Emerging Data with Antiangiogenic Therapies in Early and Advanced Non–Small-Cell Lung Cancer

Lung cancer is the leading cause of cancer-related mortality in the United States. Patients treated with adjuvant chemotherapy have a 5-year survival rate of 25% to 70% depending on stage, whereas those with advanced disease have a median survival of approximately 8 months when treated with standard platinum-based therapy. Improvements in our understanding of cancer biology have led to the development of novel agents that more precisely affect the target of interest, allowing for a more rational approach to clinical trial design. Angiogenesis, the growth of new vessels from preexisting vessels, is a fundamental step in tumor growth and progression. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), is the most studied antiangiogenic agent in patients with Non—Small-cell lung cancer (NSCLC). There was an improvement in overall survival when bevacizumab was combined with paclitaxel and carboplatin in patients with advanced NSCLC that was not seen when bevacizumab was combined with cisplatin and gemcitabine. Studies with bevacizumab in the adjuvant and advanced setting are ongoing in patients with NSCLC. Small-molecule inhibitors targeting the VEGF receptor and the tyrosine kinase receptor have also shown promise when combined with standard chemotherapy, but their role in the treatment of patients with NSCLC remains to be determined. This article reviews clinical trials that have incorporated antiangiogenic agents in the treatment of patients with NSCLC.     

Safety profile and tolerability of antiangiogenic agents in non-small-cell lung cancer

Recent advances in understanding the importance of angiogenesis to tumor growth and distant metastasis has driven the development of antiangiogenic therapies for the treatment of non-small-cell lung cancer (NSCLC). The anti-vascular endothelial growth factor (VEGF) monoclonal antibody, bevacizumab, is the only US Food and Drug Administration-approved antiangiogenic agent for advanced NSCLC. Accumulated safety data with bevacizumab in NSCLC shows that patients are at risk for hemorrhage, venous thromboembolism, hypertension, and proteinuria. Investigational agents that target VEGF via a different mechanism (such as aflibercept [VEGF Trap]) or simultaneously inhibit multiple molecular pathways involved in angiogenesis (ie, multitargeted tyrosine kinase inhibitors [TKIs]) and vascular disrupting agents (VDAs) that target existing tumor vasculature are in various stages of clinical development for NSCLC, and safety profiles are emerging for these classes of agents. This review describes the molecular rationale for targeting angiogenic pathways in anticancer therapy and summarizes safety and tolerability data from clinical trials of bevacizumab or aflibercept in combination with chemotherapy and the investigational TKIs and VDAs in patients who have advanced NSCLC.     

Anti‐angiogenic therapies for gastric cancer

Tumor angiogenesis plays an important role in cancer cell proliferation and metastasis. In gastric cancer, among the numerous clinical trials investigating various anti‐angiogenic therapies, such as antivascular endothelial growth factor (VEGF) or anti‐VEGF receptor (VEGFR)‐2 monoclonal antibodies, VEGF‐Trap and VEGFR tyrosine kinase inhibitors, the anti‐VEGFR‐2 antibody ramucirumab was shown to prolong overall survival not only as a single agent but also in combination with paclitaxel as a second‐line chemotherapy. Additionally, apatinib, a selective VEGFR‐2 tyrosine kinase inhibitor, prolonged survival as a third‐line or later treatment option in patients with advanced gastric cancer. Preliminary results of studies investigating ramucirumab plus immune checkpoint inhibitors in gastric cancer were encouraging, and further investigations are ongoing. In China, apatinib in combination with cytotoxic agents is being investigated for systemic chemotherapy or maintenance therapy as an earlier treatment option. The clinical activity in gastric cancer of the multikinase inhibitor regorafenib was suggested in a randomized phase II study. A global phase III trial comparing regorafenib with placebo is currently ongoing. Further studies of anti‐angiogenic therapy combined with not only chemotherapy but also immune checkpoint inhibitors are also being pursued, providing hope for improved survival in patients with gastric cancer.     

Angiogenesis inhibitors in lung cancer: a promise fulfilled

Sustained angiogenesis is one of the hallmarks of carcinogenesis. Vascular endothelial growth factor (VEGF) is a crucial molecule mediating proangiogenic signals against which a number of therapeutic approaches have been designed, such as monoclonal antibodies, small-molecule receptor kinase inhibitors, and nucleic acid inhibitors. The VEGF signaling pathway as a target in lung cancer therapy was validated by a randomized phase III study of platinum agent-based combination chemotherapy with or without bevacizumab, a recombinant humanized monoclonal antibody against VEGF-A, in first-line, nonsquamous, metastatic non-small-cell lung cancer. This trial demonstrated an improvement in overall survival among patients who received bevacizumab in comparison with those who received carboplatin and paclitaxel alone. In this review, we will discuss various aspects of this pivotal trial and highlight issues relevant to angiogenesis inhibition in the treatment of non-small-cell lung cancer.     

Emerging antiangiogenic therapies for non-small-cell lung cancer

Lung cancer remains the leading cause of cancer-related deaths. Antiangiogenic therapy has increasingly been studied for advanced non-small-cell lung cancer (NSCLC). Bevacizumab is the only approved antiangiogenic agent for NSCLC and has shown progression-free survival benefits in large Phase III studies and an overall survival benefit in the Phase III E4599 trial in advanced nonsquamous NSCLC. New antiangiogenic treatment strategies are being evaluated that target multiple receptors within a family (VEGF receptor [VEGFR]-1, VEGFR-2) or multiple angiogenic pathways (targets VEGFR and PDGF receptor pathways), and agents that inhibit alternative mediators of angiogenesis (integrins and established vasculature). As data become available from ongoing studies, it will be important to determine how these new antiangiogenic agents will best fit into the current NSCLC treatment paradigm.     

Emerging antiangiogenic therapies for non-small-cell lung cancer

Lung cancer remains the leading cause of cancer-related deaths. Antiangiogenic therapy has increasingly been studied for advanced non-small-cell lung cancer (NSCLC). Bevacizumab is the only approved antiangiogenic agent for NSCLC and has shown progression-free survival benefits in large Phase III studies and an overall survival benefit in the Phase III E4599 trial in advanced nonsquamous NSCLC. New antiangiogenic treatment strategies are being evaluated that target multiple receptors within a family (VEGF receptor [VEGFR]-1, VEGFR-2) or multiple angiogenic pathways (targets VEGFR and PDGF receptor pathways), and agents that inhibit alternative mediators of angiogenesis (integrins and established vasculature). As data become available from ongoing studies, it will be important to determine how these new antiangiogenic agents will best fit into the current NSCLC treatment paradigm.     

Bevacizumab in the treatment of non-small-cell lung cancer

Lung cancer is the leading cause of cancer death in the United States. The majority of patients present with advanced disease, and treatment with standard cytotoxic chemotherapy improves survival and quality of life in patients with a preserved functional status. However, the prognosis is poor with the majority of patients dying in less than a year. Treatment with standard cytotoxic chemotherapy has reached a therapeutic plateau, and new therapeutic approaches have investigated therapies that target the specific molecular pathways involved in carcinogenesis and angiogenesis. The most promising strategy for inhibiting angiogenesis involves agents that either target the proangiogenesis growth factor, vascular endothelial growth factor A (VEGF) by preventing binding to the receptor or inhibiting the downstream signaling of the vascular endothelial growth factor receptor. The only therapeutic agent approved for the treatment of lung cancer is bevacizumab, a monoclonal antibody that binds to VEGF. A recent phase III trial revealed a statistically significant improvement in response rate, progression free and overall survival with combination of bevacizumab with chemotherapy over chemotherapy alone. Attempts to identify surrogate markers of antiangiogenesis activity are currently ongoing, and may assist in the selection of patients for antiangiogenesis therapy and the development of this class of agents.     

The value of platinum compounds in non-small-cell lung cancer

The value of platinum compounds has come into question with the advent of newer chemotherapy agents in the management of patients with advanced non-small-cell lung cancer. These newer agents, which include the taxanes, topoisomerase I inhibitors, gemcitabine, and vinorelbine, appear to have higher single-agent response rates and more favorable toxicity profiles when compared to the platinum compounds. However, the toxicity of the platinum compounds is now minimized with the advent of more effective antiemetics. In addition, phase III clinical trials have demonstrated that the strategy of cisplatin dose intensity and prolonged duration of therapy with platinum compounds does not improve overall survival; therefore, moderate doses of cisplatin and a shorter duration of therapy can be given to further decrease toxicity. Furthermore, while phase II trials utilizing nonplatinum-based combination chemotherapy appear to demonstrate superior response rates and survival in comparison to platinum-based doublets, results of phase III trials have demonstrated no improvement in survival. Platinum combination chemotherapy remains the standard approach for stage IV non-small-cell lung cancer. More substantial advances will likely be made with novel molecular targeted therapy, such as the epidermal growth factor receptor inhibitors, which demonstrate synergy with the platinum compounds.     

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.     

Combining anti-VEGF approaches with oxaliplatin in advanced colorectal cancer

Angiogenesis, the formation of blood vessels, is a vital process in tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is a potential target for antiangiogenic therapy because its overexpression has been associated with tumor vascularity, poor prognosis, and aggressive disease in many malignancies, including colorectal cancer (CRC). Bevacizumab is a recombinant humanized monoclonal antibody against VEGF. It is the first angiogenesis inhibitor to show significant activity in patients and, when combined with chemotherapy, leads to a significant survival benefit in CRC. This monoclonal antibody has been approved for first-line therapy in combination with intravenous 5-fluorouracil-containing regimens in patients with metastatic CRC. Vatalanib (PTK787/ZK222584) is an oral antiangiogenic tyrosine kinase inhibitor of the VEGF receptor. Currently, it is being evaluated in combination with FOLFOX (5-fluorouracil/leucovorin/oxaliplatin) in metastatic CRC. This article reviews the process of angiogenesis and the successful translation of antiangiogenic agents into the clinic. Specifically, studies evaluating VEGF-targeted agents in combination with oxaliplatin-containing regimens in CRC are discussed.     

Tumor progression-dependent angiogenesis in gastric cancer and its potential application

Despite improvements in the early diagnosis, prognosis and therapeutic strategies for gastric cancer (GC), human GC remains one of the most frequently diagnosed malignant tumors in the world, and the survival rate of GC patients remains very poor. Thus, a suitable therapeutic strategy for GC is important for prolonging survival. Both tumor cells themselves and the tumor microenvironment play an important role in tumorigenesis, including angiogenesis, inflammation, immunosuppression and metastasis. Importantly, these cells contribute to gastric carcinogenesis by altering the angiogenic phenotype switch. The development, relapse and spreading of tumors depend on new vessels that provide the nutrition, growth factors and oxygen required for continuous tumor growth. Therefore, a state of tumor dormancy could be induced by blocking tumor-associated angiogenesis. Recently, several antiangiogenic agents have been identified, and their potential for the clinical management of GC has been tested. Here, we provide an up-to-date summary of angiogenesis and the angiogenic factors associated with tumor progression in GC. We also review antiangiogenic agents with a focus on the anti-vascular endothelial growth factor receptor (VEGFR)-mediated pathway for endothelial cell growth and their angiogenesis ability in GC. However, most antiangiogenic agents have reported no benefit to overall survival (OS) compared to chemotherapy alone in local or advanced GC. In phase III clinical trials, only ramucirumab (anti-VEGFR blocker) and apatinib (VEGFR-TKI blocker) have reported an improved median overall response rate and prolonged OS and progression-free survival outcomes as a 2nd-line agent combined with chemotherapy treatment in advanced GC. By providing insights into the molecular mechanisms of angiogenesis associated with tumor progression in GC, this review will hopefully aid the optimization of antiangiogenesis strategies for GC therapy in combination with chemotherapy and adjuvant treatment.     

High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer.

Vascular endothelial growth factor (VEGF), a potent angiogenic factor, has been reported to be associated with a poor prognosis in primary breast cancer and in several other cancer types. In the present study, we have measured with ELISA the levels of VEGF in cytosolic extracts of 845 primary breast tumors of patients who developed a recurrence during follow-up. All of the patients received tamoxifen (n = 618) or cyclophosphamide, methotrexate, 5-fluorouracil (CMF) or 5-fluorouracil, Adriamycin, cyclophosphamide (FAC) chemotherapy (n = 227) as first-line systemic therapy after diagnosis of advanced disease. VEGF levels were not related to age or menopausal status but were negatively related to the cytosolic levels of estrogen receptor and progesterone receptor (P < 0.0001). In patients who relapsed within 1 year after primary surgery, tumor VEGF levels were higher than in patients who showed a longer disease-free interval (P = 0.0005). In patients with a first relapse in the viscera, VEGF levels were higher compared with those that relapsed to the bone or soft tissue (P = 0.0004). In univariate analysis for response to first-line tamoxifen therapy, patients with high or intermediate levels showed a poor rate of response, compared with patients with low tumor-VEGF levels (P = 0.0001). Similarly, in multivariate analysis for response to tamoxifen treatment, corrected for age, site of relapse, disease-free interval, and estrogen receptor and progesterone receptor status, VEGF status was an independent predictive factor (P = 0.009). In concordance, higher levels of VEGF were associated with a short progression-free survival and postrelapse overall survival (both, P < 0.0001). On first-line chemotherapy, the rate of response decreased with higher tumor levels of VEGF, both in univariate (P = 0.003) and in multivariate analysis (P = 0.004). Furthermore, higher VEGF levels were associated with a short progression-free survival (P = 0.003) and postrelapse overall survival (P = 0.001). In conclusion, the tumor VEGF level is an important independent marker that predicts a poor efficacy of both tamoxifen and chemotherapy in advanced breast cancer. Knowledge of the tumor level of VEGF might be helpful in selecting individual patients who may benefit from treatments with antiangiogenic agents combined with conventionally used drugs.     

Targeted therapy using novel agents in the treatment of non-small-cell lung cancer

Patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis and high mortality. The therapeutic improvement caused by the new generation of cytotoxic agents seems to have reached a plateau. The main categories of targeted therapeutics applicable for NSCLC include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibitors, gene therapy, and vaccines. Several major classes of agents directed at specific cellular mechanisms exist for the treatment of NSCLC. The anti-epidermal growth factor receptor (EGFR) group contains trastuzumab and IMC-C225, monoclonal antibodies against EGFRs that are overexpressed in many cancers. OSI-774 and ZD1839 are inhibitors of EGFR tyrosine kinase, a key enzyme of the signaling pathway. Farnesyl transferase inhibitors, such as SCH66336, and protein kinase C inhibitors, such as ISIS 3521, have also shown antitumor activity. Antiangiogenesis agents that have shown promise include TNP-470, recombinant endostatin, and angiostatin. Antibodies to vascular endothelial growth factor (VEGF) also seem to control tumor progression and may prolong survival. LY317615, an inhibitor of protein kinase Cb, augmented the tumor growth delay produced by cytotoxic drugs. All of these agents are in different phases of clinical testing and have shown encouraging activity as single agents or in combination with chemotherapy drugs. These new agents are more target specific, less toxic, easier to administer, and may lead to enhanced safety and survival for patients with advanced NSCLC.     

Tumoral angiogenesis and breast cancer

Breast cancer (BC) is the most common neoplasm in women in Western countries. Tumoral angiogenesis (TA) is essential for the growth and spread of BC cells. There are at least 6 different angiogenic growth factors associated with TA in BC. The major mediator of TA is vascular endothelial growth factor (VEGF), a homodimeric heparin-binding glycoprotein. VEGF signals through VEGF receptor-2 (VEGFR-2), the major VEGF signalling receptor that mediates sprouting angiogenesis. Recently, different antiangiogenic agents have shown efficacy in the treatment of advanced BC. Bevacizumab, a humanised monoclonal antibody against VEGF, in combination with taxanes improves progression-free survival and overall response rate in first-line therapy. Other new antiangiogenic agents, called multi-kinase inhibitors (sunitinib and pazopanib), are under investigation. Finally, a schedule of treatment called metronomic chemotherapy, with antiangiogenic activity, has also demonstrated efficacy in the treatment of advanced BC.     

Epidermal growth factor receptor inhibitors in the treatment of non-small-cell lung cancer.

Remarkable developments in the systemic treatment of advanced non-small-cell lung cancer have taken place in the past few years. Targeted therapies have been largely employed in patients with far advanced disease, and some of them have demonstrated consistent activity in this setting. Epidermal growth factor receptor (EGFR) inhibitors cause dramatic response in approximately 10% of white patients who had received prior chemotherapy. Responses are higher in Asians. These findings are at least partly caused by the substantially higher incidence of EGFR mutations in Asians compared with whites. Studies of EGFR inhibitors in combination chemotherapy in front-line therapy of advanced non-small-cell lung cancer have, however, failed to improve survival, and better understanding of interactions between chemotherapeutic agents and EGFR inhibitors will be essential in the development of more effective strategies.     

Nintedanib in combination with docetaxel for second-line treatment of advanced non-small-cell lung cancer

Non-small lung cancer (NSCLC) is a lethal malignancy when diagnosed in advanced stage. The evolution of chemotherapy and the development of agents targeting certain molecular pathways involved in tumor progression improved the prognosis. Nintedanib is a new tyrosine kinase inhibitor, which exerts its activity by blocking VEGF, FGF and PDGF receptors and inhibits the angiogenic signaling by preventing receptor dimerization. Several Phase I and II studies proved its safety and efficacy in diverse solid tumors. In patients with advanced NSCLC, the administration of nintedanib may offer an additional chemotherapy benefit in terms of response rate, progression-free survival and overall survival particularly in patients with adenocarcinoma histology, with manageable toxicity. Here, we present an analytical review of literature regarding nintedanib and we focus on its particular importance in NSCLC treatment.     

Bevacizumab in non-small-cell lung cancer: a review

Current targeted strategies for cancer focus on the blockade of growth factor receptors and the inhibition of angiogenesis. The VEGF pathway has become an attractive target in multiple malignancies, including lung cancer. Bevacizumab, a monoclonal antibody against VEGF, increased survival in non-small-cell lung cancer (NSCLC) patients when added to standard carboplatin/paclitaxel chemotherapy. The pivotal Phase III study (ECOG 4599) in NSCLC showed longer overall survival: 12.3 versus 10.3 months and a higher median progression-free survival of 6.2 versus 4.5 months when chemotherapy was associated with bevacizumab. Benefits were confirmed in terms of progression-free survival in the European Phase III study (AVAiL). Subsequently, bevacizumab gained US FDA and European Medicines Agengy approval as a first-line therapy for advanced NSCLC. Bevacizumab's safety profile is well established: most adverse events are mild to moderate and can be managed using standard interventions. This article presents an overview of the current data on bevacizumab for NSCLC.     

Multidisciplinary management of childhood sarcoma: time to expand

Current targeted strategies for cancer focus on the blockade of growth factor receptors and the inhibition of angiogenesis. The VEGF pathway has become an attractive target in multiple malignancies, including lung cancer. Bevacizumab, a monoclonal antibody against VEGF, increased survival in non-small-cell lung cancer (NSCLC) patients when added to standard carboplatin/paclitaxel chemotherapy. The pivotal Phase III study (ECOG 4599) in NSCLC showed longer overall survival: 12.3 versus 10.3 months and a higher median progression-free survival of 6.2 versus 4.5 months when chemotherapy was associated with bevacizumab. Benefits were confirmed in terms of progression-free survival in the European Phase III study (AVAiL). Subsequently, bevacizumab gained US FDA and European Medicines Agengy approval as a first-line therapy for advanced NSCLC. Bevacizumab’s safety profile is well established: most adverse events are mild to moderate and can be managed using standard interventions. This article presents an overview of the current data on bevacizumab for NSCLC.     

Chemotherapy for non-small-cell lung cancer. Part 2: Advanced disease

The prognosis of patients with advanced non-small-cell lung cancer (NSCLC) remains poor. Systemic chemotherapy prolongs survival in this group of patients and palliates symptoms compared to best supportive care alone but more effective therapeutic strategies are needed. Novel agents that selectively target biological pathways of tumor growth offer hope of improving response and survival rates beyond what has been achieved with standard cytotoxic chemotherapy. Part 2 of this two-part article addresses the role of chemotherapy in locally advanced and advanced NSCLC, including the use of novel agents, considerations in elderly patients, and studies of second-line treatment.     

Promising developments in targeted therapies for non-small-cell lung cancer

Despite advances in chemotherapy, radiation therapy, and surgery, the overall survival for patients with lung cancer remains poor. Thus, novel therapeutic approaches are warranted. As knowledge of the molecular abnormalities and dysregulated cellular processes contributing to the pathogenesis and progression of lung cancer has been acquired, intense interest has been directed at developing agents that target these abnormalities. New agents targeting aberrant receptor tyrosine kinases, the Ras oncoprotein, mediators of metastases and angiogenesis, and the tumor suppressor gene p53 have, among other agents, shown promise in preclinical studies. Early clinical trials with these agents in patients with advanced malignancies suggest preliminary evidence of clinical activity and possible applications in non-small-cell lung cancer (NSCLC). Ongoing clinical trials will help clarify the settings in which these agents are of greatest therapeutic value, the optimal schedule of administration, toxicities associated with chronic administration, and hopefully, provide additional insight into the biology of lung cancer. Selected clinical trials will be presented to highlight the use of rationally designed, targeted therapies for patients with NSCLC.