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ESMO Open Dec 2022A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy.
BACKGROUND
A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy.
MATERIALS AND METHODS
We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population.
RESULTS
One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed.
CONCLUSIONS
The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.
Topics: Humans; Sorafenib; Carcinoma, Hepatocellular; Bevacizumab; Non-alcoholic Fatty Liver Disease; Propensity Score; Retrospective Studies; Liver Neoplasms
PubMed: 36208496
DOI: 10.1016/j.esmoop.2022.100591 -
JAMA Network Open Aug 2023Although bevacizumab has been used in the treatment of ovarian cancer, its optimal use is unknown.
IMPORTANCE
Although bevacizumab has been used in the treatment of ovarian cancer, its optimal use is unknown.
OBJECTIVE
To investigate time-dependent changes in the outcomes of bevacizumab therapy.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study was conducted using published data from 7 previous randomized phase 3 clinical trials with bevacizumab (ICON7, GOG-0218, BOOST, GOG-0213, OCEANS, AURERIA, and MITO16B) from January 10 to January 31, 2023. From 2 ancillary analyses of the ICON7 trial with individual patient data and tumor gene expression profiles, an ICON7-A cohort was generated comprising 745 cases. From other studies, published Kaplan-Meier curves were graphically analyzed.
EXPOSURES
Bevacizumab treatment vs placebo or no treatment.
MAIN OUTCOMES AND MEASURES
Restricted mean survival time and relative risk of progression at a given time point between bevacizumab treatment and control groups.
RESULTS
In the ICON7-A cohort (n = 745), restricted mean survival analysis showed that bevacizumab treatment (n = 384) had significantly better progression-free survival (PFS) than the control (n = 361) before bevacizumab discontinuation (restricted mean survival time ratio, 1.08; 95% CI, 1.05-1.11; P < .001), but had significantly worse PFS after bevacizumab discontinuation (0.79; 95% CI, 0.69-0.90; P < .001), showing rebound. In a post hoc analysis, the rebound was similarly observed both in homologous recombination deficiency (HRD) (before, 1.05; 95% CI, 1.02-1.09; P < .001; after, 0.79; 95% CI, 0.63-0.98; P = .04) and non-HRD tumors (before, 1.08; 95% CI, 1.03-1.15; P < .001; after, 0.71; 95% CI, 0.56-0.90; P < .001) of the serous subtype, but not in the nonserous subtype (before, 1.11; 95% CI, 1.05-1.18; P < .001; after, 0.94; 95% CI, 0.78-1.15; P = .57). In Kaplan-Meier curve image-based analysis, the trend of rebound effect was consistently observed in the overall ICON7 and GOG-0218 cohorts and their subgroups stratified by prognostic factors, homologous recombination-associated mutations, and chemotherapy sensitivity. In contrast, no such trend was observed in the studies GOG-0213, OCEANS, AURERIA, and MITO16B, in which patients who experienced relapse received bevacizumab until progression.
CONCLUSIONS AND RELEVANCE
In ovarian cancer, bevacizumab may reduce progression for approximately 1 year after initiation, but discontinuation may increase subsequent progression in the serous subtype regardless of HRD status. The results suggest that in the first-line treatment, bevacizumab may be more beneficial in patients with a shorter prognosis who are less likely to experience the rebound outcome.
Topics: Humans; Female; Bevacizumab; Cohort Studies; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Recurrence, Local; Ovarian Neoplasms
PubMed: 37531111
DOI: 10.1001/jamanetworkopen.2023.26834 -
Cancer Research Nov 2023Bevacizumab is an anti-VEGF monoclonal antibody that plays an important role in the combination treatment of advanced colorectal cancer. However, resistance remains a...
UNLABELLED
Bevacizumab is an anti-VEGF monoclonal antibody that plays an important role in the combination treatment of advanced colorectal cancer. However, resistance remains a major hurdle limiting bevacizumab efficacy, highlighting the importance of identifying a mechanism of antiangiogenic therapy resistance. Here, we investigated biophysical properties of the extracellular matrix (ECM) related to metabolic processes and acquired resistance to bevacizumab. Evaluation of paired pre- and posttreatment samples of liver metastases from 20 colorectal cancer patients treated with combination bevacizumab therapy, including 10 responders and 10 nonresponders, indicated that ECM deposition in liver metastases and a highly activated fatty acid oxidation (FAO) pathway were elevated in nonresponders after antiangiogenic therapy compared with responders. In mouse models of liver metastatic colorectal cancer (mCRC), anti-VEGF increased ECM deposition and FAO in colorectal cancer cells, and treatment with the FAO inhibitor etomoxir enhanced the efficacy of antiangiogenic therapy. Hepatic stellate cells (HSC) were essential for matrix stiffness-mediated FAO in colon cancer cells. Matrix stiffness activated lipolysis in HSCs via the focal adhesion kinase (FAK)/yes-associated protein (YAP) pathway, and free fatty acids secreted by HSCs were absorbed as metabolic substrates and activated FAO in colon cancer cells. Suppressing HSC lipolysis using FAK and YAP inhibition enhanced the efficacy of anti-VEGF therapy. Together, these results indicate that bevacizumab-induced ECM remodeling triggers lipid metabolic cross-talk between colon cancer cells and HSCs. This metabolic mechanism of bevacizumab resistance mediated by the physical tumor microenvironment represents a potential therapeutic target for reversing drug resistance.
SIGNIFICANCE
Extracellular matrix stiffening drives bevacizumab resistance by stimulating hepatic stellate cells to provide fuel for mCRC cells in the liver, indicating a potential metabolism-based therapeutic strategy for overcoming resistance.
Topics: Animals; Mice; Humans; Bevacizumab; Liver Neoplasms; Colorectal Neoplasms; Colonic Neoplasms; Stromal Cells; Lipids; Tumor Microenvironment
PubMed: 37610655
DOI: 10.1158/0008-5472.CAN-23-0025 -
Clinical Pharmacokinetics Nov 2016Clinical response to bevacizumab varies between patients treated for metastatic colorectal cancer (mCRC). The aim of this study was to quantify individual factors... (Observational Study)
Observational Study
OBJECTIVE
Clinical response to bevacizumab varies between patients treated for metastatic colorectal cancer (mCRC). The aim of this study was to quantify individual factors affecting bevacizumab pharmacokinetic variability and assess the relationship between bevacizumab concentrations and clinical outcomes.
METHODS
Bevacizumab pharmacokinetics were assessed in 130 mCRC patients using a two-compartment pharmacokinetic population model. Overall and progression-free survival (PFS) were analyzed using Cox models.
RESULTS
The bevacizumab volume of distribution increased with height (p = 10) and was higher in patients with a 3/3 variable number tandem repeat of the FCGRT (Fc fragment of IgG receptor and transporter) gene (p = 0.039). The elimination rate constant increased with baseline carcinoembryonic antigen (CEA) and vascular endothelial growth factor (VEGF) concentrations, and was higher in patients with extra-hepatic metastases (p = 0.00029, 0.011, and 0.014). A bevacizumab trough concentration ≤15.5 mg/L was associated with both shorter overall survival and PFS (hazard ratio [95 % CI] 1.90 [1.20-2.99] and 1.76 [1.20-2.58], respectively).
CONCLUSION
High tumour burden is associated with low bevacizumab concentrations, and high bevacizumab concentration are associated with both decreased overall and progression-free survivals.
Topics: Aged; Angiogenesis Inhibitors; Bevacizumab; Carcinoembryonic Antigen; Colorectal Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Liver Neoplasms; Male; Middle Aged; Models, Biological; Polymorphism, Genetic; Vascular Endothelial Growth Factor A
PubMed: 27312193
DOI: 10.1007/s40262-016-0406-3 -
Journal of Vascular Research 2022Tumors induce angiogenesis to acquire oxygen and nutrition from their adjacent microenvironment. Tumor angiogenesis has been believed to be induced primarily by the... (Review)
Review
Tumors induce angiogenesis to acquire oxygen and nutrition from their adjacent microenvironment. Tumor angiogenesis has been believed to be induced primarily by the secretion of vascular endothelial growth factor-A (VEGF-A) from various tumors. VEGF-A binds to VEGF receptor 2 (VEGFR2), resulting in subsequent activation of cellular substances regulating cell proliferation, survival, and angiogenesis. Antiangiogenic therapies targeting the VEGF-A/VEGFR2 axis, including bevacizumab and ramucirumab, humanized monoclonal antibodies against VEGF-A and VEGFR2, respectively, have been proposed as a promising strategy aimed at preventing tumor growth, invasion, and metastasis. Phase III clinical trials using bevacizumab and ramucirumab have shown that not all tumor patients benefit from such antiangiogenic agents, and that some patients who initially benefit subsequently become less responsive to these antibodies, suggesting the possible existence of VEGF-independent angiogenic factors. In this review, we focus on VEGF-independent and VEGFR2-dependent tumor angiogenesis, as well as VEGFR2-independent tumor angiogenesis. Additionally, we discuss VEGF-independent angiogenic factors which have been reported in previous studies. Various molecular targeting drugs are currently being evaluated as potential antitumor therapies. We expect that precision medicine will permit the development of innovative antiangiogenic therapies targeting individual angiogenic factors selected on the basis of the genetic screening of tumors.
Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Bevacizumab; Humans; Neoplasms; Neovascularization, Pathologic; Tumor Microenvironment; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 35152220
DOI: 10.1159/000521584 -
Nature Communications Nov 2023Atezolizumab (anti-PD-L1) combined with bevacizumab (anti-VEGFA) is the first-line immunotherapy for advanced hepatocellular carcinoma (HCC), but the number of patients...
Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8 exhausted-like T cells.
Atezolizumab (anti-PD-L1) combined with bevacizumab (anti-VEGFA) is the first-line immunotherapy for advanced hepatocellular carcinoma (HCC), but the number of patients who benefit from this regimen remains limited. Here, we combine dual PD-L1 and VEGFA blockade (DPVB) with low-dose radiotherapy (LDRT), which rapidly inflames tumors, rendering them vulnerable to immunotherapy. The combinatorial therapy exhibits superior antitumor efficacy mediated by CD8 T cells in various preclinical HCC models. Treatment efficacy relies upon mobilizing exhausted-like CD8 T cells (CD8 Tex) with effector function and cytolytic capacity. Mechanistically, LDRT sensitizes tumors to DPVB by recruiting stem-like CD8 Tpex, the progenitor exhausted CD8 T cells, from draining lymph nodes (dLNs) into the tumor via the CXCL10/CXCR3 axis. Together, these results further support the rationale for combining LDRT with atezolizumab and bevacizumab, and its clinical translation.
Topics: Humans; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; B7-H1 Antigen; Liver Neoplasms; Bevacizumab; Cell Line, Tumor; Vascular Endothelial Growth Factor A
PubMed: 38001101
DOI: 10.1038/s41467-023-43462-1 -
Retina (Philadelphia, Pa.) Dec 2022Anti-vascular endothelial growth factor therapies have proven effective in treating retinal diseases but come with a high financial burden to the patient and health care... (Review)
Review
BACKGROUND/PURPOSE
Anti-vascular endothelial growth factor therapies have proven effective in treating retinal diseases but come with a high financial burden to the patient and health care system. Biosimilar drugs present an opportunity to decrease the cost of these important ophthalmic medications, and several ophthalmic biosimilars are expected to be approved and enter the market in the coming years. The objectives of this review are to educate ophthalmologists on the safety and efficacy of biosimilars in ophthalmology in the United States and European Union, review the biosimilar manufacturing and approval process, and describe the upcoming ophthalmic biosimilars.
RESULTS
Two ranibizumab biosimilars are currently approved in the United States and European Union. Additional ranibizumab biosimilars, as well as biosimilars for aflibercept and bevacizumab, are currently in clinical development.
CONCLUSION
Biosimilar use in ophthalmology is expected to grow with the patent expiration of two major anti-vascular endothelial growth factor drugs, ranibizumab and aflibercept, and the development of an ophthalmology-specific bevacizumab biosimilar. Financial savings from biosimilar use in ophthalmology have the potential to reduce economic burden, increase treatment adherence, and ultimately improve health outcomes.
Topics: United States; Humans; Biosimilar Pharmaceuticals; Endothelial Growth Factors; Ophthalmology; Bevacizumab; Ranibizumab
PubMed: 36394884
DOI: 10.1097/IAE.0000000000003626 -
International Journal of Molecular... Jul 2023A combination of atezolizumab with bevacizumab (AB) is the first regimen that has shown superiority compared to sorafenib and is now being used as the systemic treatment... (Review)
Review
A combination of atezolizumab with bevacizumab (AB) is the first regimen that has shown superiority compared to sorafenib and is now being used as the systemic treatment of choice for hepatocellular carcinoma (HCC) patients with Barcelona Liver Cancer Clinic stage C. However, a considerable number of patients do not achieve survival or significant responses, indicating the need to identify predictive biomarkers for initial and on-treatment decisions in HCC patients receiving AB. In this manuscript, we summarized the current data from both experimental and clinical studies. This review will be beneficial for both clinicians and researchers in clinical practice as well as those designing experimental, translational, or clinical studies.
Topics: Humans; Bevacizumab; Carcinoma, Hepatocellular; Liver Neoplasms; Antibodies, Monoclonal, Humanized
PubMed: 37511558
DOI: 10.3390/ijms241411799 -
World Journal of Gastroenterology Mar 2023Hepatocellular carcinoma (HCC) is most commonly found in the context of liver cirrhosis and, in rare cases, in a healthy liver. Its prevalence has risen in recent years,... (Review)
Review
Hepatocellular carcinoma (HCC) is most commonly found in the context of liver cirrhosis and, in rare cases, in a healthy liver. Its prevalence has risen in recent years, particularly in Western nations, due to the increasing frequency of non-alcoholic fatty liver disease. Advanced HCC has a poor prognosis. For many years, the only proven therapy for unresectable HCC (uHCC) was sorafenib, a tyrosine kinase inhibitor. Recently, the synergistic effect of an immune checkpoint inhibitor, atezolizumab, and bevacizumab outperformed sorafenib alone in terms of survival, making it the recommended first-line therapy. Other multikinase inhibitors, lenvatinib and regorafenib, were also recommended as first and second-line drugs, respectively. Intermediate-stage HCC patients with retained liver function, particularly uHCC without extrahepatic metastasis, may benefit from trans-arterial chemoembolization. The current problem in uHCC is selecting a patient for the best treatment while considering the preexisting liver condition and liver function. Indeed, all study patients had a Child-Pugh class A, and the best therapy for other individuals is unknown. Additionally, in the absence of a medical contraindication, atezolizumab could be combined with bevacizumab for uHCC systemic therapy. Several studies are now underway to evaluate immune checkpoint inhibitors in combination with anti-angiogenic drugs, and the first findings are encouraging. The paradigm of uHCC therapy is changing dramatically, and many obstacles remain for optimum patient management in the near future. The purpose of this commentary review was to give an insight into current systemic treatment options for patients with uHCC who are not candidates for surgery to cure the disease.
Topics: Humans; Carcinoma, Hepatocellular; Sorafenib; Bevacizumab; Liver Neoplasms; Immune Checkpoint Inhibitors
PubMed: 36970588
DOI: 10.3748/wjg.v29.i10.1551 -
Indian Journal of Pharmacology 2019Vascular endothelial growth factor (VEGF) inhibitors, ranibizumab, aflibercept, and pegaptanib are approved treatments for certain eye diseases that occurs especially in... (Review)
Review
Vascular endothelial growth factor (VEGF) inhibitors, ranibizumab, aflibercept, and pegaptanib are approved treatments for certain eye diseases that occurs especially in the elderly. These drugs are mostly inaccessible due to their high cost. Bevacizumab is a VEGF inhibitor, approved for cancer treatment. Being a cheaper alternative, it is extensively used off-label as an intravitreal injection for the treatment of eye diseases. In this article, we have analyzed similarities and differences between bevacizumab and ranibizumab, and potential long-term safety concerns with off-label use of bevacizumab. We also analyzed legal, regulatory, and ethical background of off-label use and provided recommendations to resolve this issue. Based on the extensive clinical data, actions taken, and recommendations provided by agencies such as the National Institute for Health and Care Excellence, International Council of Ophthalmology, United Kingdom and Thailand regulatory agency, intravitreal bevacizumab has adequate evidence for controlled licensing. Claiming better safety for ranibizumab at the expense of nonaffordability cannot be considered a positive risk-benefit scenario. Intravitreal bevacizumab is being used and will continue to be used off-label, if not regulatory controlled. Licensing will ensure the availability of intravitreal bevacizumab to the patients with eye diseases, without any legal or ethical concerns for the clinicians, and will also assist in generating long-term safety data. Safest delivery formulation and dosage form should be considered for approval. Both the regulatory agency and technical experts should join and take critical decision, which will be a big step forward to making a cost-effective drug available to the public.
Topics: Angiogenesis Inhibitors; Animals; Bevacizumab; Eye Diseases; Humans; Intravitreal Injections; Legislation, Drug; Off-Label Use; Pharmacovigilance; Ranibizumab; Thailand
PubMed: 32029959
DOI: 10.4103/ijp.IJP_413_19