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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 -
Annals of Oncology : Official Journal... Aug 2023In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the PAOLA-1/ENGOT-ov25 primary analysis, maintenance olaparib plus bevacizumab demonstrated a significant progression-free survival (PFS) benefit in newly diagnosed advanced ovarian cancer patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab, irrespective of surgical status. Prespecified, exploratory analyses by molecular biomarker status showed substantial benefit in patients with a BRCA1/BRCA2 mutation (BRCAm) or homologous recombination deficiency (HRD; BRCAm and/or genomic instability). We report the prespecified final overall survival (OS) analysis, including analyses by HRD status.
PATIENTS AND METHODS
Patients were randomized 2 : 1 to olaparib (300 mg twice daily; up to 24 months) plus bevacizumab (15 mg/kg every 3 weeks; 15 months total) or placebo plus bevacizumab. Analysis of OS, a key secondary endpoint in hierarchical testing, was planned for ∼60% maturity or 3 years after the primary analysis.
RESULTS
After median follow-up of 61.7 and 61.9 months in the olaparib and placebo arms, respectively, median OS was 56.5 versus 51.6 months in the intention-to-treat population [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.76-1.12; P = 0.4118]. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 105 (19.6%) olaparib patients versus 123 (45.7%) placebo patients. In the HRD-positive population, OS was longer with olaparib plus bevacizumab (HR 0.62, 95% CI 0.45-0.85; 5-year OS rate, 65.5% versus 48.4%); at 5 years, updated PFS also showed a higher proportion of olaparib plus bevacizumab patients without relapse (HR 0.41, 95% CI 0.32-0.54; 5-year PFS rate, 46.1% versus 19.2%). Myelodysplastic syndrome, acute myeloid leukemia, aplastic anemia, and new primary malignancy incidence remained low and balanced between arms.
CONCLUSIONS
Olaparib plus bevacizumab provided clinically meaningful OS improvement for first-line patients with HRD-positive ovarian cancer. These prespecified exploratory analyses demonstrated improvement despite a high proportion of patients in the placebo arm receiving poly(ADP-ribose) polymerase inhibitors after progression, confirming the combination as one of the standards of care in this setting with the potential to enhance cure.
Topics: Humans; Female; Bevacizumab; Ovarian Neoplasms; Antineoplastic Agents; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Maintenance Chemotherapy
PubMed: 37211045
DOI: 10.1016/j.annonc.2023.05.005 -
Targeted Oncology Jul 2023Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have transformed the ovarian cancer (OC) treatment landscape. This narrative review provides a comprehensive... (Review)
Review
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have transformed the ovarian cancer (OC) treatment landscape. This narrative review provides a comprehensive overview of data for the PARPis olaparib, niraparib, and rucaparib in patients with OC and discusses their role in disease management, with a focus on the use of PARPis as maintenance therapy in the United States (US). Olaparib was the first PARPi to be approved as first-line maintenance monotherapy in the US, with maintenance niraparib subsequently approved in the first-line setting. Data also support the efficacy of rucaparib as first-line maintenance monotherapy. PARPi maintenance combination therapy (olaparib plus bevacizumab) also provides benefit in patients with newly diagnosed advanced OC whose tumors tested positive for homologous recombination deficiency (HRD). Biomarker testing is critical in the newly diagnosed setting to identify patients most likely to benefit from PARPi maintenance therapy and guide treatment decisions. Clinical trial data support the use of PARPis (olaparib, niraparib, rucaparib) as second-line or later maintenance therapy in patients with platinum-sensitive relapsed OC. Although distinct differences in tolerability profile were observed between PARPis, they were generally well tolerated, with the majority of adverse events managed by dose modification. PARPis had no detrimental effect on patients' health-related quality of life. Real-world data support the use of PARPis in OC, although some differences between PARPis are apparent. Data from trials investigating novel combination strategies, such as PARPis plus immune checkpoint inhibitors, are awaited with interest; the optimal sequencing of novel therapies in OC remains to be established.
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Quality of Life; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Bevacizumab
PubMed: 37268756
DOI: 10.1007/s11523-023-00970-w -
Journal of Clinical Oncology : Official... Apr 2024In the treatment of non-small-cell lung cancer (NSCLC) with a driver mutation, the role of anti-PD-(L)1 antibody after tyrosine kinase inhibitor (TKI) remains unclear.... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In the treatment of non-small-cell lung cancer (NSCLC) with a driver mutation, the role of anti-PD-(L)1 antibody after tyrosine kinase inhibitor (TKI) remains unclear. This randomized, open-label, multicenter, phase III study evaluates the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in or -mutated NSCLC that progressed before TKI therapy.
MATERIALS AND METHODS
We compared the clinical efficacy of ABCP followed by maintenance therapy with atezolizumab plus bevacizumab with pemetrexed plus carboplatin or cisplatin (PC) followed by pemetrexed maintenance. The primary end point was progression-free survival (PFS).
RESULTS
A total of 228 patients with activating mutation (n = 215) or translocation (n = 13) were enrolled from 16 sites in the Republic of Korea and randomly assigned at 2:1 ratio to either ABCP (n = 154) or PC arm (n = 74). The median follow-up duration was 26.1 months (95% CI, 24.7 to 28.2). Objective response rates (69.5% 41.9%, < .001) and median PFS (8.48 5.62 months, hazard ratio [HR], 0.62 [95% CI, 0.45 to 0.86]; = .004) were significantly better in the ABCP than PC arm. PFS benefit increased as PD-L1 expression increased, with an HR of 0.47, 0.41, and 0.24 for PD-L1 ≥1%, ≥10%, and ≥50%, respectively. Overall survival was similar between ABCP and PC arm (20.63 20.27 months, HR, 1.01 [95% CI, 0.69 to 1.46]; = .975). The safety profile of the ABCP arm was comparable with that previously reported, with no additional safety signals, but higher rates of treatment-related adverse events were observed compared with the PC arm.
CONCLUSION
To our knowledge, this study is the first randomized phase III study to demonstrate the clinical benefit of anti-PD-L1 antibody in combination with bevacizumab and chemotherapy in patients with or -mutated NSCLC who have progressed on relevant targeted therapy.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Bevacizumab; Carboplatin; Lung Neoplasms; B7-H1 Antigen; Pemetrexed; ErbB Receptors; Receptor Protein-Tyrosine Kinases; Antineoplastic Combined Chemotherapy Protocols; Antibodies, Monoclonal, Humanized
PubMed: 37861993
DOI: 10.1200/JCO.23.01891 -
Journal of Clinical Oncology : Official... Oct 2023Platinum-based doublets with concurrent and maintenance bevacizumab are standard therapy for ovarian cancer (OC) relapsing after a platinum-free interval (PFI) >6... (Randomized Controlled Trial)
Randomized Controlled Trial
Atezolizumab Combined With Bevacizumab and Platinum-Based Therapy for Platinum-Sensitive Ovarian Cancer: Placebo-Controlled Randomized Phase III ATALANTE/ENGOT-ov29 Trial.
PURPOSE
Platinum-based doublets with concurrent and maintenance bevacizumab are standard therapy for ovarian cancer (OC) relapsing after a platinum-free interval (PFI) >6 months. Immunotherapy may be synergistic with bevacizumab and chemotherapy.
PATIENTS AND METHODS
ATALANTE/ENGOT-ov29 (ClinicalTrials.gov identifier: NCT02891824), a placebo-controlled double-blinded randomized phase III trial, enrolled patients with recurrent epithelial OC, one to two previous chemotherapy lines, and PFI >6 months. Eligible patients were randomly assigned 2:1 to atezolizumab (1,200 mg once every 3 weeks or equivalent) or placebo for up to 24 months, combined with bevacizumab and six cycles of chemotherapy doublet, stratified by PFI, PD-L1 status, and chemotherapy regimen. Coprimary end points were investigator-assessed progression-free survival (PFS) in the intention-to-treat (ITT) and PD-L1-positive populations (alpha .025 for each population).
RESULTS
Between September 2016 and October 2019, 614 patients were randomly assigned: 410 to atezolizumab and 204 to placebo. Only 38% had PD-L1-positive tumors. After 3 years' median follow-up, the PFS difference between atezolizumab and placebo did not reach statistical significance in the ITT (hazard ratio [HR], 0.83; 95% CI, 0.69 to 0.99; = .041; median 13.5 11.3 months, respectively) or PD-L1-positive (HR, 0.86; 95% CI, 0.63 to 1.16; = .30; median 15.2 13.1 months, respectively) populations. The immature overall survival (OS) HR was 0.81 (95% CI, 0.65 to 1.01; median 35.5 30.6 months with atezolizumab placebo, respectively). Global health-related quality of life did not differ between treatment arms. Grade ≥3 adverse events (AEs) occurred in 88% of atezolizumab-treated and 87% of placebo-treated patients; grade ≥3 AEs typical of immunotherapy were more common with atezolizumab (13% 8%, respectively).
CONCLUSION
ATALANTE/ENGOT-ov29 did not meet its coprimary PFS objectives in the ITT or PD-L1-positive populations. OS follow-up continues. Further research on biopsy samples is warranted to decipher the immunologic landscape of late-relapsing OC.
Topics: Female; Humans; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Bevacizumab; Carcinoma, Ovarian Epithelial; Neoplasm Recurrence, Local; Ovarian Neoplasms; Platinum; Quality of Life
PubMed: 37643382
DOI: 10.1200/JCO.23.00529 -
Liver Cancer Sep 2023Atezolizumab plus bevacizumab therapy is extremely effective in the treatment of intermediate-stage hepatocellular carcinoma (HCC), with a response rate of 44%, as...
Achievement of Complete Response and Drug-Free Status by Atezolizumab plus Bevacizumab Combined with or without Curative Conversion in Patients with Transarterial Chemoembolization-Unsuitable, Intermediate-Stage Hepatocellular Carcinoma: A Multicenter Proof-Of-Concept Study.
INTRODUCTION
Atezolizumab plus bevacizumab therapy is extremely effective in the treatment of intermediate-stage hepatocellular carcinoma (HCC), with a response rate of 44%, as reported in the IMbrave150 trial. When tumor shrinkage is obtained, achieving complete response (CR) is possible in many cases using curative conversion with resection, ablation, or superselective transarterial chemoembolization (TACE) with curative intent. This concept, i.e., curative conversion by combining systemic therapy and locoregional therapy, has not been reported before. This multicenter proof-of-concept study was conducted to show the value of curative conversion in immunotherapy-treated intermediate-stage HCC meeting TACE-unsuitable criteria.
METHODS
This study included 110 consecutive Child-Pugh A patients who received atezolizumab plus bevacizumab as first-line treatment for unresectable and TACE-unsuitable intermediate-stage HCC at seven centers in Japan. CR rate, drug-free rate, time to CR, change in liver function, efficacy in positron emission tomography (PET)-positive HCC, progression-free survival (PFS), and overall survival (OS) were assessed in patients who achieved CR using resection, ablation, superselective TACE with curative intent following atezolizumab plus bevacizumab or atezolizumab plus bevacizumab alone.
RESULTS
Clinical or pathological CR was achieved in 38 patients (35%) (median observation period: 21.2 months). The modalities of curative conversion in 35 patients were as follows: resection, 7; ablation, 13; and superselective TACE, 15. Three patients achieved clinical CR with atezolizumab plus bevacizumab therapy alone. Among the 38 CR patients, 25 achieved drug-free status. PFS was not reached, and 3 patients experienced recurrence after reaching CR. Regarding OS, there were no deaths in any of the CR patients. The albumin-bilirubin score did not deteriorate after locoregional therapy or resection. Of seven PET-positive patients who achieved CR with atezolizumab plus bevacizumab followed by curative conversion, five achieved drug-free status.
CONCLUSION
The achievement of CR rate by curative conversion in patients treated with atezolizumab plus bevacizumab as the preceding therapy for unresectable and TACE-unsuitable intermediate-stage HCC was 35%. Overall, 23% of patients achieved drug-free status and no recurrence was observed from this patient subgroup with CR and drug-free status. Thus, achieving CR and/or drug-free status should be a therapeutic goal for patients with intermediate-stage HCC without vascular invasion or extrahepatic spread.
PubMed: 37901197
DOI: 10.1159/000529574 -
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 -
Drug Design, Development and Therapy 2023Degenerative eye conditions such as age-related macular degeneration (AMD), diabetic retinopathy, and retinal vein occlusion are major contributors to significant vision... (Review)
Review
Degenerative eye conditions such as age-related macular degeneration (AMD), diabetic retinopathy, and retinal vein occlusion are major contributors to significant vision loss in developed nations. The primary therapeutic approach for managing complications linked to these diseases involves the intravitreal delivery of anti-vascular endothelial growth factor (VEGF) treatments. Faricimab is a novel, humanised, bispecific antibody that simultaneously binds all VEGF-A isoforms and Angiopoietin-2, which has been approved by regulatory agencies, such as the US Food and Drug Administration (FDA), the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA), for the treatment of neovascular AMD and diabetic macular oedema (DMO). Intravitreal faricimab holds the promise of reducing the treatment burden for patients with these conditions by achieving comparable or superior therapeutic outcomes with fewer clinic visits. The scope of faricimab's application includes addressing complex macular conditions such as DMO. This review intends to elucidate the distinctive pharmacological characteristics of faricimab and provide an overview of the key clinical trials and real-world studies that assess its effectiveness and safety in treating degenerative macular diseases.
Topics: Humans; Vascular Endothelial Growth Factor A; Ranibizumab; Angiogenesis Inhibitors; Bevacizumab; Receptors, Vascular Endothelial Growth Factor; Visual Acuity; Wet Macular Degeneration; Macular Edema; Diabetic Retinopathy; Intravitreal Injections
PubMed: 37746113
DOI: 10.2147/DDDT.S427416