Background Bevacizumab Research Articles

Bevacizumab-induced hypertension in patients with glioblastoma: a systematic review and meta-analysis

Abstract Background Bevacizumab is a monoclonal antibody medication used as standard treatment for different types of cancers, one of them is glioblastoma, which is the most common primary brain tumor. Purpose We aimed to assess bevacizumab and its effects on inducing hypertension in patients with glioblastoma. Methods PubMed, Embase and Cochrane databases were searched until February 13th, 2024 for randomized control trials (RCTs) comparing bevacizumab alone with control or bevacizumab in combination with other chemotherapies in patients with glioblastoma. Data was examined using the Mantel-Haenszel method and we computed risk ratio (RRs) for binary endpoints and 95% confidence intervals (Cls). Heterogeneity was assessed using I² statistics. Meta-regression analysis was conducted to evaluate a possible link between the occurrence of hypertension and mortality or progression-free survival. R software version 4.2.3 was used for statistical analysis. Results 5 RCTs and 1 non-randomized study were included with a total of 1402 patients, of whom 608 (43,36%) were assigned to the bevacizumab and 794(56,64%) composed the control group. Compared with bevacizumab, the control achieved statistically significant lower rates of hypertension occurrence (RR 6,31; CI: 2,13 - 18,65; p=0.000872; I²=54%). Subgroup analysis of bevacizumab alone versus bevacizumab in combination with other chemotherapies tended towards the combination group(RR 2,24; CI: 1,19 - 4,21; p= 0.012497; I² = 68%). Mortality was significantly higher in the bevacizumab group (OR 1,60; CI: 1,02 - 2,52; p=0,040443; I²= 0%). Progression-free survival did not reach a statistically significant difference between groups (OR 1,07; CI: 0,33 - 3,43; p= 0,907923; I²= 45%) and meta-regression analysis showed no significant link between hypertension and mortality or progression-free survival. Conclusion Concerning the treatment of glioblastoma, our results showed that induced hypertension is more likely to happen in patients treated with bevacizumab. Significant statistical difference in the mortality was observed between the use of bevacizumab and control. However, the current data is insufficient to determine a link between hypertension and prognostic value through meta-regression analysis.General Analysis

A pharmacovigilance study of adverse event profiles and haemorrhagic safety of bevacizumab based on the FAERS database

ABSTRACT Background Bevacizumab is used for the treatment of advanced malignant tumors; it acts by inhibiting angiogenesis. This study aimed to examine adverse events (AEs) of bevacizumab, especially hemorrhage, using the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Research Design and Methods The reporting odds ratio (ROR) and proportional reporting ratio (PRR) were used to analyze the AEs of bevacizumab using FAERS registration data from January 2004 to September 2022. Clinical information regarding hemorrhagic signals was further analyzed. Results The number of bevacizumab-associated AE reports was 96,477. Our study found that 892 significant preferred terms (PTs) were spread throughout 25 organ systems. The system organ classes (SOCs) focus on general disorders, administration site conditions, blood and lymphatic system disorders, injury, poisoning, and procedural complications. A total of 2,847 bevacizumab-related hemorrhage cases were reported, and 37 hemorrhagic signals were identified. Hemorrhagic signals were focused on SOC levels in vascular, gastrointestinal, and nervous system disorders. Colorectal, lung, and breast cancers are the three most common malignancies associated with BV-induced hemorrhage. Conclusion The AE report from the present study confirms the majority of label information for bevacizumab, while also identifying new AEs. In addition, this was a large descriptive study of bevacizumab-induced hemorrhage.

Factors affecting prognosis in patients treated with bevacizumab plus paclitaxel as first-line chemotherapy for HER2-negative metastatic breast cancer: an international pooled analysis of individual patient data from four prospective observational studies

BackgroundBevacizumab (BV) plus paclitaxel (PTX) is a treatment option in patients with HER2-negative metastatic breast cancer (mBC). We conducted an international pooled analysis with individual patient data to evaluate the effectiveness of BV + PTX as a first-line treatment for HER2-negative mBC patients under routine practice.MethodsA total of 2,474 mBC patients treated with BV + PTX from four prospective observational studies were analyzed. The primary endpoint was overall survival (OS). The other endpoints including identifying independent prognostic factors and validation of the modified Prognostic Factor Index (PFI) developed in the ATHENA trial.ResultsMedian follow-up time was 10.9 months (M). Median OS were 21.4 M (95% confidential interval 19.8–22.7 M). The seven independent prognostic factors (tumor subtype, age, ECOG performance status (PS), disease-free interval (DFI), liver metastases, number of metastatic organs, and prior anthracycline and/or taxane treatment) for OS found in this analysis included the five risk factors (RFs [DFI < 24 months, ECOG PS 2, liver metastases and/or > 3 metastasis organ sites, TNBC, prior anthracycline and/or taxane therapy]). High- (> 3 RFs [median OS 12.6 M]) and intermediate-risk groups (2 RFs [median OS 18.0 M]) had a significantly worse prognosis than the low-risk group (< 1 RF [median OS 27.4 M]), (p < 0.0001).ConclusionsThis international pooled analysis showed the effectiveness of first-line BV + PTX for HER2-negative mBC patients identifying seven independent prognostic factors as real-world evidence. The usefulness of the modified PFI developed in the ATHENA trial in predicting OS among patients receiving BV + PTX was also verified.

A randomized, double-blind, single-dose, parallel phase I clinical trial to compare the bioequivalence, immunogenicity, and safety of bevacizumab biosimilar and bevacizumab in healthy Chinese subjects

ABSTRACT Background Bevacizumab, a humanized monoclonal antibody against VEGF, can be used as a target therapy for colorectal cancer. A phase I clinical trial was conducted to compare the bioequivalence, immunogenicity, and safety of bevacizumab biosimilar (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.) and Bevacizumab (Roche Diagnostics GmbH) in healthy Chinese males. Research design & method Healthy Chinese subjects (N = 98) were randomly divided into two groups. A single-dose bevacizumab biosimilar or Bevacizumab was given per cycle. Plasma drug concentrations were detected by liquid chromatography–tandem mass spectrometry (LC-MC/MS) assay. We detected the levels of anti-drug antibody (ADA) to evaluate drug immunogenicity and the safety of drugs throughout the study. Results The geometric mean ratios (GMRs) of AUC0-t, Cmax, and AUC0-∞ for bevacizumab biosimilar and Bevacizumab were 96.27%, 93.69%, and 97.01%, respectively. The 90% CIs were all within 80–125%, meeting the bioequivalence standards. The levels of ADA were similar. In addition, the two drugs both demonstrated excellent safety in the trial. Conclusion This study showed that bevacizumab biosimilar and Bevacizumab had similar pharmacokinetics (PK) parameters and safety in healthy Chinese subjects.

Neoadjuvant Bevacizumab Plus Docetaxel/Cisplatin/Capecitabine Chemotherapy in Locally Advanced Gastric Cancer Patients: A Pilot Study.

BackgroundBevacizumab (BEV) plus chemotherapy as a neoadjuvant regimen presents good efficacy in patients with locally advanced cancer. However, its role in patients with locally advanced gastric cancer (LAGC) is not clear. Thus, the study aimed to assess the efficacy and safety of neoadjuvant BEV plus chemotherapy in patients with LAGC.MethodsTwenty resectable patients with LAGC who received BEV plus docetaxel/cisplatin/capecitabine (DCC) chemotherapy for 3 cycles with 21 days as one cycle as neoadjuvant regimen were involved. Besides, their treatment response, survival profiles, and adverse events were assessed.ResultsIn total, two (10.0%), 9 (45.0%), 8 (40.0%), and 1 (5.0%) patients achieved complete remission, partial remission, stable disease, and progressive disease (PD) according to imaging evaluation, which resulted in 55.0% of objective response rate and 95.0% of disease control rate, respectively. Moreover, the number of patients with pathological response grades 1, 2, and 3 was 8 (40.0%), 8 (40.0%), and 3 (15.0%); while 1 (5.0%) patient did not receive surgery due to PD, thus the data of this patient was not assessable. Meanwhile, 18 (90.0%) patients achieved R0 resection. Regarding survival profile, the median disease-free survival or overall survival were both not reached. The 1-year, 2-, and 3-year disease-free survival rates were 88.8, 80.7, and 67.3%. Meanwhile, the 1-, 2-, and 3-year overall survival rates were 100.0%, 75.8%, and 75.8%, respectively. Additionally, the main adverse events were anemia (90.0%), alopecia (90.0%), leukopenia (70.0%), and anorexia (65.0%). Indeed, most adverse events were of grade 1 or 2 and were manageable.ConclusionNeoadjuvant BEV plus DCC chemotherapy presents a favorable pathological response and survival profile with acceptable safety in patients with LAGC.

Evaluating the Optimal Sequence of Treatment With EGFR Inhibitors and Bevacizumab in RAS Wild-Type Metastatic Colorectal Cancer.

BackgroundEpithelial growth factor receptor inhibitors (EGFRi) and bevacizumab are the two main target therapies available for first-line treatment of RAS wild-type (wt) metastatic colorectal cancer (mCRC). However, the optimal sequencing of these agents remains unclear. In this study, we aimed to evaluate the optimal sequence with EGFRi and bevacizumab in first- and second-line treatment.MethodsThis was a retrospective cohort study with RAS wt mCRC patients identified by extended RAS analysis between 2013 and 2020 at a comprehensive cancer center. All patients had to be treated with a sequence of systemic treatment that included an EGFRi and bevacizumab in first and second line, in either order. Two groups were defined according to treatment sequence: first-line EGFRi followed by second-line bevacizumab (cohort A) or the reverse sequence (cohort B). Primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival with first-line treatment (PFS1), progression-free survival with second-line treatment (PFS2), objective response rate (ORR), and serious adverse events (grade ≥ 3). Survival was estimated using the Kaplan-Meier method, and survival differences between groups were compared using the log-rank test. Univariate analyses were performed using Cox proportional hazard model.ResultsA total of 124 patients were included (93 in cohort A and 31 in cohort B). There were no statistical significant differences in median OS (A: 34.9 months vs B: 29.2 months; p=0.590), PFS1 (A: 13.1 months vs B: 8.2 months; p=0.600), and PFS2 (A: 7.4 months vs B: 5.5 months; p=0.110) between groups. No significant differences were also found between treatment sequences in subgroups defined by age, gender, primary tumor location, sidedness, timing of metastasis, number of metastatic sites, multimodal therapy, primary tumor resection, and first-line chemotherapy backbone. ORR was significantly higher with first-line treatment with EGFRi (A: 55.9% vs B: 22.6%; p=0.001). At the final follow-up, the proportion of patients with SAEs was similar between treatment sequences (p=0.827).DiscussionOur study showed no impact of the treatment sequence with EGFRi and bevacizumab in the survival of RAS wt mCRC. However, patients treated with first-line EGFRi had significantly higher response rates, thus favoring its use in patients with symptomatic tumors and borderline resectable metastasis. Prospective trials are warranted to define the optimal sequence of treatment in RAS wt mCRC patients.

A randomized, double-blind, parallel-group phase I study comparing the pharmacokinetics, safety, and immunogenicity of LY01008, a candidate bevacizumab biosimilar, with its reference product Avastin® in healthy Chinese male subjects

ABSTRACT Background Bevacizumab, an inhibitor of angiogenesis, has been approved in several anti-cancer therapies. This study compared the pharmacokinetic (PK) profiles, safety, and immunogenicity of a bevacizumab biosimilar, LY01008, with those of European Union – approved bevacizumab (Avastin®) in healthy Chinese males. Research Design and Methods In this double-blind, open-label, parallel-group study, healthy Chinese male subjects were randomized 1:1 to receive either LY01008 or Avastin® 3 mg/kg intravenously. Primary study endpoints were PK parameters such as the area under the concentration-time curve (AUC) from time zero to infinity (AUC0–∞), AUC from time zero to last quantifiable concentration (AUC0–t), and maximum serum concentration (Cmax). Secondary study endpoints included safety, tolerability, and immunogenicity. Results One hundred and twelve subjects were randomized to receive LY01008 (n = 56) or Avastin® (n = 56). The 90% CIs of the GMRs of AUC0–t, AUC0–∞, and Cmax of LY01008 to Avastin® were all within the bioequivalence margin. Other PK parameters, safety, and immunogenicity profiles were comparable across the two treatment groups. Conclusions This study demonstrated equivalent PK, comparable safety, and similar immunogenicity of LY01008 to Avastin® in healthy subjects, thus paving the way for further clinical evaluation. Trial Registration The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT05110118).

Analytical similarity assessment of MYL-1402O to reference Bevacizumab

ABSTRACT Background Bevacizumab (BEV) is a recombinant humanized monoclonal immunoglobulin G1 antibody that binds to vascular endothelial growth factor (VEGF)-A and acts as an antiangiogenic agent. It is approved for treatment of many cancer indications, including metastatic colorectal cancer and nonsquamous non–small cell lung cancer. Research Design and Methods The analytical similarity of the BEV biosimilar MYL-1402O to reference BEV sourced from the European Union and United States was assessed using physicochemical and functional tests to support the clinical development of MYL-1402O. Assessment of physicochemical and analytical similarity showed that MYL-1402O has the same amino acid sequence and similar posttranslational modification profile as the reference BEV products. Results The functional and biologic activity of MYL-1402O assessed using inhibition of VEGF-induced cell proliferation in human umbilical vein endothelial cells, inhibition of VEGF-induced VEGF receptor 2 phosphorylation, and fragment antigen and fragment crystallizable receptor binding, was comparable to reference BEV products. Conclusions The totality of the data assessment confirms the high degree of similarity of MYL-1402O to reference BEV with respect to physicochemical and in vitro functional properties. The product quality data presented here, along with data from phase 1 clinical studies, demonstrate the similarity of MYL-1402O to reference BEV products, supporting further clinical development of this BEV biosimilar.

Bevacizumab-associated thrombotic microangiopathy treated with eculizumab: Acase series and systematic review of the literature.

Bevacizumab is a recombinant monoclonal antibody against the vascular endothelial growth factor A (VEGF-A) ligand that is used in the management of various solid malignancies. The adverse effect profiles of angiogenesis inhibitors, such as bevacizumab, have become increasingly well characterized and include renal manifestations such as hypertension, proteinuria, and thrombotic microangiopathy. Eculizumab inhibits terminal-complement activation and is used to treat atypical hemolytic uremic syndrome. There has been growing usage of eculizumab to treat bevacizumab-associated thrombotic microangiopathy. We performed a systematic review of the literature to identify full-text articles that describe the use of eculizumab for bevacizumab-associated thrombotic microangiopathy. Our systematic review identified 522 unique articles of which 5 were included in the final review. 9 cases, including 2 new cases presented in this review, were identified in which eculizumab was used in the management of bevacizumab-associated thrombotic microangiopathy. Hematologic parameters and kidney function stabilized or improved in all cases, and the 2 patients who required renal replacement therapy were able to discontinue dialysis. Given the findings of this systematic review, the use of eculizumab in the treatment of bevacizumab-associated thrombotic microangiopathy warrants further study, particularly in severe cases.

Severe proteinuria during the administration of bevacizumab plus mFOLFOX6 in a colorectal cancer patient after kidney transplantation: a case report

BackgroundBevacizumab (BEV) leads to proteinuria and renal damage. It is not clear whether the administration of immunosuppressive drugs after renal transplantation affects the safety of BEV administration. We report a case of severe proteinuria caused by BEV plus 5-fluorouracil, levofolinate, and oxaliplatin (mFOLFOX6) in a patient who had previously undergone kidney transplantation and the administration of tacrolimus.Case presentationThe patient was a 67-year-old man with a history of diabetes and hypertension. He developed chronic renal failure 14 years earlier and underwent right kidney transplantation from a living donor followed by the administration of tacrolimus and mycophenolate mofetil for immunosuppression. After kidney transplantation, the patient was diagnosed with colorectal cancer with multiple lung and liver metastases and received BEV plus mFOLFOX6. After 5 cycles, proteinuria was observed, with a urinary protein concentration of > 300 mg/dL (urine protein creatinine ratio: 3.5), and after 16 cycles, the urinary protein concentration was > 1000 mg/dL (urine protein creatinine ratio: 7.1). Subsequently, BEV was discontinued, and only mFOLFOX6 administration was continued. Tacrolimus continued to be administered during chemotherapy. There was no association between serum tacrolimus concentration and proteinuria.ConclusionsIn this case, BEV administration caused severe proteinuria without affecting blood levels of tacrolimus. Patients with risk factors for renal impairment should be carefully evaluated for the risks and benefits of BEV administration.

Effect of bevacizumab against cystic components of brain tumors

BackgroundBevacizumab improves symptoms via reducing the peritumoral edema and/or normalizing blood brain barrier, and occasionally via reducing the tumor size. However, the effect against active cystic components has not been documented yet.Materials and MethodsBetween 2008 and 2018, 139 patients with primary or metastatic brain tumors were treated with bevacizumab (BEV) in our institution. The images and symptoms before and after administration of BEV were examined, and changes in size of cysts were evaluated as follows: CR (complete disappearance), PR (reduction by ≥50%), MR (reduction by ≥25%), SD (size change <25%), PD (increase by ≥25%). The effect of BEV on tumor itself was determined according to Response Assessment in Neuro‐Oncology criteria.ResultsOf the 139 patients, 21 (15.1%) had cystic components. The best responses of cysts to BEV treatment were as follows: CR 6, PR 7, MR 4, SD 4. The group of patients with progressively increasing cysts prior to BEV treatment had significant cyst size reduction compared to stable cyst size groups, at initial imaging after BEV (mean 62.6% vs 22.5%, P = .0055) and at best response timing (mean 76.3% vs 32.8%, P = .0050). Patients with cysts showed significant improvement in symptoms after the treatment with BEV compared to patients without cysts (P = .0033). However, response rate was not different between patients with or without cysts. Overall survival after starting BEV was not different between glioblastoma patients with or without cysts.ConclusionBevacizumab is effective against progressively increasing cysts. Although cysts reduction effect and tumor response and/or overall survival are independent, BEV may be effective in patients who are symptomatic due to cyst enlargement.

Risk Factors and Adequate Management for Complications of Bevacizumab Treatment Requiring Surgical Intervention in Patients With Metastatic Colorectal Cancer

BackgroundBevacizumab (BV) has been approved for treating colorectal cancer since 2004. Although BV use may lead to adverse effects, few studies have reported incidences requiring surgical intervention. We aimed to identify the risk factors and adequate interventions for complications requiring surgical intervention after BV treatment. Patients and MethodsWe retrospectively reviewed the records of patients with metastatic colorectal cancer treated with BV in our institute from January 2009 to December 2016. The baseline patient characteristics were used to evaluate the potential risk factors for complications requiring surgery. ResultsOf the 1008 patients recruited for this study, 60 (5.9%) experienced complications necessitating surgery after BV therapy. Gastrointestinal perforation was the most frequently observed complication, occurring in 36 patients (3.5%), and diverting colostomy was the most commonly performed intervention (22 patients, 36.6%). Multivariate analysis helped identify poor differentiation, signet ring cell carcinoma, stent insertion status, rectal location of the primary tumor, and intact primary tumor status as the risk factors. Survival time remained unchanged regardless of a complication that required surgery. ConclusionCareful monitoring during BV treatment for metastatic colorectal cancer is essential for patients who have a predisposition to complications that may require surgery. After detection, adequate and timely surgical management is imperative for ensuring patient survival.

Clinical predictors of bevacizumab-associated intestinal perforation in non-small cell lung cancer.

Background Bevacizumab (Bev) is generally well-tolerated, and Bev-associated intestinal perforation (BAP) is a rare albeit serious side effect in cases of non-small cell lung cancer (NSCLC). Therefore, the present study aimed to identify clinical predictors of BAP to help predict and manage the development of life-threatening intestinal complications among patients receiving Bev. Methods This retrospective study evaluated demographic, clinical, and treatment factors for patients with NSCLC who were treated with Bev between February 2010 and August 2015 at our center. Results We identified 314 regimens (208 patients; median age: 65years; 115 women) for analysis, which included 119 first-line regimens, 74s-line regimens, and 121 third-line or later regimens. BAP occurred in 7 cases (2.23% among all regimens and 3.37% among all patients), which generally occurred during first- or second-line treatment and was caused by ulcerative colitis (1 case), colon diverticulitis (1 case), and idiopathic perforations (5 cases). Univariate analyses revealed that BAP was significantly associated with deteriorating PS during the first cycle of chemotherapy (odd ratio [OR]: 11.07, 95% confidence interval [CI]: 2.37-51.63, p = 0.0022), grade ≥ 3 diarrhea (OR: 11.37, 95% CI: 2.37-54.50, p = 0.0024), febrile neutropenia (OR: 9.16, 95% CI: 1.98-42.49, p = 0.0047), and stomatitis (OR: 4.60, 95% CI: 1.01-21.04, p = 0.0492). Conclusions Among patients with NSCLC, BAP was associated with deteriorating PS during the first cycle of chemotherapy, grade ≥ 3 diarrhea, febrile neutropenia, and stomatitis. Therefore, careful observation is needed for patients with NSCLC who receive Bev in any line of treatment, especially if they develop serious side effects that affect their PS or mucous membrane.

47P Loss-of-function PTPRT and PTPRD mutations predict bevacizumab resistance in metastatic colorectal cancer patients

Background Bevacizumab is a VEGF-directed anti-angiogenic therapy for KRAS- mutated metastatic colorectal cancer (mCRC) patients. However, some patients do not benefit from the treatment and there is no appropriate biomarker for the response prediction The aim of this study was to identify genetic markers that might predict the response to bevacizumab treatment. Methods 34 archived primary tumor tissues of stage IV mCRC cancer were analyzed, including 17 bevacizumab responders and 17 non-responders. We assessed all coding exons in 409 cancer-related genes for base substitutions, indels, and copy number alterations. Theaveragesequencing depthwas > 1,000 x. Results We observed 414 genomic alterations in 194 genes in all tumors (mean 12.1, range 6-19). The average number of genomic alterations was similar in responder (12.1 range 3-18) and non-responders (12.2, range 7-19) tumors. The most commonly mutated in both groups genes were TP53, APC, SYNE1 and PTPRT. Pathway analyses of altered genes revealed aberration in p53, Wnt, and JAK/STAT in both groups. Up to 35% of mCRC patients harbor mutations or copy number alterations in the PTPRT or PTPRD, protein tyrosine phosphatases in the JAK/STAT pathway. Interestingly, loss- of-function mutation or copy number loss of PTPRT/PTPRD were found to be enriched in the bevacizumab resistance tumors (p = 0.0072). Conclusions Our data suggest that PTPRT and PTPRD loss-of-function alterations may serve as a predictive biomarker of sensitivity to bevacizumab treatment in mCRCs. Legal entity responsible for the study The study was funded by a biotech company Funding ACT Genomics Disclosure All authors have declared no conflicts of interest.

Clinical effectiveness of bevacizumab in patients with recurrent brain tumours: A population-based evaluation.

Background Bevacizumab is an antiangiogenic agent active in patients with recurrent malignant gliomas. However, evidence for its clinical efficacy is relatively limited so that bevacizumab is approved for this indication in Canada and the United States, but not in the European Union. We reviewed the effectiveness of bevacizumab in patients with recurrent brain tumour using a large population database. Methods This was a retrospective, multicentre, study conducted at the BC Cancer Agency, a public cancer care organisation for the residents of the Canadian province of British Columbia. Cases were identified from the provincial registry and drug database. Patients were eligible if they were treated with bevacizumab with or without lomustine or etoposide for recurrent brain tumour between April 2011 and March 2014. The primary end points were progression-free survival. Secondary endpoints were overall survival and objective response rate. Results A total of 160 patients were included, with a median age of 55 years. The most common diagnosis was glioblastoma multiforme (70.6%), followed by oligodendroglioma (10.6%). Half of the patients had prior metronomic dosing of temozolomide. The median duration of therapy was 3 months. The median progression-free survival was 4.0 months and the 6-month progression-free survival was 29.4%. The median overall survival was 7 months and the 9-month and 12-month overall survival was 28.1% and 20.6%, respectively. The objective response rate was 23.1%. The most common documented reason for bevacizumab discontinuation was disease progression (66.9%), followed by toxicity (6.9%). Conclusions Bevacizumab therapy seems to be effective in delaying disease progression in patients with recurrent brain tumour, but with limited benefits on the overall survival, when used outside the clinical trial setting.

Bevacizumab Continuation Versus Treatment Holidays After First-Line Chemotherapy With Bevacizumab in Patients With Metastatic Colorectal Cancer: A Health Economic Analysis of a Randomized Phase 3 Trial (SAKK 41/06)

BackgroundBevacizumab (BEV)-containing therapies are costly. We performed a health economic analysis of a randomized phase 3 study (SAKK 41/06) that compared BEV continuation as a single agent (BEV) with treatment holidays (no BEV) after completing 4 to 6 cycles of first-line chemotherapy plus BEV in metastatic colorectal cancer patients. Patients and MethodsCosts for first-line chemotherapy with BEV, BEV continuation therapy, hospitalizations (length of stay), control visits, diagnostic tests, and second-line and later rounds of chemotherapy were collected. Mean costs per patient per treatment arm and an incremental cost-effectiveness ratio were calculated. Probabilistic sensitivity analysis was performed to account for uncertainty in the input parameters. ResultsThe total incurred mean costs per patient were 126,631 Swiss francs (CHF) [95% confidence interval (CI), 116,521-136,740] for BEV versus CHF100,146 (95% CI, 92,811-107,481) for no BEV. The incremental cost effectiveness ratio was CHF108,991 per life-year gained (LYG; 95% CI from probabilistic sensitivity analysis, 62,890-248,515). Compared to a willingness-to-pay threshold of CHF100,000/LYG, there was 42% probability that BEV continuation was cost effective, which decreased to 20% at a threshold of CHF75,000/LYG. Economic equality was reached in only 0.07% of cases. ConclusionThe clinical conclusion that BEV continuation as a single agent after completion of first-line chemotherapy is of low therapeutic value is supported by this health economic analysis. Costs increase without significant clinical benefit in this setting.

MEK inhibitor can reverse the resistance to bevacizumab in A549 cells harboring Kirsten rat sarcoma oncogene homolog mutation.

BackgroundBevacizumab (BV) is broadly used to treat a number of cancers; however, BV resistance mechanisms and strategies to overcome this resistance are yet to be determined.MethodsWe established xenograft mice models harboring Kirsten rat sarcoma oncogene homolog (KRAS) mutations based on the A549 cell line, and tested the responses of xenograft tumors to a series of drugs in ex vivo and in vivo experiments. Changes in transcriptive level were analyzed by ribonucleic acid (RNA) sequencing and the expressions of connexins were determined by immunohistochemistry staining.Results A549 cell mutation type (KRAS G12S) was confirmed by sequencing. After treating the xenograft tumors with BV, the median interval time from BV administration to tumor volume more than 2.5‐fold of the original was 37 days, compared with 21 days in the control (P = 0.025). A549 cells showed resistantance to selumitinib (MEK inhibitor) but were sensitive to selumitinib plus BEZ235 (phosphoinositide 3‐kinase/mammalian target of rapamycin dual inhibitor). However, selumitinib could effectively reverse the resistance to BV in in vivo experiments. RNA sequencing showed that mouse genes, but not human genes, activated the mitogen‐activated protein kinase signaling pathway, accompanied by activation of the Wnt and Hedgehog pathways. Connexin43 (S261) was phosphorylated before and during BV treatment, and subsequently transitioned to negative phosphorylated‐connexin 43‐S261 after resistance to BV.ConclusionCombining an MEK inhibitor with BV was a potential strategy to reverse initial BV resistance. Phosphorylated‐connexin 43 might be associated with the response to BV.

Assessment of chemotherapy strategy using bevacizumab for non-squamous non-small cell lung cancer in a real-world setting: A multi-institutional observational study

Abstract Micro-abstract We retrospectively analyzed 162 patients with non-squamous non-small cell lung cancer (NSCLC) who underwent first-line chemotherapy with bevacizumab (BEV); 127 patients without driver oncogenes, 17 patients with EGFR major mutations, 12 patients with ALK rearrangements, 4 patients with EGFR minor mutations and 2 patients with rare types of histology. Background BEV has been approved for treatment of non-squamous NSCLC and is authenticated as one of the key drugs in the treatment of advanced non-squamous NSCLC. Patients and methods We retrospectively analyzed patients with stage IIIB/IV non-squamous NSCLC who underwent chemotherapy with BEV in first-line setting. Results In 162 patients who underwent chemotherapy combined with BEV as first-line treatment, the median overall survival (OS) and progression-free survival (PFS) were 23.5 months and 6.8 months, respectively. The PFS did not differ significantly by the presence of driver oncogenes. In patients without driver oncogenes, more patients who received carboplatin plus pemetrexed with BEV could complete at least 4 cycles of induction therapy and more of these patients proceeded to maintenance therapy than those who received carboplatin plus paclitaxel with BEV, which resulted in better outcome associated with carboplatin plus pemetrexed with BEV. Continuation of BEV beyond first progression did not show any survival benefit. In EGFR mutation-positive patients, the order of BEV-containing regimen and TKI did not influence on OS. None of 18 patients with brain metastases detected at diagnosis developed intracranial hemorrhage. Conclusions PFS of first-line chemotherapy using BEV was not influenced by the existence of driver oncogenes. In patients without driver mutations in real clinical practice, as the first-line partner regimen with BEV, carboplatin plus pemetrexed may be more feasible as compared to carboplatin plus paclitaxel. BEV use beyond first progression did not deliver significant survival benefit. BEV was safe for brain metastases.

TCH-025 Long-Term Study of the Formation of Aggregates in Undiluted Bevacizumab 25 mg/ml

Background Bevacizumab, the active substance of Avastin®, is a humanised monoclonal antibody that acts as angiogenesis inhibitor, a drug that slows the growth of new blood vessels. It is used...

Bevacizumab Added to Neoadjuvant Chemotherapy for Breast Cancer

A B S T R AC T BACKGROUND Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)–negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response. METHODS