-
Journal of Thoracic Oncology : Official... Nov 2021We report the final overall survival (OS) analyses of atezolizumab-carboplatin-paclitaxel (ACP [experimental arm]) and OS data with approximately 39.8 months of median...
INTRODUCTION
We report the final overall survival (OS) analyses of atezolizumab-carboplatin-paclitaxel (ACP [experimental arm]) and OS data with approximately 39.8 months of median follow-up with atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) versus bevacizumab-carboplatin-paclitaxel (BCP) in chemotherapy-naive patients with metastatic nonsquamous NSCLC in the phase 3 IMpower150 study (NCT02366143).
METHODS
In this randomized, open-label study (N = 1202), coprimary end points included investigator-assessed progression-free survival and OS in intention-to-treat (ITT) wild-type (WT; no EGFR or ALK alterations) patients. Secondary and exploratory end points included OS in ITT and programmed death-ligand 1 (PD-L1) subgroups defined by the VENTANA SP142 and SP263 immunohistochemistry assays.
RESULTS
At the final analysis with ACP versus BCP (data cutoff: September 13, 2019; minimum follow-up: 32.4 mo), ACP had numerical, but not statistically significant, improvements in OS (ITT-WT: median OS = 19.0 versus 14.7 mo; hazard ratio = 0.84; 95% confidence interval: 0.71-1.00). OS benefit was sustained with ABCP versus BCP (ITT-WT: 19.5 versus 14.7 mo; hazard ratio = 0.80; 95% confidence interval: 0.67-0.95). Exploratory analyses in the SP142-defined PD-L1 subgroups revealed longer median OS with ABCP and ACP versus BCP in PD-L1-high and PD-L1-positive subgroups; in the PD-L1-negative subgroups, median OS was similar with ACP and ABCP versus BCP. Safety was consistent with that in earlier analyses (data cutoff: January 22, 2018).
CONCLUSIONS
At the final IMpower150 OS analysis, ACP had numerical, but not statistically significant, OS improvement versus BCP. Updated data with an additional 20 months of follow-up revealed continued OS improvement with ABCP versus BCP in all patients.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carboplatin; Humans; Lung Neoplasms; Paclitaxel; Survival Analysis
PubMed: 34311108
DOI: 10.1016/j.jtho.2021.07.009 -
Cancer Treatment Reviews Jun 2020When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and... (Review)
Review
When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and the first approved angiogenesis inhibitor. Marking the beginning for a new line of anti-cancer treatments, bevacizumab remains the most extensively characterized anti-angiogenetic treatment. Initially approved for treatment of metastatic colorectal cancer in combination with chemotherapy, its indications now include metastatic breast cancer, non-small-cell lung cancer, glioblastoma, renal cell carcinoma, ovarian cancer and cervical cancer. This review provides an overview of the clinical experience and lessons learned since bevacizumab's initial approval, and highlights how this knowledge has led to the investigation of novel combination therapies. In the past 15 years, our understanding of VEGF's role in the tumor microenvironment has evolved. We now know that VEGF not only plays a major role in controlling blood vessel formation, but also modulates tumor-induced immunosuppression. These immunomodulatory properties of bevacizumab have opened up new perspectives for combination therapy approaches, which are being investigated in clinical trials. Specifically, the combination of bevacizumab with cancer immunotherapy has recently been approved in non-small-cell lung cancer and clinical benefit was also demonstrated for treatment of hepatocellular carcinoma. However, despite intense investigation, reliable and validated biomarkers that would enable a more personalized use of bevacizumab remain elusive. Overall, bevacizumab is expected to remain a key agent in cancer therapy, both due to its established efficacy in approved indications and its promise as a partner in novel targeted combination treatments.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Bevacizumab; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Molecular Targeted Therapy; Neoplasms; Neovascularization, Pathologic; Randomized Controlled Trials as Topic
PubMed: 32335505
DOI: 10.1016/j.ctrv.2020.102017 -
Autophagy Jan 2024Bevacizumab plays an important role in the first and second line treatment for metastatic colorectal cancer (CRC). And induction of hypoxia and the tumors response to it...
Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer.
Bevacizumab plays an important role in the first and second line treatment for metastatic colorectal cancer (CRC). And induction of hypoxia and the tumors response to it plays an important role in determining the efficacy of antiangiogenic therapy while the connection between them remains unclear. Here, we found that lactate accumulated in the tumor environment of CRC and acted as substrates for histone lactylation, and this process was further induced by cellular enhanced glycolysis in hypoxia. We determined that CRC patients resistant to bevacizumab treatment presented with elevated levels of histone lactylation and inhibition of histone lactylation efficiently suppressed CRC tumorigenesis, progression and survival in hypoxia. Histone lactylation promoted the transcription of RUBCNL/Pacer, facilitating autophagosome maturation through interacting with BECN1 (beclin 1) and mediating the recruitment and function of the class III phosphatidylinositol 3-kinase complex, which had a crucial role in hypoxic cancer cells proliferation and survival. Moreover, combining inhibition of histone lactylation and macroautophagy/autophagy with bevacizumab treatment demonstrated remarkable treatment efficacy in bevacizumab-resistance patients-derived pre-clinical models. These findings delivered a new exploration and important supplement of metabolic reprogramming-epigenetic regulation, and provided a new strategy for improving clinical efficacy of bevacizumab in CRC by inhibition of histone lactylation. 2-DG: 2-deoxy-D-glucose; BECN1: beclin 1; CQ: chloroquine; CRC: colorectal cancer; DMOG: dimethyloxalylglycine; H3K18la: histone H3 lysine 18 lactylation; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Nala: sodium lactate; PDO: patient-derived orgnoid; PDX: patient-derived xenograft; RUBCNL/Pacer: rubicon like autophagy enhancer; SQSTM1/p62: sequestosome 1.
Topics: Humans; Autophagy; Beclin-1; Bevacizumab; Colorectal Neoplasms; Epigenesis, Genetic; Histones; Hypoxia; Lactic Acid; Lysine
PubMed: 37615625
DOI: 10.1080/15548627.2023.2249762 -
Asia-Pacific Journal of Ophthalmology...Retinal vein occlusion represents the second leading cause of retinal vascular disorders, with a uniform sex distribution worldwide. A thorough evaluation of... (Review)
Review
Retinal vein occlusion represents the second leading cause of retinal vascular disorders, with a uniform sex distribution worldwide. A thorough evaluation of cardiovascular risk factors is required to correct possible comorbidities. The diagnosis and management of retinal vein occlusion have changed tremendously in the last 30 years, but the assessment of retinal ischemia at baseline and during follow-up examinations remains crucial. New imaging techniques have shed light on the pathophysiology of the disease and laser treatment, once the only therapeutic option, is now only one of the possible approaches with antivascular endothelial growth factors and steroid injections being preferred in most cases. Nowadays long-term outcomes are better than those achievable 20 years ago and yet, many new therapeutic options are under development, including new intravitreal drugs and gene therapy. Despite this, some cases still develop sight-threatening complications deserving a more aggressive (sometimes surgical) approach. The purpose of this comprehensive review is to reappraise some old but still valid concepts and to integrate them with new research and clinical data. The work will provide an overview of the disease's pathophysiology, natural history, and clinical features along with a detailed discussion on the advantages of multimodal imaging and of the different treatment strategies with the aim of providing retina specialists with the most updated knowledge in the field.
Topics: Humans; Retinal Vein Occlusion; Angiogenesis Inhibitors; Retina; Intravitreal Injections; Bevacizumab
PubMed: 36912792
DOI: 10.1097/APO.0000000000000598 -
The Indian Journal of Medical Research Aug 2021Cervical cancer is one of the most common cancers in the world both in terms of incidence and mortality, more so important in low- and middle-income countries. Surgery... (Review)
Review
Cervical cancer is one of the most common cancers in the world both in terms of incidence and mortality, more so important in low- and middle-income countries. Surgery and radiotherapy remain the backbone of treatment for non-metastatic cervical cancer, with significant improvement in survival provided by addition of chemotherapy to radiotherapy. Survival as well as quality of life is improved by chemotherapy in metastatic disease. Platinum-based chemotherapy with/without bevacizumab is the mainstay of treatment for metastatic disease and has shown improvement in survival. The right combinations and sequence of treatment modalities and medicines are still evolving. Data regarding the molecular and genomic biology of cervical cancer have revealed multiple potential targets for treatment, and several new agents are presently under evaluation including targeted therapies, immunotherapies and vaccines. This review discusses briefly the current standards, newer updates as well as future prospective approaches in systemic therapies for cervical cancer.
Topics: Bevacizumab; Female; Humans; Immunotherapy; Quality of Life; Uterine Cervical Neoplasms
PubMed: 35295013
DOI: 10.4103/ijmr.IJMR_4454_20 -
Hepatology (Baltimore, Md.) Sep 2022No effective treatments are available for liver fibrosis. Angiogenesis is deeply involved in liver fibrogenesis. However, current controversial results suggest it is...
BACKGROUND AND AIMS
No effective treatments are available for liver fibrosis. Angiogenesis is deeply involved in liver fibrogenesis. However, current controversial results suggest it is difficult to treat liver fibrosis through vascular targeting. There are three different microvessels in liver: portal vessels, liver sinusoids, and central vessels. The changes and roles for each of the three different vessels during liver fibrogenesis are unclear. We propose that they play different roles during liver fibrogenesis, and a single vascular endothelial cell (EC) regulator is not enough to fully regulate these three vessels to treat liver fibrosis. Therefore, a combined regulation of multiple different EC regulatory signaling pathway may provide new strategies for the liver fibrosis therapy. Herein, we present a proof-of-concept strategy by combining the regulation of leukocyte cell-derived chemotaxin 2 (LECT2)/tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 signaling with that of vascular endothelial growth factor (VEGF)/recombinant VEGF (rVEGF) signaling.
APPROACH AND RESULTS
The CCl -induced mouse liver fibrosis model and NASH model were both used. During fibrogenesis, vascular changes occurred at very early stage, and different liver vessels showed different changes and played different roles: decreased portal vessels, increased sinusoid capillarization and the increased central vessels the increase of portal vessels alleviates liver fibrosis, the increase of central vessels aggravates liver fibrosis, and the increase of sinusoid capillarization aggravates liver fibrosis. The combinational treatment of adeno-associated viral vector serotype 9 (AAV9)-LECT2-short hairpin RNA (shRNA) and rVEGF showed improved therapeutic effects, but it led to serious side effects. The combination of AAV9-LECT2-shRNA and bevacizumab showed both improved therapeutic effects and decreased side effects.
CONCLUSIONS
Liver vascular changes occurred at very early stage of fibrogenesis. Different vessels play different roles in liver fibrosis. The combinational treatment of AAV9-LECT2-shRNA and bevacizumab could significantly improve the therapeutic effects on liver fibrosis.
Topics: Animals; Bevacizumab; Disease Models, Animal; Liver; Liver Cirrhosis; Mice; RNA, Small Interfering; Vascular Endothelial Growth Factor A
PubMed: 34940991
DOI: 10.1002/hep.32299 -
The New England Journal of Medicine Aug 2022In eyes with diabetic macular edema, the relative efficacy of administering aflibercept monotherapy as compared with bevacizumab first with a switch to aflibercept if... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In eyes with diabetic macular edema, the relative efficacy of administering aflibercept monotherapy as compared with bevacizumab first with a switch to aflibercept if the eye condition does not improve sufficiently (a form of step therapy) is unclear.
METHODS
At 54 clinical sites, we randomly assigned eyes in adults who had diabetic macular edema involving the macular center and a visual-acuity letter score of 24 to 69 (on a scale from 0 to 100, with higher scores indicating better visual acuity; Snellen equivalent, 20/320 to 20/50) to receive either 2.0 mg of intravitreous aflibercept or 1.25 mg of intravitreous bevacizumab. The drug was administered at randomization and thereafter according to the prespecified retreatment protocol. Beginning at 12 weeks, eyes in the bevacizumab-first group were switched to aflibercept therapy if protocol-specified criteria were met. The primary outcome was the mean change in visual acuity over the 2-year trial period. Retinal central subfield thickness and visual acuity at 2 years and safety were also assessed.
RESULTS
A total of 312 eyes (in 270 adults) underwent randomization; 158 eyes were assigned to receive aflibercept monotherapy and 154 to receive bevacizumab first. Over the 2-year period, 70% of the eyes in the bevacizumab-first group were switched to aflibercept therapy. The mean improvement in visual acuity was 15.0 letters in the aflibercept-monotherapy group and 14.0 letters in the bevacizumab-first group (adjusted difference, 0.8 letters; 95% confidence interval, -0.9 to 2.5; P = 0.37). At 2 years, the mean changes in visual acuity and retinal central subfield thickness were similar in the two groups. Serious adverse events (in 52% of the patients in the aflibercept-monotherapy group and in 36% of those in the bevacizumab-first group) and hospitalizations for adverse events (in 48% and 32%, respectively) were more common in the aflibercept-monotherapy group.
CONCLUSIONS
In this trial of treatment of moderate vision loss due to diabetic macular edema involving the center of the macula, we found no evidence of a significant difference in visual outcomes over a 2-year period between aflibercept monotherapy and treatment with bevacizumab first with a switch to aflibercept in the case of suboptimal response. (Funded by the National Institutes of Health; Protocol AC ClinicalTrials.gov number, NCT03321513.).
Topics: Adult; Angiogenesis Inhibitors; Bevacizumab; Diabetes Mellitus; Diabetic Retinopathy; Humans; Intravitreal Injections; Macular Edema; Ranibizumab; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Vascular Endothelial Growth Factor A
PubMed: 35833805
DOI: 10.1056/NEJMoa2204225 -
Ophthalmology Dec 2022To compare bevacizumab, ranibizumab, aflibercept, and laser treatment as primary therapies for retinopathy of prematurity (ROP) in terms of retreatment rate. (Meta-Analysis)
Meta-Analysis Review
TOPIC
To compare bevacizumab, ranibizumab, aflibercept, and laser treatment as primary therapies for retinopathy of prematurity (ROP) in terms of retreatment rate.
CLINICAL RELEVANCE
Anti-VEGF agents are increasingly used as primary treatment for ROP and may provide superior outcomes compared with laser in posterior disease. Head-to-head comparisons between different anti-VEGFs are lacking.
METHODS
We searched CENTRAL, Embase, MEDLINE, and CINAHL databases for randomized controlled trials and nonrandomized comparative studies that had been reported as of March 2022. We included studies that used bevacizumab, ranibizumab, aflibercept or laser for ROP with comparable cohorts and treatment criteria. Studies were evaluated by the Grading of Recommendations, Assessment, Development and Evaluation framework, and those with biased case selection, nonrandomized case-control, or lack of control group were excluded. Frequentist meta-analyses of proportions determined the absolute primary retreatment rate of each modality and Bayesian network meta-analyses compared pairs of treatments in type 1 and Zone I ROP.
RESULTS
In all, 30 studies (4686 eyes) were included in the network meta-analyses. For type 1 ROP, single-treatment success rates (i.e., likelihood of needing no further treatment) were 89.3% (95% confidence interval [CI]: 83.8%-93.8%; n = 1552) for laser, 87.0% (95% CI: 78.6%-93.8%; n = 2081) for bevacizumab, 80.7% (95% CI: 62.0%-94.4%; n = 326) for aflibercept, and 74.0% (95% CI: 62.7%-84.1%; n = 727) for ranibizumab. Bayesian network meta-analysis indicates that laser treatment is associated with a significant 62% (95% credible interval [CrI]: 16%-83%) reduction in retreatment risk compared with ranibizumab, while no significant difference was found among other pairwise comparisons. The mean ± standard error of the mean times to secondary treatment following primary aflibercept (12.96 ± 0.47 weeks) and bevacizumab (11.36 ± 0.54 weeks) therapy were significantly longer than that for primary ranibizumab (9.29 ± 0.43weeks) therapy (P = 7 × 10 and P = 9 × 10, respectively). For Zone I ROP, single-treatment success rates were 91.2% (95% CI: 83.6-96.9; n = 231) for bevacizumab, 78.3% (95% CI: 61.4-91.9; n = 100) for ranibizumab, and 65.9% (95% CI: 41.4-87.2; n = 158) for laser treatment. In this case, Bayesian network meta-analysis suggests that primary bevacizumab is associated with a significant 67% (95% CrI:10%-90%) reduction in retreatment risk compared with laser treatment.
CONCLUSIONS
Laser was associated with a lower rate of retreatment than ranibizumab in type 1 ROP (Zones I and II combined), while bevacizumab was associated with a lower rate of retreatment than laser in Zone I ROP. Aflibercept and bevacizumab demonstrate longer duration of action than ranibizumab for ROP.
Topics: Humans; Infant, Newborn; Ranibizumab; Bevacizumab; Network Meta-Analysis; Retinopathy of Prematurity; Bayes Theorem; Vascular Endothelial Growth Factor A; Recombinant Fusion Proteins; Angiogenesis Inhibitors; Lasers; Retreatment; Intravitreal Injections; Laser Coagulation
PubMed: 35842190
DOI: 10.1016/j.ophtha.2022.06.042 -
Cancer Treatment Reviews Dec 2022Metastatic triple-negative breast cancer (mTNBC) is a poor prognostic disease with limited treatments and uncertain therapeutic algorithms. We performed a systematic... (Review)
Review
Metastatic triple-negative breast cancer (mTNBC) is a poor prognostic disease with limited treatments and uncertain therapeutic algorithms. We performed a systematic review and multiple Bayesian network meta-analyses according to treatment line to establish an optimal therapeutic sequencing strategy for this lethal disease. We included 125 first-line trials (37,812 patients) and 33 s/further-lines trials (11,321 patients). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rates (ORR), overall survival (OS) and safety, for first and further lines, separately. We also estimated separate treatment rankings for the first and subsequent lines according to each endpoint, based on (surface under the cumulative ranking curve) SUCRA values. No first-line treatment was associated with superior PFS and OS than paclitaxel ± bevacizumab. Platinum-based polychemotherapies were generally superior in terms of ORR, at the cost of higher toxicity.. PARP-inhibitors in germline-BRCA1/2-mutant patients, and immunotherapy + chemotherapy in PD-L1-positive mTNBC, performed similar to paclitaxel ± bevacizumab. In PD-L1-positive mTNBC, pembrolizumab + chemotherapy was better than atezolizumab + nab-paclitaxel in terms of OS according to SUCRA values. In second/further-lines, sacituzumab govitecan outperformed all other treatments on all endpoints, followed by PARP-inhibitors in germline-BRCA1/2-mutant tumors. Trastuzumab deruxtecan in HER2-low mTNBC performed similarly and was the best advanced-line treatment in terms of PFS and OS after sacituzumab govitecan, according to SUCRA values. Moreover, comparisons with sacituzumab govitecan, talazoparib and olaparib were not statistically significant. The most effective alternatives or candidates for subsequent lines were represented by nab-paclitaxel (in ORR), capecitabine (in PFS) and eribulin (in PFS and OS).
Topics: Humans; Triple Negative Breast Neoplasms; Bevacizumab; Poly(ADP-ribose) Polymerase Inhibitors; Network Meta-Analysis; B7-H1 Antigen; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Paclitaxel; Algorithms
PubMed: 36202026
DOI: 10.1016/j.ctrv.2022.102468 -
Nature Communications Apr 2023Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) pathway is a powerful tool to combat tumor growth and progression; however, drug...
Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) pathway is a powerful tool to combat tumor growth and progression; however, drug resistance frequently emerges. We identify CD5L (CD5 antigen-like precursor) as an important gene upregulated in response to antiangiogenic therapy leading to the emergence of adaptive resistance. By using both an RNA-aptamer and a monoclonal antibody targeting CD5L, we are able to abate the pro-angiogenic effects of CD5L overexpression in both in vitro and in vivo settings. In addition, we find that increased expression of vascular CD5L in cancer patients is associated with bevacizumab resistance and worse overall survival. These findings implicate CD5L as an important factor in adaptive resistance to antiangiogenic therapy and suggest that modalities to target CD5L have potentially important clinical utility.
Topics: Humans; Vascular Endothelial Growth Factor A; Bevacizumab; Antibodies, Monoclonal; Neoplasms; Angiogenesis Inhibitors; Apoptosis Regulatory Proteins; Receptors, Scavenger
PubMed: 37100807
DOI: 10.1038/s41467-023-36910-5