Application Of Bevacizumab Research Articles

Study and analysis of the use of bevacizumab in the treatment of breast cancer

This study aimed to explore the application of bevacizumab in breast cancer treatment. We reviewed the research progress and current status of bevacizumab, analyzed its mechanism of action, and introduced protein expression analysis to further investigate its therapeutic effect. Bevacizumab is an angiogenesis inhibitor that prevents tumor growth by binding to and blockingvascular endothelial growth factor (VEGF). Data were obtained derived from the United States Society of Clinical Oncology (ASCO), which employed reversed-phase protein array technology (RPPA) to analyze the expression levels of related proteins. This included data on 210 proteins from 55 CTx samples and 54 Bev + CTx samples. We conducted a follow-up analysis based on the existing studies of nine protein signatures with corresponding beta coefficients identified by Lasso regression. However, only the first eight proteins were analyzed due to insufficient data. Additionally, we analyzed four of the 210 proteins with high expression levels. Statistical analysis revealed differences in protein the expression levels between the CTx and Bev + CTx groups, though these differences were not statistically significant. Clustering results displayed protein expression data through heat maps, revealing a clustering relationship among several proteins. This study provides a reference for the application of bevacizumab in breast cancer treatment.

BIOM-07. SURVIVAL-ASSOCIATED GENETIC VARIATIONS IN TAIWANESE GLIOBLASTOMA MULTIFORME PATIENTS - A RETROSPECTIVE NGS STUDY

Abstract This retrospective study, conducted at Taichung Veterans General Hospital in Taiwan, employed Next-Generation Sequencing (NGS) technology to analyze genetic variations associated with survival in patients with glioblastoma multiforme (GBM). The study encompassed 30 newly diagnosed GBM patients, divided into two groups based on survival duration: long-term (over two years) and short-term (under two years). The findings are outlined below: Key Mutations: Significant mutations included CHEK2, IDH1, and TP53, along with variations in the TERT promoter and TP53 RNA splicing sites. Correlation Between Mutations and Survival: Contrary to Western data, TP53 mutations were more prevalent in the long-term survival group, suggesting that regional genetic differences may influence GBM prognosis. Therapeutic Effectiveness: The application of bevacizumab was significantly associated with improved survival rates, indicating its potential efficacy in treatment. The study highlights the critical role of personalized medicine in the treatment of GBM in Taiwan and points to the necessity of further research into the genetic characteristics and treatment responses of GBM patients in Taiwan and potentially other non-Western regions. These insights underline the importance of continuing to explore effective personalized treatment strategies and enhancing our understanding of genetic determinants in diverse populations. Moreover, the prevalence of certain mutations in Taiwanese patients, which differ from those commonly observed in Western populations, prompts a reevaluation of global treatment frameworks and suggests the potential for region-specific therapeutic protocols. The implication of these findings extends beyond immediate clinical applications, providing a foundation for future clinical trials and research into genetic markers that could dictate treatment choices. In conclusion, this study not only underscores the importance of individualized treatment plans based on genetic profiling but also highlights the variations in genetic mutations across different populations, which could have profound implications for the management of GBM worldwide. Further investigation into these disparities and their implications on treatment efficacy is essential for advancing GBM treatment and improving patient outcomes globally.

Application of bevacizumab in the management of meningiomas: a systematic review and meta-analysis.

Meningiomas are the most common intracranial lesions and constitute one-third of diagnoses. Surgical resection is the gold-standard treatment option. In case of treatment failure, therapeutic options are limited. Bevacizumab is a vascular endothelial growth factor ligand-binding monoclonal antibody that prevents angiogenesis. This study aims to investigate the efficacy and feasibility of bevacizumab in meningiomas On December 30, 2023, a systematic search was conducted according to PRISMA guidelines using the PubMed, Scopus, Web of Science, and Embase databases. This study is conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart. Our study included 12 studies, comprising 243 individuals and 310 tumors. Most of the studies were retrospective (80%). Most of the patients were male (47.9%). The bevacizumab was mostly administered intravenously at 10mg/kg every two weeks (77.8%). The mean progression-free survival (PFS) and overall survival (OS) were 19.1 ± 4.7 and 23.9 ± 8.4 months, respectively. The response rate was 0.33 (95%CI: 0.14-0.60). The PFS-6, PFS-12, and PFS-24 were 0.80 (95% CI: 0.64-0.89), 0.66 (95%CI: 0.46-0.82), and 25% (95%CI: 0.16-0.37), respectively. The OS-6, OS-12, and OS-24 were 0.89 (95% CI: 0.80-0.96), 0.86 (95%CI: 0.65-0.95), and 0.48 (95%CI: 0.16-0.82), respectively. The meta-regression identified the total number of individuals, number of tumors, gender, WHO II/III, and prior resection as a possible source of heterogeneity for outcomes. This study highlights the effectiveness of bevacizumab in meningiomas, especially in refractory, high-grade, or neurofibromatosis patients.

Extracellular vesicle-bound VEGF in oral squamous cell carcinoma and its role in resistance to Bevacizumab Therapy

BackgroundVascular endothelial growth factor (VEGF) is an important proangiogenic factor and has been considered as a key target of antiangiogenetic therapy in oral squamous cell carcinoma (OSCC). However, clinical application of bevacizumab, a specific VEGF antibody, didn’t improve the survival rate of OSCC patients. One possible explanation is that VEGF gene expresses diverse isoforms, which associate with extracellular vesicles (EVs), and EVs potentially contribute to VEGF resistance to bevacizumab. However, clear solution is lacking in addressing this issue.MethodsExpression of VEGF isoforms in OSCC cells was confirmed by reverse transcription and polymerase chain reaction (RT-PCR) and western blot. EVs isolated from OSCC cell’s conditioned medium (CM) were characterized by western blot, transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Flow cytometry, immunogold labeling and western blot were applied to study the VEGF on EVs. Tube formation assay and Matrigel plug angiogenesis assay were used for analyzing the angiogenesis capacity of EV-VEGF.ResultsThe most popular isoforms expressed by VEGF gene are VEGF121, VEGF165 and VEGF189. In this study, we demonstrated that all three isoforms of mRNA could be detected at varying levels in OSCC cells, while only VEGF165 and VEGF189 proteins were found. CM derived from OSCC cells, both soluble and non-soluble forms of VEGF could be detected. We further confirmed the presence of VGEF189 bound to EVs as a non-soluble form. EV-bound VEGF189 presented angiogenic activity, which could not be neutralized by bevacizumab. It was found that VEGF189 bound to EVs by heparan sulfate proteoglycans (HSPG). In addition, the angiogenic effect of EV-VEGF could be reversed by surfen, a kind of HSPG antagonist both in vitro and in vivo.ConclusionAntagonists targeting HSPG might potentially overcome the resistance of EV-VEGF to bevacizumab and serve as an alternative for anti-VEGF therapy in OSCC.

Advances in the use of bevacizumab for the treatment of respiratory papilloma

Respiratory papilloma is a relatively common benign tumor of the respiratory tract, and a few patients may develop malignant changes. The disease has an insidious onset and lacks specific clinical manifestations, and its manifestations are closely related to the growth mode, location and size of the tumor. It can involve multiple parts, such as the larynx, trachea, bronchus, and lung parenchyma, which cause coughing, hoarseness, dysphonia, and, in severe cases, may lead to obstruction of the respiratory tract. At present, the treatment of respiratory papilloma lacks standardization, and there is no effective method to cure the disease. Surgery remains the main treatment for alleviating patients' symptoms and preventing airway obstruction. However, due to the high recurrence rate of respiratory papilloma, multiple surgeries are often needed, which reduces the quality of life of patients and increases their disease burden and economic burden. Bevacizumab, a vascular endothelial growth factor-binding antibody inhibitor, is a promising adjuvant treatment modality that shows good potential for reducing symptoms and the frequency of surgery. This article aimed to review the efficacy and safety of bevacizumab for the treatment of respiratory papilloma and discuss the differences and efficacy of the systemic application and intralesional injection of bevacizumab for the treatment of respiratory papilloma.

The Predictors of Early Treatment Effectiveness of Intravitreal Bevacizumab Application in Patients with Diabetic Macular Edema.

The aim of this study was to establish whether multiple blood parameters might predict an early treatment response to intravitreal bevacizumab injections in patients with diabetic macular edema (DME). Seventy-eight patients with non-proliferative diabetic retinopathy (NPDR) and DME were included. The treatment response was evaluated with central macular thickness decrease and best corrected visual acuity increase one month after the last bevacizumab injection. Parameters of interest were the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), vitamin D, and apolipoprotein B to A-I ratio (ApoB/ApoA-I). The NLR (2.03 ± 0.70 vs. 2.80 ± 1.08; p < 0.001), MLR (0.23 ± 0.06 vs. 0.28 ± 0.10; p = 0.011), PLR (107.4 ± 37.3 vs. 135.8 ± 58.0; p = 0.013), and SII (445.3 ± 166.3 vs. 675.3 ± 334.0; p < 0.001) were significantly different between responder and non-responder groups. Receiver operator characteristics analysis showed the NLR (AUC 0.778; 95% CI 0.669-0.864), PLR (AUC 0.628; 95% CI 0.511-0.735), MLR (AUC 0.653; 95% CI 0.536-0.757), and SII (AUC 0.709; 95% CI 0.595-0.806) could be predictors of response to bevacizumab in patients with DME and NPDR. Patients with severe NPDR had a significantly higher ApoB/ApoA-I ratio (0.70 (0.57-0.87) vs. 0.61 (0.49-0.72), p = 0.049) and lower vitamin D (52.45 (43.10-70.60) ng/mL vs. 40.05 (25.95-55.30) ng/mL, p = 0.025). Alterations in the NLR, PLR, MLR, and SII seem to provide prognostic information regarding the response to bevacizumab in patients with DME, whilst vitamin D deficiency and the ApoB/ApoA-I ratio could contribute to better staging.

Supratarsal Injection of Bevacizumab in the Treatment of Vernal Kerato Conjunctivitis

Purpose: To evaluate the effectiveness of supratarsal injection of Bevacizumab in the treatment of Vernal Kerato-conjunctivitis (VKC). Study Design: Quasi experimental study. Place and Duration of Study: LRBT Karachi from September 2022 to September 2023. Methods: This study included 110 eyes of 60 patients with VKC and divided into two groups by convenient sampling. In one group (n=30) 0.1ml of Bevacizumab 2.5%was injected in supratarsal space with 27-gauge needle under topical anaesthesia. Other group (n=30) received conventional treatment. The sign and symptoms were checked at one week and at one month in all patients. The qualitative variables were presented as frequency and percentage while quantitative variables were shown as mean ± standard deviation. Chi square test was applied for comparison. Results: Mean age of the patients was 12.4 +1.9 years. There were 46 (76.0%) males. Itching and photophobia was not seen in 50% of the patients treated with Bevacizumab while this percentage was 13.3% and 10% respectively in case of conventional treatment. Similarly, redness, discharge and limbal papillae were not seen in 70%, 73.3% and 83.3% respectively after Bevacizumab application. While it was 16.6%, 30% and 10% respectively after conventional treatment. Significant improvement in itching, photophobia, redness, discharge and limbal papilla was observed in the group of patients who received supratarsal Bevacizumab injection as compared to those who received conventional treatment (p&lt;0.05). Conclusion: Bevacizumab is a safe and effective treatment in patients of VKC refractory to conventional treatment.

Abstract 2712: Development of GB268, a tri-specific antibody targeting PD-1/CTLA-4/VEGF, with enhanced anti-tumor efficacy and reduced toxicity in pre-clinical studies

Abstract Background: Immunotherapy using immune checkpoint modulators such as anti-PD1/PD-L1 have been widely used in cancer therapy. Combination of checkpoint inhibition using anti-PD1 and anti-CTLA4 has improved therapeutic efficacy but is also accompanied by severe immune related adverse events (irAEs) which limited their clinical use. Bi-specific antibody targeting PD-1/CTLA-4 such as cadonilimab has shown improved clinical benefits with reduced irAEs in cervical cancer. Vascular endothelial growth factor (VEGF) is overexpressed in various solid tumors and anti-VEGF agents inhibit neovascularization and shrink tumor with time. Combined application of bevacizumab and PD-1/PD-L1 blockade displays durable and improved anti-tumor effects. We have recently developed a novel tri-specific antibody GB268, specifically targeting PD-1, CTLA-4 and VEGF with fine-tuned activity &amp; potency for each arm to simultaneously block PD-1/CTLA-4 mediated immune-suppression and VEGF mediated tumor angiogenesis. Methods: GB268 is a hexavalent antibody with symmetrical structure, composed of anti-PD-1 VHH antibody, anti-CTLA-4 VHH antibody, and anti-VEGF conventional antibody. The Fc part is silenced by introducing L234A/L235A mutations. Comprehensive in vitro and in vivo characterization of GB268 have been carried out. Along with in vivo efficacy studies, toxicity has also been evaluated with a murine arthritis model in hPD1/hCTLA4 double-KI mice to assess immune related AEs. Results: GB268 specifically bound to PD-1, VEGF, and CTLA-4 with high affinity and completely blocked PD-1 and VEGF pathways in reporter systems. To reduce the CTLA4 inhibition-induced AEs, the CTLA-4 arm was intentionally designed to only partially block the interaction of CTLA4 to its ligands CD80/CD86, and furthermore, the blockade of CTLA-4 was highly dependent on PD-1 expression. GB268 displayed robust anti-tumor efficacy with attenuated toxicity in murine models. In multiple PBMC-humanized models including A375 melanoma model, HT29 colorectal cancer model, and NCI-H460 NSCLC model, etc., GB268 exhibited significantly better anti-tumor efficacy, compared to PD-1/CTLA-4 bsAb and PD-1/VEGF bsAb, or in the combination of monoclonal antibodies to PD-1, CTLA-4 or VEGF. In arthritis induction model using hPD1/hCTLA4 double KI mice, GB268 had improved tolerance than cadonilimab and at least 20-fold better safety profile than ipilimumab combined with nivolumab. Conclusions: GB268 is a first-in-class anti-PD-1/CTLA-4/VEGF tri-specific antibody with innovative design. Preclinical data demonstrated GB268 is very effective in provoking anti-tumor responses. At the meantime, immune-related AEs is alleviated. Thus, GB268 may emerge as a promising novel therapeutics for cancer treatment. Citation Format: Qinglin Du, Yaxua Lv, Juehua Xu, Fei Peng, Huanhuan Cao, Xueyan Yang, Zhen Qian, Xueqin Li, Yiqi Cao, Qian Ding, Yongcong Tan, Shuhua Han. Development of GB268, a tri-specific antibody targeting PD-1/CTLA-4/VEGF, with enhanced anti-tumor efficacy and reduced toxicity in pre-clinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2712.

Targeting the microenvironment in the treatment of arteriovenous malformations

Extracranial arteriovenous malformations (AVMs) are regarded as rare diseases and are prone to complications such as pain, bleeding, relentless growth, and high volume of shunted blood. Due to the high vascular pressure endothelial cells of AVMs are exposed to mechanical stress. To control symptoms and lesion growth pharmacological treatment strategies are urgently needed in addition to surgery and interventional radiology. AVM cells were isolated from three patients and exposed to cyclic mechanical stretching for 24 h. Thalidomide and bevacizumab, both VEGF inhibitors, were tested for their ability to prevent the formation of circular networks and proliferation of CD31+ endothelial AVM cells. Furthermore, the effect of thalidomide and bevacizumab on stretched endothelial AVM cells was evaluated. In response to mechanical stress, VEGF gene and protein expression increased in patient AVM endothelial cells. Thalidomide and bevacizumab reduced endothelial AVM cell proliferation. Bevacizumab inhibited circular network formation of endothelial AVM cells and lowered VEGF gene and protein expression, even though the cells were exposed to mechanical stress. With promising in vitro results, bevacizumab was used to treat three patients with unresectable AVMs or to prevent regrowth after incomplete resection. Bevacizumab controlled bleeding, pulsation, and pain over the follow up of eight months with no patient-reported side effects. Overall, mechanical stress increases VEGF expression in the microenvironment of AVM cells. The monoclonal VEGF antibody bevacizumab alleviates this effect, prevents circular network formation and proliferation of AVM endothelial cells in vitro. The clinical application of bevacizumab in AVM treatment demonstrates effective symptom control with no side effects.Graphical abstractMechanical stress increases VEGF expression in endothelial AVM cells, possibly causing the VEGF upregulation in the microenvironment of AVM cells. The resulting RAS/RAF/MEK/ERK signaling in leads to progression of fast-flow malformations. The monoclonal VEGF-A antibody bevacizumab alleviates this effect, prevents circular network formation and proliferation of AVM endothelial cells in vitro. Sporadically occurring slow-flow malformations (LMs, VMs) have mutations in TEK or PIK3CA. TEK encodes the endothelial receptor tyrosine kinase TIE2. Sporadic extracranial fast-flow malformations (AVMs) show mutations in KRAS, BRAF and MAP2K1, which encodes the dual specificity mitogen-activated protein kinase MEK1. Combined targeting of the molecular causes of the disease could be key to achieve symptom control and reduce lesion growth. Orange: gain-of-function; Blue, circled with orange: enhanced signaling.

Long-term effects of intraoperative topical bevacizumab in sutureless scleral tunnel trabeculectomy: a prospective clinical trial.

To investigate the long-term efficacy and safety of the novel method sutureless trabeculectomy with topical administration of bevacizumab. Primary open-angle glaucoma patients with intraocular pressure (IOP) > 21mmHg despite maximum tolerated medication were included in a single-blind prospective interventional clinical trial. Group 1 underwent sutureless scleral tunnel trabeculectomy with intraoperative topical administration of bevacizumab (1.25mg) applied on the scleral incision for 1min. Group 2 underwent sutureless trabeculectomy alone and group 3 (control group) underwent conventional trabeculectomy with mitomycin C (MMC). Outcome measures were surgical success, IOP, number of needed anti-glaucoma medications, and complications. Patients were followed for two years. Finally, 50 eyes from group 1, 46 from group 2, and 47 from group 3 were analyzed. At the end of 24months, 52% (n = 26) of group 1, 34.8% (n = 16) of group 2, and 57.4% (n = 27) of group 3 had complete success (IOP < 18mmHg without medication). The difference was only significant between groups 2 and 3 (p = 0.003). 94% (n = 47) of group 1, 89.1% (n = 41) of group 2, and 91.5% (n = 43) of group 3 had qualified success (IOP < 18mmHg with ≤ 2 anti-glaucoma medications) (p = 0.69). There was a significant difference in the overall IOP mean between the three groups (p < 0.0001). There was no significant difference between the three groups in complication rates and the number of needed anti-glaucoma medications for IOP control. Sutureless trabeculectomy with topical application of bevacizumab showed comparable surgical success rates with conventional trabeculectomy and MMC in long-term follow-up. Additionally, adjuvant use of topical bevacizumab had a significant positive impact on long-term IOP control.

Use of Bevacizumab in recurrent glioblastoma: a scoping review and evidence map

BackgroundGlioblastoma (GBM) is the most malignant primary tumor in the brain, with poor prognosis and limited effective therapies. Although Bevacizumab (BEV) has shown promise in extending progression-free survival (PFS) treating GBM, there is no evidence for its ability to prolong overall survival (OS). Given the uncertainty surrounding BEV treatment strategies, we aimed to provide an evidence map associated with BEV therapy for recurrent GBM (rGBM).MethodsPubMed, Embase, and the Cochrane Library were searched for the period from January 1, 1970, to March 1, 2022, for studies reporting the prognoses of patients with rGBM receiving BEV. The primary endpoints were overall survival (OS) and quality of life (QoL). The secondary endpoints were PFS, steroid use reduction, and risk of adverse effects. A scoping review and an evidence map were conducted to explore the optimal BEV treatment (including combination regimen, dosage, and window of opportunity).ResultsPatients with rGBM could gain benefits in PFS, palliative, and cognitive advantages from BEV treatment, although the OS benefits could not be verified with high-quality evidence. Furthermore, BEV combined therapy (especially with lomustine and radiotherapy) showed higher efficacy than BEV monotherapy in the survival of patients with rGBM. Specific molecular alterations (IDH mutation status) and clinical features (large tumor burden and double-positive sign) could predict better responses to BEV administration. A low dosage of BEV showed equal efficacy to the recommended dose, but the optimal opportunity window for BEV administration remains unclear.ConclusionsAlthough OS benefits from BEV-containing regimens could not be verified in this scoping review, the PFS benefits and side effects control supported BEV application in rGBM. Combining BEV with novel treatments like tumor-treating field (TTF) and administration at first recurrence may optimize the therapeutic efficacy. rGBM with a low apparent diffusion coefficient (ADCL), large tumor burden, or IDH mutation is more likely to benefit from BEV treatment. High-quality studies are warranted to explore the combination modality and identify BEV-response subpopulations to maximize benefits.

Efficacy and safety in unresectable hepatocellular carcinoma using atezolizumab plus bevacizumab in later-line: A retrospective analysis of real-world evidence.

e16173 Background: As far, no data has been published about later-line application of atezolizumab plus bevacizumab (T+A) in patients with unresectable hepatocellular carcinoma (uHCC). Methods: We retrospectively recruited uHCC patients who treated with later-line T+A. Efficacy endpoints included overall survival (OS) and progression free survival (PFS), in accordance with RECIST v1.1. Safety was evaluated with CTCAE v5.0. We also continually enrolled uHCC patients who received later-line regorafenib plus PD-1 inhibitors (Reg+PD-1) as a comparison. Results: Total 33 patients were continually included, 12 used T+A and 21 chose Reg+PD-1. Baseline performance status, liver function and BCLC tumor stage were similar between two cohorts. At data cut-off at February 2023, following median following-up at 18.9 months, median OS in cohort T+A and Reg+PD-1 were 8.2 (95%CI: 5.8-10.6) vs 15.6 (95%CI: 7.6-23.6) (p = 0.237). Median PFS in cohort T+A and Reg+PD-1were 5.1 (95%CI: 1.1-9.1) vs 3.5 (95%CI: 2.1-4.9) (p = 0.575). OS rate and PFS rate are listed. None of efficacy endpoints reached statistical difference. All patients suffered from AEs. No AEs-related death occurred. Conclusions: Efficacy and safety of later-line T+A in uHCC patients was similar with those who used regorafenib plus PD-1 inhibitors, which needed to be further confirmed. [Table: see text]

Efficacy of Simultaneous Application of Subretinal Tissue Plasminogen Activator and Bevacizumab for Submacular Hemorrhages.

The aim of the study was to evaluate the patients who received simultaneous subretinal tissue plasminogen activator (tPA) and bevacizumab for submacular hemorrhages secondary to neovascular age-related macular degeneration. This retrospective study included patients who underwent pars plana vitrectomy (PPV) with simultaneous subretinal tPA and subretinal bevacizumab with 18% SF6 tamponade. Anatomical and functional results of the patients before surgery and at the 1st, 6th, and 12th months after surgery, additional treatments, and complications after PPV were evaluated. Eight eyes of eight patients were included in the study. The mean age of the patients was 72.38±92.3. The mean time from the onset of symptoms to treatment was 5.13±1.88 days. The patients' mean best-corrected visual acuity (BCVA) was 2.23±0.14 logMAR at baseline. Mean BCVA increased significantly at 1st, 6th, and 12th months to 1.68±0.47 logMAR, 1.58±0.49 logMAR, and 1.51±0.58 logMAR, respectively (p=0.001 at all). The mean central foveal thickness (CFT) in measurable patients was 836.8±627.02 μm at baseline. Mean CFT decreased significantly to 370.13±66.13 μm in the 1st month, 373.38±78.33 μm in the 6th month, and 367.75±116.43 μm in the 12th month (p<0.05). The maximum measurable subretinal hemorrhage height at baseline was 814.2±556.45 μm. The mean number of anti-VEGFs performed for 12 months after surgery was 4.13±2.1. At month 12, the ellipsoid zone could not be detected in 6 (75%) patients. Administration of subretinal bevacizumab and subretinal tPA effectively removes subretinal hemorrhage under the fovea. Intravitreal anti-VEGF treatment must be continued, as choroidal neovascular membrane activity continues after surgery.

First-line fluoropyrimidine plus bevacizumab followed by irinotecan-escalation versus initial fluoropyrimidine, irinotecan and bevacizumab in patients with metastatic colorectal cancer – Final survival and per-protocol analysis of the randomised XELAVIRI trial (AIO KRK 0110)

BackgroundThe randomised open-label phase III XELAVIRI trial failed to demonstrate non-inferiority of the sequential application of fluoropyrimidine plus bevacizumab followed by additional irinotecan at first progression (Arm A) versus initial combination of all agents (Arm B) for untreated metastatic colorectal cancer in the initial analysis of time-to-failure-of-strategy (TFS, 90% confidence boundary of 0.8). Here, we evaluate efficacy in the full analysis set (FAS), the per-protocol set, in addition to age-related and molecular subgroups. MethodsMedian TFS, overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan–Meier method and log-rank test. Cox regression models assessed hazard ratios (HRs) and confidence intervals (CIs) (TFS: 90%; OS, PFS: 95%). ResultsOf 421 patients, 390 (92.6%), 391 (92.9%) and 357 (84.8%) events for TFS, OS and PFS were observed in the FAS with a median follow-up of 54.2 months (Arm A) versus 52.9 months (Arm B). Non-inferiority of sequential treatment for TFS was missed in the FAS (HR 0.93; 90% CI, 0.79–1.10; P = 0.482) and not shown in the per-protocol set (HR 0.93; 90% CI, 0.75–1.13, P = 0.433). Formal non-inferiority for TFS was observed for patients older than 70 years (HR 1.06; 90% CI, 0.80–1.41; P = 0.670) and patients with RAS mutant tumours (HR 1.12; 90% CI, 0.87–1.43; P = 0.465). In RAS/BRAF wild-type tumours, combination treatment was significantly superior to sequential therapy in all end-points. ConclusionsIn the overall population, XELAVIRI just missed to demonstrate the non-inferiority of sequential compared to combination therapy for TFS. However, the non-inferiority of sequential treatment was observed in elderly patients and RAS mutant tumours. Trial registrationTrial registration ID (clinicaltrials.gov) NCT01249638.

Use of Bevacizumab and Aflibercept in the Treatment of Diabetic Macular Edema: Cost-effectiveness Analysis

Background: The aim of this study was to evaluate the efficacy of aflibercept by comparison with bevacizumab in the treatment of diabetic macular edema.Methods: The study included 159 patients; the first group consisted of 58 patients who underwent intravitreal application of aflibercept, and the second group of 101 patients underwent intravitreal application of bevacizumab.Main Findings: There was a statistically significant decrease in edema during the optical coherence tomography (OCT) scans after the application of bevacizumab (533±152 μm vs. 384±104 μm, p&lt;0.001) and aflibercept (500±110 μm vs. 354±80 μm, p&lt;0.001). Moreover, a significant increase in central visual acuity was observed both for bevacizumab (0.29±0.20 μm vs. 0.36±0.22 μm, p&lt;0.001) and aflibercept (0.40±0.30 μm vs. 0.48±0.31 μm, p&lt;0.001). Principal Conclusion: Anintravitreal application of either aflibercept or bevacizumab resulted in a significant reduction in macular edema and a significant increase in central visual acuity. Although statistically more efficient, aflibercept use can hardly be justified, due to the high cost associated with its use. Bevacizumab achieved a higher cost-effectiveness compared with aflibercept. Therefore, its use should be considered depending on various healthcare systems, as well as socio-economic factors. Key words: diabetic retinopathy, diabetic macular edema, bevacizumab, aflibercept, optical coherence tomography, visual acuity

Bevacizumab Eye Drops Vs. Intra-meibomian Gland Injection of Bevacizumab for Meibomian Gland Dysfunction-Associated Posterior Blepharitis.

AimsThis study aimed to evaluate the efficacy and safety of bevacizumab eye drops compared with those of an intra-meibomian gland (MG) injection of bevacizumab when performed in conjunction with standard lid hygiene in patients with meibomian gland dysfunction (MGD)-associated posterior blepharitis.MethodsThis prospective, open-label, observer-blinded randomized controlled trial included 60 eyes of 30 patients with MGD-associated posterior blepharitis who exhibited lid margin telangiectasia, treated at the Chula Refractive Surgery Center of King Chulalongkorn Memorial Hospital. Patients were randomized to receive lid hygiene plus 0.05% bevacizumab eye drops or a single intra-MG injection of 2.5% bevacizumab. All patients were instructed to perform routine lid hygiene care as demonstrated in an instructional video. Primary outcomes included telangiectasia grading and the lid margin neovascularized area (LMNA). Secondary outcomes included the Ocular Surface Disease Index (OSDI) score, corneal staining, meibum quality, meiboscore, conjunctival redness, fluorescein break-up time (FBUT), lipid layer thickness, treatment compliance, and adverse events. All parameters were evaluated before and 3 months after treatment.ResultsAfter treatment, there were no significant differences in telangiectasia grade and LMNA between groups (mean difference, −0.14, 95% CI −0.42 to 0.15, p = 0.338, −0.1, 95% CI −1.1 to 0.8, p = 0.761, respectively); however, the injection group exhibited significant improvements in both telangiectasia grade and LMNA, while, in the eye drop group, only telangiectasia grade showed a significant improvement relative to baseline. The injection group also exhibited significant improvements in corneal staining (mean difference, −0.78, 95% CI −1.29 to −0.27, p = 0.003), meiboscores (mean difference, −0.37, 95% CI −0.52 to −0.21, p <0.001), and FBUT (mean difference, 1.25, 95% CI 0.21–2.29, p = 0.019) compared to the eye drop group. OSDI scores, corneal staining, meibum quality, meiboscores, and conjunctival redness significantly improved relative to baseline in both groups. No local and systemic adverse event was observed at month 3 in both groups.ConclusionWhen performed with regular lid hygiene, intra-MG injection and topical application of bevacizumab are safe and effective for improving lid margin telangiectasia and the signs and symptoms of MGD-associated posterior blepharitis. This therapy may represent an alternative or adjunctive treatment for patients with MGD-associated posterior blepharitis.

Combined Application of Bevacizumab and Pd-1 Blockade Displays Durable Treatment Effects by Increasing the Infiltration And Cytotoxic Function of Cd8 + T Cells in Lung Cancer

Aim: VEGF/VEGFR inhibitors may help immune checkpoint inhibitors expand the population that will benefit from treatment. The authors investigated the efficacy of combined bevacizumab and PD-1 antibody. Materials & methods: C57BL/6J mice were injected subcutaneously with 1×106 Lewis lung carcinoma cells. The mice were intraperitoneally injected with 0.25mg anti-PD-1 inhibitors and/or 15mg/kg bevacizumab. Tumor tissues were harvested. The authors reported that a non-small cell lung cancer patient received 200 mg PD-1 antibodycombined with 7.5mg/kg bevacizumab as fourth-line treatment. Results: Bevacizumab combined with PD-1 antibody induced a strong and durable antitumor effect. Bevacizumab combined with PD-1 antibody improved abnormal tumor vessels and enhanced the cytotoxic function and infiltration of T lymphocytes. The patient's survival time was significantly prolonged. Conclusion: Bevacizumab combined with anti-PD-1 antibody induces a durable antitumor effect by increasing the infiltration and cytotoxic function of CD8+ T cells in lung cancer.

Application of Bevacizumab Combined With Chemotherapy in Patients With Colorectal Cancer and Its Effects on Brain-Gut Peptides, Intestinal Flora, and Oxidative Stress.

ObjectiveTo investigate the efficacy of bevacizumab combined with chemotherapy in the treatment of colorectal cancer (CRC) and to analyze the effects on brain peptides, intestinal flora, and oxidative stress in CRC patients.MethodsEighty two patients with CRC who were admitted to our hospital from March 2018 to June 2021 were selected as the research subjects and divided into the control group (n = 41) and the observation group (n = 41). The control group was treated with XELOX chemotherapy, and the observation group was additionally treated with bevacizumab, which was repeated every 3 weeks for a total of two treatments. The therapeutic effects of the two groups were evaluated after treatment. The brain-gut peptide index, intestinal flora index and oxidative stress index were detected, and the adverse reactions of the two groups were recorded.ResultsIn the control group, ER was 36.59% (15/41) and DCR was 73.17% (30/41). In the observation group, ER was 63.41% (26/41) and DCR was 90.24% (37/41). ER and DCR in the observation group were higher than those in the control group (P < 0.05). After treatment, the levels of motilin and gastrin in the observation group were lower than those in the control group, and ghrelin was higher than that in the control group (P < 0.05). After treatment, the levels of Bifidobacterium, Lactobacilli and Enterococcus in the observation group were higher than those in the control group, and the level of Escherichia coli was lower than that in the control group (P < 0.05). After treatment, the SOD level of the observation group was lower than that of the control group, and the MDA level was higher than that of the control group.ConclusionBevacizumab combined with chemotherapy has good efficacy in the treatment of colorectal cancer patients, which can effectively improve the gastrointestinal motility of patients, regulate the intestinal flora of the body, rebuild the microecological balance, effectively reduce the oxidative stress response of patients, and reduce the incidence of adverse reactions.

Efficacy and Safety of Bevacizumab in Pretreated Metastatic Breast Cancer: A Systematic Review and Meta-Analysis.

The use of bevacizumab in patients with previously treated metastatic breast cancer (MBC) is controversial. This meta-analysis was carried out to evaluate the efficacy and safety of the regimen including bevacizumab among patients with pretreated MBC. We systematically searched PubMed, the Cochrane Library, Web of Science, and Embase databases for randomized controlled trials evaluating bevacizumab combined with chemotherapy for previously treated MBC patients. The primary endpoints were progression-free survival (PFS) and objective response rate (ORR). The secondary endpoints were overall survival (OS) and toxicity. The risk of bias was assessed by the Cochrane Collaboration's tool. The pooled hazard ratio (HR) and risk ratio (RR) with 95% confidence intervals (CIs) were calculated for the identified studies. This study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Four studies involving 1,640 individuals were included. Pooling results showed that the PFS of bevacizumab-containing groups (HR 0.82; 95% CI 0.73-0.93, p = 0.002) was significantly better than that of the control groups, especially when bevacizumab was administered as the second-line treatment for patients with human epidermal growth factor receptor 2 (HER2)-negative MBC (HR 0.77; 95% CI 0.66-0.88, p = 0.0002). The ORR in the bevacizumab-containing group was superior to that in the control group, both in the general (RR 1.45; 95% CI 1.18-1.78, p = 0.0004) and HER2-negative groups (RR 1.30; 95% CI 1.03-1.63, p = 0.03). However, no significant effect on OS was demonstrated for the addition of bevacizumab to the second-line treatment for HER2-negative MBC (HR 0.93; 95% CI 0.79-1.10, p = 0.39). Comparatively, proteinuria was more common in the bevacizumab-containing group. In addition, the application of bevacizumab tended to result in therapy discontinuation due to treatment-related toxicity. Bevacizumab-containing chemotherapy, in light of its favorable effects on clinical outcomes, could be a preferred therapeutic option for patients with MBC, for whom the disease must be rapidly relieved. Further studies are warranted for exploring the advantageous patients with the receipt of bevacizumab in multiline treatment.

Clinical applications of bevacizumab in the treatment of colorectal and ovarian cancer.

The development of biological drugs, which began in the 1980s, has revolutionized the treatment of numerous oncological diseases and severely disabling autoimmune diseases, with widely demonstrated evidence of benefit. Today, biological drugs represent an important and continuously developing category and are used both as a support therapy in onco-hematology and as molecules with their own therapeutic activity, such as monoclonal antibodies. Among these, bevacizumab represents a drug of relevant clinical value, used as antiangiogenic therapy in numerous cancers, in particular colorectal and ovarian cancers. The expiry of the patent period of monoclonal antibodies, including bevacizumab, has opened up to the development of biosimilar drugs, represented by structurally similar molecules with pharmacokinetic, pharmacodynamic and clinical characteristics equivalent to a biological drug already present in clinical use (originator biologic). The development process of these drugs is contained in the guidelines of the major regulatory bodies (FDA/EMA) and is faster than that provided for the originator biologic. Since biosimilars have a lower cost than reference drugs, their use represents a possibility of containing health care costs and of satifying the growing demand in terms of efficacy and personalization of pharmacological therapies. Considering the particular severity of the diseases treated, including colorectal and ovarian cancers, biosimilar drugs must be used with full awareness, in terms of efficacy and safety, since their approval is based on a rigorous analytical process, as well as preclinical and clinical evaluation.