Growth Factor Monoclonal Antibody Bevacizumab Research Articles

Appliation of the combination of antiangiogenic agents and EGFR-TKIs in advanced NSCLC treatment

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and anti-angiogenic drugs have individually demonstrated clinical benefit in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Recent studies demonstrate that the combination of anti-EGFR and anti-angiogenesis can more significantly enhance clinical benefit, and even can remit EGFR-TKIs resistance in the treatment of advanced NSCLC. According to the different kinds of anti-angiogenesis drugs, recent clinical studies mainly include the combination of anti-vascular endothelial growth factor monoclonal antibody bevacizumab plus EGFR-TKIs and multi-targeted receptor anti-angiogenic tyrosine kinase inhibitor plus EGFR-TKIs, and the former results show a more significant improvement in terms of safety and efficacy in the treatment of advanced NSCLC. Therefore, the combination of bevacizumab plus EGFR-TKIs can be used as a new treatment standard in the treatment of some patients with NSCLC. Key words: Carcinoma, non-small-cell lung; Angiogenesis inhibitors; Epidermal growth factor receptor-tyrosine kinase inhibitors

Should Combination Chemotherapy Serve as the Backbone in Clinical Trials of Advanced Pancreatic Cancer?

The objective of this study was to evaluate whether building upon multidrug chemotherapy regimens represents a viable strategy in pancreatic cancer clinical trial design. We performed a pooled analysis of all single-arm phase II studies in which a specific targeted agent (the anti-vascular endothelial growth factor monoclonal antibody bevacizumab) was added to gemcitabine-based cytotoxic doublets. The primary end point was overall survival (OS). Secondary end points included objective response rate, CA-19-9 biomarker response rate, and adverse event frequencies. Kaplan-Meier methods estimated time-to-event end points, whereas the Cox proportional hazard model estimated univariate hazard ratios of death. For the 300 patients included in the pooled analysis, median OS was 9.1 months (95% confidence interval, 8.3-10.2). Differences in OS were observed according to patients' baseline performance status (median OS, 10.4 vs 8.6 months for Eastern Cooperative Oncology Group 0 vs 1, respectively). Moreover, bevacizumab-related adverse events were not observed at increased frequency with gemcitabine-based doublets compared with historic data. Recognizing the limitations of cross-study comparisons, these results compare favorably to those from Cancer and Leukemia Group B 80303, a phase III trial testing bevacizumab in combination with gemcitabine alone. This is the largest data set available to demonstrate the feasibility of building upon more intensive chemotherapy backbones in clinical trials of novel targeted agents in pancreatic cancer.

Vascular endothelia growth factor targeted therapy may improve the effect of dendritic cell-based cancer immune therapy

Glioblastoma (GBM) is the most com-mon and most lethal subtype of glioma and, despite advances, therapy prognosis re-mains poor with a median survival of ~15 months and a 2-year survival rate of 26% [1]. Standard therapy consists of tumor re-section, radiation and chemotherapy and a majority of patients receive antiangioge-netic therapy with the humanized anti-vas -cular endothelial growth factor monoclonal antibody bevacizumab as second-line ther-apy. In a randomized Phase II clinical trial we use an individualized cancer immune therapy concept based on dendritic cells (DC-CIT) as add on to first-line therapy [2]. Our cancer vaccine AV0113 is comprised of two main components: Type 1 dendritic cells, that are characterized by the secretion of the immune regulatory molecule IL-12 to polarize the immune system towards a cy-tolytic immune response, are derived from the patient’s monocytes and are pulsed with tumor antigens, that are extracted from the patient’s autologous tumor tissue. AV0113 represents a fully individualized somatic cell therapy.

Recent advances in the treatment of metastatic renal cell carcinoma

In the past 5 years, the treatment of patients with metastatic renal cell carcinoma has changed dramatically from being largely cytokine-based with the emergence of targeted therapy. Following the elucidation of various molecular pathways in renal cell carcinoma, targeted agents (particularly vascular endothelial growth factor-targeting antiangiogenic agents) now form the backbone of most therapeutic strategies for patients with metastatic renal cell carcinoma and the outcome of treatment has improved. However, many tumors eventually develop resistance to targeted therapy due to secondary mutation of the target protein or compensatory changes within the target pathway that bypass the site of inhibition. On the other hand, there are new forms of immunotherapy that hold the promise of improving the outcome for patients with metastatic renal cell carcinoma. In this article, we describe some of these new therapies, including the anti-vascular endothelial growth factor monoclonal antibody bevacizumab, several receptor tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib, axitinib, and tivozanib), the mammalian target of rapamycin inhibitors temsirolimus and everolimus, and new immunotherapy modalities, such as anti-cytotoxic T-lymphocyte-associated antigen 4 antibody and anti-programmed cell death 1/programmed cell death-ligand 1 antibody. We also discuss their role in the current management of patients with metastatic renal cell carcinoma.

Carcinomatous meningitis: Leptomeningeal metastases in solid tumors.

Leptomeningeal metastasis (LM) results from metastatic spread of cancer to the leptomeninges, giving rise to central nervous system dysfunction. Breast cancer, lung cancer, and melanoma are the most frequent causes of LM among solid tumors in adults. An early diagnosis of LM, before fixed neurologic deficits are manifest, permits earlier and potentially more effective treatment, thus leading to a better quality of life in patients so affected. Apart from a clinical suspicion of LM, diagnosis is dependent upon demonstration of cancer in cerebrospinal fluid (CSF) or radiographic manifestations as revealed by neuraxis imaging. Potentially of use, though not commonly employed, today are use of biomarkers and protein profiling in the CSF. Symptomatic treatment is directed at pain including headache, nausea, and vomiting, whereas more specific LM-directed therapies include intra-CSF chemotherapy, systemic chemotherapy, and site-specific radiotherapy. A special emphasis in the review discusses novel agents including targeted therapies, that may be promising in the future management of LM. These new therapies include anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib in nonsmall cell lung cancer, anti-HER2 monoclonal antibody trastuzumab in breast cancer, anti-CTLA4 ipilimumab and anti-BRAF tyrosine kinase inhibitors such as vermurafenib in melanoma, and the antivascular endothelial growth factor monoclonal antibody bevacizumab are currently under investigation in patients with LM. Challenges of managing patients with LM are manifold and include determining the appropriate patients for treatment as well as the optimal route of administration of intra-CSF drug therapy.

Intravitreal bevacizumab as adjunctive treatment for retinopathy of prematurity

While laser photocoagulation remains the standard of care in the treatment of advanced retinopathy of prematurity (ROP), regression is not seen in all cases (especially in aggressive posterior disease) following laser alone. We report the results of the use of the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in eyes with ROP at high risk for progression. Records of all infants with ROP treated with bevacizumab were reviewed. Bevacizumab was given when conventional laser therapy was not possible in patients with poor pupillary dilation from iris rubeosis, dense vitreous hemorrhage, or increasing vascular activity and vitreoretinal traction despite completed laser therapy. We recorded birth weight, gestational age at birth, severity of ROP, anatomic result, any additional ophthalmic interventions, and early or late adverse systemic effects. Thirteen eyes of 7 infants (median gestational age, 25 weeks; median birth weight, 700 g; follow-up, 9 months [range, 2-17]) were treated with an intravitreal injection of 0.75 mg bevacizumab under sterile conditions by 1 surgeon following detailed discussion with family and attending neonatologists. Injection was not used as monotherapy in any case. Definitive treatment (laser or vitrectomy) was completed successfully within 72 hours of injection. No systemic complication attributable to bevacizumab treatment has been recorded within 2 to 17 months of follow-up. Treatment with bevacizumab may be used to improve visualization for more definitive laser or surgical treatment and may facilitate disease regression without obvious systemic toxicity. Optimization of dosing, timing, and indications will require additional study.

News on treatment: long-term results, multiple-generic substitution and a new therapeutic principle

Treatment is what really counts for our patients. The prerequisites for successful treatment and improvement of quality of life and functions may be summarised as the four CDs: correct diagnosis, correct drug, correct dosage and correct duration. The correct dosage and the correct duration, with re-evaluations of the patients to monitor the efficacy of the treatment, are of particular importance and are often neglected. This month’s Journal Club will focus on three related aspects of treatment: 1) Long-term effects of pallidal deep brain stimulation in tardive dystonia. 2) The risks and costs of multiple-generic substitution, an issue which is becoming increasingly relevant due to the multiplegenerics on the market. 3) A new treatment principle for vestibular schwannomas in neurofibromatosis type 2: use of the anti-vascular endothelial growth factor monoclonal antibody bevacizumab. Long-term effects of pallidal deep brain stimulation in tardive dystonia

Erlotinib and Bevacizumab Have Synergistic Activity against Melanoma

Melanoma is one of the most aggressive types of cancer with currently no chance of cure once the disease has spread to distant sites. Therapeutic options for advanced stage III and IV are very limited, mainly palliative, and show response in only approximately 20% of all cases. The presented preclinical study was done to investigate the influence of a combined treatment of the epidermal growth factor receptor inhibitor erlotinib and the vascular endothelial growth factor monoclonal antibody bevacizumab in melanoma. The epidermal growth factor receptor was expressed in all cell lines tested, and treatment with erlotinib did inhibit the activation of the MEK/extracellular signal-regulated kinase and AKT signaling pathways. Whereas in vitro no influence on tumor cell proliferation was seen with erlotinib or bevacizumab monotherapy, a decreased invasive potential on erlotinib treatment in a three-dimensional Matrigel assay was observed. Furthermore, both drugs inhibited proliferation and sprouting of endothelial cells. In vivo, in a severe combined immunodeficient mouse xenotransplantation model, reduction in tumor volume under combined treatment with erlotinib and bevacizumab was superior to the additive effect of both single agents. This was associated with reduced cell proliferation, increased apoptosis, and a reduction in tumor angiogenesis compared with control or single treatment groups. Likewise, the reduction in the extent of lymph node and lung metastasis was most pronounced in animals treated with both drugs. The presented data strongly support the use of a combination of erlotinib and bevacizumab as a novel treatment regimen for metastatic melanoma.

What Role Do Combinations of Interferon and Targeted Agents Play in the First-Line Therapy of Metastatic Renal Cell Carcinoma?

Interferons (IFNs) are a class of cytokines with pleotropic actions that regulate a variety of cellular activities. Clinical trials with recombinant IFNs (IFN-α2a and IFN-α2b) have demonstrated clinical activity in patients with advanced renal cell carcinoma (RCC). Their efficacy is characterized by a low overall tumor regression rate of < 15%, progression-free survival of 4-5 months, and overall median survival of 10-18 months. This cytokine became the standard of care for patients with metastatic RCC and was then used as the comparator arm in a series of phase II and III clinical trials that have defined a new treatment paradigm for patients with advanced RCC. This paradigm uses the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib, the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, and the vascular endothelial growth factor monoclonal antibody bevacizumab. These 3 categories of agents were then investigated in combination with IFN-α in a series of preclinical and clinical studies. The collective data from these reports suggest the combination of IFN-α and bevacizumab is active and has a role in RCC therapy, whereas combinations with the TKIs or mTOR inhibitors have limited efficacy and/or excessive toxicity. The clinical and preclinical studies leading to these conclusions are reviewed herein.

New Horizons in Chemotherapy: Platforms for Combinations in First-Line Advanced Non-small Cell Lung Cancer

The treatment of advanced non-small cell lung cancer has evolved substantially during the last decade. Chemotherapy with a platinum-based doublet prolongs survival and improves quality of life in patients with good performance status. Recently, the addition of bevacizumab and the use of epidermal growth factor receptor inhibitors in appropriately selected patients have further improved the outcome of patients with advanced non-small cell lung cancer. Newer targeted agents are being developed and tested in the clinical arena at a rapid pace. In addition, the identification by clinical or molecular criteria of patient populations that benefit the most from these agents is under active investigation. In contrast, the development of newer cytotoxic agents, with innovative mechanisms of action, has been comparatively disappointing. Whether standard cytotoxic drugs are required as newer biologic agents are more frequently used or whether a more active and safer chemotherapy can be used as a template for combinations with biologic agents remains an important research topic.

M02-02: Update of EGFR inhibitors and radiation in the management of non-small cell lung cancer…where do we go next?

M02-02: Update of EGFR inhibitors and radiation in the management of non-small cell lung cancer…where do we go next?

Broadening the clinical use of platinum drug–based chemotherapy with new analogues

The three platinum-containing drugs that have been thus far approved by the FDA – cisplatin, carboplatin and oxaliplatin – have had a significant effect in the treatment of patients with some malignancies such as testicular, ovarian and colorectal cancer. However, much more remains to be achieved to widen the therapeutic use of this important class of drug, either via further analogue development or by judicious use of combining the existing drugs with new molecularly targeted agents. Two analogues arising from an academic (Institute of Cancer Research)/pharmaceutical (Johnson Matthey/AnorMed) collaboration – satraplatin (JM-216) and picoplatin (JM-/AMD-473) – have recently shown promising clinical activity; satraplatin (an orally available drug) in hormone-refractory prostate cancer and picoplatin in small-cell lung cancer. There have also been advances in delivery vehicles for platinum drugs (e.g., the diaminocyclohexane [DACH]-based AP-5346 and aroplatin/liposomal cis-bis-neodecanoato-trans-(R,R)-1,2-diaminocyclohexane platinum (II) [L-NDDP] are in early clinical development). Platinum-based drugs have also been successfully combined with molecularly targeted drugs (e.g., the recent approval of the vascular endothelial growth factor monoclonal antibody bevacizumab with carboplatin and paclitaxel in patients with NSCLC).

New target agents in the treatment of colorectal cancer patients

Colorectal cancer (CRC) is the third most common cancer in the Western world. Approximately 60% of patients with CRC require systemic therapy for metastatic disease, either at diagnosis or at disease recurrence. Until recently, classic chemotherapeutic agents have been combined in the treatment of advanced CRC. Novel targeted agents, such as the anti-vascular endothelial growth factor monoclonal antibody bevacizumab or anti-human epidermal growth factor receptor-directed compounds (e.g., cetuximab), have demonstrated substantial efficacy in large clinical trials. Early evidence suggests potential synergism among these classes of compounds or with conventional chemotherapy. The relationships between growth factors, cell surface receptors and their second messengers in the development and progression of human malignancies are not new concepts. The use of therapeutic targeting of these molecular structures in colorectal cancer is enhancing the treatment of colorectal cancer. This review briefly overviews the clinical status of new drugs, after the antibodies cetuximab and bevacizumab, from various mechanistic groups, discussing their advancement in clinical development towards their use in CRC.

Combining Targeted Therapies and Drugs with Multiple Targets in the Treatment of NSCLC

The first generation of clinical trials of targeted agents in non-small cell lung cancer (NSCLC) treatment has concluded. To date, only a few of these new agents can offer hope of a substantial impact on the natural history of the disease. Nevertheless, clinically meaningful advances have already been achieved. In chemotherapy-refractory advanced NSCLC patients, gefitinib and erlotinib, two epidermal growth factor receptor tyrosine kinase inhibitors, represent a further chance for tumor control and symptom palliation. In chemotherapy-naive, advanced, nonsquamous NSCLC patients, the combination of the anti-vascular endothelial growth factor monoclonal antibody bevacizumab with chemotherapy was demonstrated to produce better survival outcomes than with chemotherapy alone. The relative failure of first-generation targeted therapies in lung cancer may be a result of multilevel cross-stimulation among the targets of the new biological agents. Thus, blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. Preclinical evidence of the synergistic antitumor activity achievable by combining targeted agents that block multiple signaling pathways has recently been emerging. Clinical trials of multitargeted therapy may represent the second generation of studies in this field, and some of these are already ongoing. In a recent phase I/II trial, the combination of erlotinib and bevacizumab demonstrated very promising activity in the treatment of advanced NSCLC pretreated with chemotherapy. Whether the multitargeted approach is best performed using combinations of selective agents or agents that intrinsically target various targets is a matter of debate.

Phase I/II Trial Evaluating the Anti-Vascular Endothelial Growth Factor Monoclonal Antibody Bevacizumab in Combination With the HER-1/Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib for Patients With Recurrent Non–Small-Cell Lung Cancer

Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody. Erlotinib HCl (Tarceva, OSI-774; OSI Pharmaceuticals, New York, NY) is a potent, reversible, highly selective and orally available HER-1/epidermal growth factor receptor tyrosine kinase inhibitor. Preclinical data in various xenograft models produced greater growth inhibition than with either agent alone. Additionally, both agents have demonstrated benefit in patients with previously treated non-small-cell lung cancer (NSCLC). A phase I/II study in two centers examined erlotinib and bevacizumab (A+T) in patients with nonsquamous stage IIIB/IV NSCLC with > or = one prior chemotherapy. In phase I, erlotinib 150 mg/day orally plus bevacizumab 15 mg/kg intravenously every 21 days was established as the phase II dose, although no dose-limiting toxicities were observed. Phase II assessed the efficacy and tolerability of A+T at this dose. Pharmacokinetic parameters were evaluated. ResultsForty patients were enrolled and treated in this study (34 patients at phase II dose); the median age was 59 years (range, 36 to 72 years), 21 were female, 30 had adenocarcinoma histology, nine were never-smokers, and 22 had > or = two prior regimens (three patients had > or = four prior regimens). The most common adverse events were mild to moderate rash, diarrhea, and proteinuria. Preliminary data showed no pharmacokinetic interaction between A + T. Eight patients (20.0%; 95% CI, 7.6% to 32.4%) had partial responses and 26 (65.0%; 95% CI, 50.2% to 79.8%) had stable disease as their best response. The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months. Encouraging antitumor activity and safety of A + T support further development of this combination for patients with advanced NSCLC and other solid tumors.