therapeutic role and ultimately validate the efficacy of the varied anti-angiogenesis agents in soft tissue and bone sarcoma.     

小细胞肺癌分子靶向治疗研究进展

分子靶向治疗药物包括抗肿瘤血管生成剂、生长因子受体抑制剂、Scr酪氨酸激酶抑制剂、重组分子N-901、抗细胞凋亡因子Bcl-2抑制剂、Hh信号通路抑制剂等.其中抗肿瘤血管生成剂如贝伐单抗和沙力度胺均进行了大量的Ⅱ、Ⅲ试验研究用以评估其在治疗小细胞肺癌(SCLC)方面的疗效及毒性;Scr酪氨酸激酶抑制剂正在进行Ⅰ、Ⅱ期的临床试验,结果 尚未得出;重组分子N-901也正在进行一项针对广泛期SCLC的Ⅱ期的临床试验,另外Bcl-2及Hh信号通路抑制剂正在进行初期的临床试验.初步的研究数据表明SCLC对于靶向治疗不敏感,其原因有待于进一步研究.     

Angiogenesis and antiangiogenic approaches to sarcomas.

Established chemotherapy regimens for advanced or metastatic sarcoma generally have low response rates and substantial toxicity, and resistance often arises quickly, making sarcoma an ideal target for alternative treatment approaches. Antiangiogenic therapies have a number of potential advantages including decreased resistance, fewer side effects, and a broad spectrum of activity. This paper reviews the evidence supporting the use of antiangiogenic therapies for adult soft tissue sarcomas. Human sarcomas express a number of proangiogenic factors that may represent therapeutic targets, with vascular endothelial growth factor being the best characterized, and inhibitors of angiogenesis have antitumor activity in animal models of human sarcomas. Clinical trials are in early stages, although promising results have already been seen. In the future, improved drugs, refined molecular profiling of tumors, and new ways of combining antiangiogenic agents with cytotoxic agents may lead to more effective and tolerable therapies for sarcomas.     

Evaluating antiangiogenesis agents in the clinic: the Eastern Cooperative Oncology Group Portfolio of Clinical Trials.

Recent evidence indicates that treatment with a humanized monoclonal antibody (bevacizumab) directed at vascular endothelial growth factor improves response and survival in metastatic colorectal cancer when added to standard chemotherapy, validating angiogenesis as a therapeutic target. Investigators from the Eastern Cooperative Oncology Group (ECOG) have initiated a number of Phase III studies that will help further define the role of antiangiogenic agents for the treatment of breast, colon, lung, renal, and head and neck cancer, as well as melanoma and myeloma. The agents being evaluated target various biological functions involved in angiogenesis, including vascular endothelial growth factor (bevacizumab), endothelial cell proliferation (thalidomide, IFN-alpha), and matrix metalloproteinases (marimastat). These clinical trials include correlative laboratory studies aimed at elucidating how these agents may exert their clinical effects. The portfolio of Eastern Cooperative Oncology Group studies will serve to further define the role of this therapeutic strategy for patients with advanced cancer.     

Integration of novel agents in the treatment of colorectal cancer

Two of the most promising new targets in the treatment of colorectal cancer are the epithelial growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF). Agents that inhibit the EGFR or bind to VEGF have demonstrated clinical activity as single agents and in combination with chemotherapy in phase II and phase III clinical trials. The most promising of these agents are cetuximab, which blocks the binding of EGF and transforming growth factor alpha (TGF-alpha) to EGFR, and bevacizumab, which binds free VEGF. Cetuximab and irinotecan have been evaluated in two clinical studies in the USA (IMCL CP02-0141 and IMCL CP02-9923). Study IMCL CP02-0141 evaluated the antitumor activity of single-agent cetuximab in patients with irinotecan-refractory, EGFR-positive metastatic colorectal carcinoma. There were 6 partial responses in 57 treated patients, for a response rate of 10.5%. Study IMCL CP02-9923 evaluated the combination of cetuximab and irinotecan in a total of 139 patients enrolled at 27 study sites. In this trial 22.5% of patients with progressive disease on irinotecan achieved an objective response (19% by investigator assessment) showing that the combination of cetuximab and irinotecan has antitumor activity in this population. A large randomized phase II trial evaluating similar study populations in Europe confirmed these findings, demonstrating response rates for cetuximab/irinotecan and cetuximab alone of 22.9% and 10.8%, respectively. The other promising agent bevacizumab is a humanized variant of the anti-VEGF monoclonal antibody. VEGF is produced by healthy and neoplastic cells. Its activities are mediated by two receptor tyrosine kinases. VEGF signaling is often a rate-limiting step in physiologic and pathologic angiogenesis. Bevacizumab has been studied as an antiangiogenic cancer therapeutic as a single agent and in combination with chemotherapy in patients with stage III and IV colon cancer. In addition to its direct antiangiogenic effects, bevacizumab may allow more efficient delivery of chemotherapy by altering tumor vasculature and decreasing the elevated interstitial pressure common in tumors. In this regard, some of the most robust phase II data using bevacizumab are from a randomized study of chemotherapy [fluorouracil (5-FU) and leucovorin (LV)] with or without bevacizumab in metastatic colorectal cancer. In this study, treatment with bevacizumab plus 5-FU/LV resulted in higher response rates, longer median time to disease progression, and longer median survival. Recently, a phase III, multicenter, double-blind, randomized, placebo-controlled trial was designed to investigate the addition of bevacizumab to first-line irinotecan, 5-FU, and LV chemotherapy (IFL). The trial showed a higher response rate, longer time to tumor progression, and prolonged overall survival in patients with metastatic colorectal cancer. It was the first large, randomized, phase III survival trial to assess the importance of targeting VEGF and tumor angiogenesis for the treatment of human cancer. Integration of novel agents targeting VEGF and EGFR with irinotecan-based chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. The goal in the future will be to predict which specific chemotherapy and targeted agent combination will most likely benefit individual patients.     

Antiangiogenic agents in the management of non-small cell lung cancer: Where do we stand now and where are we headed?

Several therapies targeting angiogenesis are currently in development for non-small cell lung cancer (NSCLC). This review discusses results of recent clinical trials evaluating chemotherapy plus antiangiogenic therapy for NSCLC. Bevacizumab, an anti-VEGF antibody, is currently approved for the treatment of advanced NSCLC in combination with carboplatin and paclitaxel. Completed phase III trials evaluating bevacizumab plus chemotherapy have shown prolonged progression-free survival; however, not all trials showed significant improvement in overall survival (OS). Phase III trials of the tyrosine kinase inhibitors (TKIs) vandetanib and sorafenib and the vascular disrupting agent ASA404 also failed to improve OS compared with chemotherapy alone. Clinical trials are ongoing involving several new antiangiogenic therapies, including ramucirumab, aflibercept, cediranib, BIBF 1120, sunitinib, pazopanib, brivanib, ABT-869, axitinib, ABT-751, and NPI-2358; several of these agents have shown promising phase I/II results. Results from recently completed and ongoing phase III trials will determine if these newer antiangiogenic agents will be incorporated into clinical practice.     

Latest clinical evidence and further development of PARP inhibitors in ovarian cancer

For several decades, the systemic treatment of ovarian cancer has involved chemotherapy, with the relatively recent addition of antiangiogenic strategies given with chemotherapy and in the maintenance setting. In the past decade, numerous poly(ADP-ribose) polymerase (PARP)-inhibiting agents have been assessed. We review key trials that have led to the approval of three PARP inhibitors—olaparib, niraparib and rucaparib—as maintenance therapy for platinum-sensitive recurrent ovarian cancer. We discuss the efficacy and safety of these agents in the populations studied in clinical trials. We then provide an overview of the numerous avenues of ongoing research for PARP inhibitors in different treatment settings: as treatment rather than maintenance strategies and in combination with other anticancer approaches, including antiangiogenic and immunotherapeutic agents. Three phase III trials (NOVA, SOLO2 and ARIEL3) demonstrated remarkable improvement in progression-free survival (PFS) with PARP inhibitors given as maintenance therapy in patients with complete or partial response after platinum-based therapy for platinum-sensitive ovarian cancer. Differences in trial design and patient populations influence the conclusions that can be drawn from these trials. Overall survival data are pending and there is a limited experience regarding long-term safety. PARP inhibitors have transformed the management of ovarian cancer and have changed the course of disease for many patients. Although recent approvals are irrespective of BRCA mutation or homologous repair deficiency status, genetic profiles, as well as dosing schedules, tolerability and affordability, may influence patient selection and the setting in which PARP inhibitors are used. The development and evolution of PARP inhibitors continue, with new agents, strategies, combinations and indications under intensive evaluation.     

Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer

Vascular endothelial growth factor (VEGF) is one of the most important factors involved in tumor angiogenesis and has become an important target for anticancer treatment. In 2004, this approach was validated in a randomized, controlled phase III clinical trial. It was shown that the addition of bevacizumab, a humanized monoclonal antibody against VEGF-A, to conventional chemotherapy prolonged survival over chemotherapy alone in patients with metastatic colorectal cancer. In this review, we discuss the results of the clinical trials that have led to the incorporation of antiangiogenic agents into the treatment of patients with advanced colorectal cancer. We limit ourselves to the two agents that have been tested extensively in phase III trials: bevacizumab and vatalanib, a small molecule tyrosine kinase inhibitor against VEGF receptors. In addition, we discuss the adverse effects of bevacizumab and vatalanib and the clinical management of the side effects.     

Current status of anti-angiogenic agents in the treatment of ovarian carcinoma

During the last decade we have assisted in the development of new therapeutic strategies for the treatment of ovarian cancer, based on the best knowledge of molecular biology. One of the most promising strategies under investigation is antiangiogenic therapy. Bevacizumab is a monoclonal humanised antibody targeting vascular endothelial growth factor (VEGF), which has shown antitumour activity in ovarian cancer in preclinical models as well as in clinical trials, both in monotherapy and in combination with other therapies. Currently, ongoing phase III trials are testing bevacizumab as a front-line therapy with carboplatin and paclitaxel. Bevacizumab has been generally well tolerated with mild frequent toxicities (proteinuria, hypertension and bleeding). However, the drug may result in other uncommon, but potentially life-threatening side effects, such as arterial thromboembolism, wound healing complications, and gastrointestinal perforation or fistulae, which should be considered when the drug is administered. Other new therapeutic antiangiogenic strategies that include small-molecule tyrosine kinase inhibitors, antibodies neutralising the VEGF receptor (VEGFR) and soluble VEGFR hybrids (VEGF Trap) are being investigated with promising early results.     

抗血管生成药物在铂耐药卵巢癌中的应用进展

化疗药物在铂耐药卵巢癌治疗中应用非常局限,近年来,多项试验表明抗血管生成药物有改善铂耐药卵巢癌患者预后的作用。本文根据作用机制的不同,把抗血管生成药物分为血管内皮生长因子抑制剂、血管内皮生长因子受体抑制剂、酪氨酸激酶抑制剂和整合素抑制剂,分别阐述其在铂耐药卵巢癌治疗中的研究进展。     

Chemotherapy for advanced pancreatic cancer: Past,present, and future

Advanced pancreatic cancer is a devastating illness characterized by significant morbidity and a brief median survival. Although standard chemotherapy with gemcitabine achieves only modest improvements in survival and quality of life, classic cytotoxic agents, such as 5-fluorouracil, pemetrexed, irinotecan, exatecan, cisplatin, or oxaliplatin, given alone or in combination with gemcitabine, have not proved superior. Thus, more recent trials have focused on targeting the biologic characteristics of pancreatic cancer. Although phase III trials of farnesyl transferase and matrix metalloproteinase inhibitors have not improved survival, encouraging preliminary results have been observed in phase II studies of inhibitors of the vascular endothelial growth factor and the epidermal growth factor receptor.     

Novel agents in epithelial ovarian cancer

The gold standard chemotherapy for previously untreated patients with ovarian cancer is currently a combination of taxane and platinum. However, most patients still suffer relapse, and less than 20% of the patients with stage III or IV disease survive long term. With more advanced technology, newer cytotoxic agents have been identified and are currently being tested in patients with ovarian cancer. Recent advances in the understanding of ovarian cancer biology have also led to the identification of multiple molecular targets that may soon change the standard treatment of ovarian cancer. Several of these targeted agents have entered clinical trials. Small molecular-weight inhibitors, monoclonal antibodies, antisense therapy, and gene therapy are all being evaluated alone and in combination with cytotoxic chemotherapy. Several of these cytotoxic and targeted therapies are reviewed here. Ultimately, the success of ovarian cancer therapy lies not just in the availability of new agents but in the ability to identify patients with biomarkers that may predict their response to these agents.     

Monoclonal antibodies as effective therapeutic agents for solid tumors

Monoclonal antibodies (mAbs) against growth factors or their receptors have been revealed to be effective therapeutic agents for solid tumors. Trastuzumab (humanized anti-HER2 mAb) is the first mAb approved for the treatment of a solid tumor, metastatic breast cancer. Large-scale phase III clinical trials are now ongoing to further evaluate the additive effects on chemotherapy and the efficacy as a maintenance monotherapy. Another anti-HER2 mAb CH401 that we developed also seems to have good potential. This chimeric mAb completely suppressed the growth of established human tumor xenografts in SCID mice after a single injection. Furthermore, CH401 characteristically showed much stronger induction of apoptosis in HER2-overexpressing gastric cancer cells compared to trastuzumab. Additional targets now being intensively evaluated are epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). Both cetuximab (chimeric anti-EGFR mAb) and bevacizumab (humanized anti-VEGF mAb) have recently been shown to be of clinical value for metastatic colorectal cancer. Anti-idiotype mAbs are unique as active immunotherapeutic agents, and survival benefits have been observed in clinical trials for solid tumors.