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Due to its anti-angiogenic properties, trebananib is frequently employed in the treatment of cancer patients, particularly those with ovarian cancer. We conducted a meta-analysis to assess the efficacy and safety profile of trebananib in combination with other drugs for treating both ovarian and non-ovarian cancer patients. Our search encompassed PubMed, Medline, Cochrane, and Embase databases, with a focus on evaluating study quality. Data extraction was conducted from randomized controlled trials (RCTs), and RevMan 5.3 facilitated result analysis. Combining trebananib with other drugs extended progression-free survival (PFS) [HR 0.81, (95%CI: 0.65, 0.99), p = 0.04] and overall survival (OS) [HR 0.88, (95%CI: 0.79, 1.00), p = 0.04] in ovarian cancer patients. Ovarian cancer patients exhibited a higher objective response rate (ORR) with trebananib compared to non-ovarian cancer cohorts. Moreover, the incorporation of trebananib into the standard treatment regimen for malignant tumors did not significantly elevate drug-related adverse events [RR 1.05, (95% CI: 1.00, 1.11), p = 0.05]. Trebananib plus other drugs can improve the PFS, OS and ORR in patients with cancer, especially ovarian cancer. Our recommendation is to use trebananib plus other drugs to treat advanced cancer, and to continuously monitor and manage drug-related adverse events. PROSPERO (No. CRD42023466988) [ABSTRACT FROM AUTHOR]

Aggressive hepatocellular carcinoma (HCC) overexpressing Angiopoietin-2 (ANG-2) (a protein linked with angiogenesis, proliferation, and epithelial–mesenchymal transition (EMT)), shares 95% of up-regulated genes and a similar poor prognosis with the proliferative subgroup of intrahepatic cholangiocarcinoma (iCCA). We analyzed the pro-invasive effect of ANG-2 and its regulator vascular endothelial growth factor (VEGF) on HCC and CCA spheroids to uncover posUsible common ways of response. Four cell lines were used: Hep3B and HepG2 (HCC), HuCC-T1 (iCCA), and EGI-1 (extrahepatic CCA). We treated the spheroids with recombinant human (rh) ANG-2 and/or VEGF and then observed the changes at the baseline, after 24 h, and again after 48 h. Proangiogenic stimuli increased migration and invasion capability in HCC- and iCCA-derived spheroids and were associated with a modification in EMT phenotypic markers (a decrease in E-cadherin and an increase in N-cadherin and Vimentin), especially at the migration front. Inhibitors targeting ANG-2 (Trebananib) and the VEGF (Bevacizumab) effectively blocked the migration ability of spheroids that had been stimulated with rh-ANG-2 and rh-VEGF. Overall, our findings highlight the critical role played by ANG-2 and the VEGF in enhancing the ability of HCC- and iCCA-derived spheroids to migrate and invade, which are key processes in cancer progression. [ABSTRACT FROM AUTHOR]

PurposeTrebananib, a peptibody that blocks binding of angiopoietin-1 and -2 to Tie2, significantly prolonged progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer in the phase 3 TRINOVA-1 study. We report overall survival (OS) in the intent-to-treat population and clinically relevant subgroups and time to second disease progression (PFS-2).Patients and methodsWomen with recurrent disease (platinum-free interval

Angiogenesis is a known hallmark in cancer and plays a crucial role in ovarian cancer carcinogenesis and invasion. Anti- angiogenic agents are active in ovarian cancer treatment either as monotherapy or combined with chemotherapy, immunotherapy or poly ADP ribose polymerase (PARP) inhibitors. We review the mechanism of action, clinical activity and safety profile of the most important drugs either in the actual treatment or in current evaluation in the ovarian cancer treatment scenario (neoadjuvant, first line and relapse).

Despite survival gains achieved nearly two decades ago with combination platinum- and taxane-based intravenous chemotherapy, overall survival curves have remained relatively unchanged during the 21st century using newer cytotoxic agents. Although combined intravenous-intraperitoneal (IV-IP) chemotherapy is promising, tolerability remains a significant issue. An emphasis has been placed on exploring dose dense schedules and targeted agents. Vascular endothelial growth factor (VEGF) has emerged as an important therapeutic target in several solid tumors including ovarian carcinoma. The monoclonal antibody, bevacizumab, binds VEGF, thus preventing activation of the VEGF receptor (VEGFR) leading to inhibition of tumor angiogenesis. To date eight phase 3 randomized controlled trials incorporating anti-angiogenesis therapy in the treatment of newly diagnosed and recurrent ovarian carcinoma have met their primary endpoints. Four of these trials included bevacizumab and were reported from 2010 to 2012. During 2013, the other four studies were reported, each studying one of the following novel anti-angiogenesis agents: pazopanib, cediranib, trebananib, and nintedanib. Importantly, none of these drugs have been approved by the United States Food and Drug Administration (US FDA) for the treatment of ovarian cancer. The purpose of this review will be to highlight both VEGF-dependent and non-VEGF dependent angiogenic pathways in ovarian cancer and discuss the phase 3 experiences and regulatory implications of targeting the tumor microenviroment with anti-angiogenesis therapy.

Background: Targeting vascular endothelial growth factor (VEGF) alone does not improve overall survival (OS) in recurrent glioblastoma (rGBM). The angiopoiein (Ang)-TIE2 system may play a role in tumor survival under VEGF inhibition. We conducted a phase 2, double-blinded, placebo-controlled trial of bevacizumab plus trebananib (a novel Fc fusion protein that sequesters Ang1/Ang2) over bevacizumab alone in rGBM.Methods: Patients ≥18 years of age with a Karnofsky performance status ≥70 and GBM or variants in first or second relapse were randomized to bevacizumab 10 mg/kg every 2 weeks plus trebananib 15 mg/kg every week or bevacizumab plus placebo. The primary endpoint was 6-month progression-free survival (PFS).Results: After an initial 6-patient lead-in cohort confirmed the safety of combining bevacizumab and trebananib, 115 eligible patients were randomized to the control (n = 58) or experimental treatment (n = 57). In the control arm, 6-month PFS was 41.1%, median survival time was 11.5 months (95% CI, 8.4-14.2 months), median PFS was 4.8 months (95% CI, 3.8-7.1 months), and radiographic response (RR) was 5.9%. In the experimental arm, 6-month PFS was 22.6%, median survival time was 7.5 months (95% CI, 6.8-10.1 months), median PFS was 4.2 months (95% CI, 3.7-5.6 months), and RR was 4.2%. The rate of severe toxicities was not significantly different between arms.Conclusion: The combination of bevacizumab and trebananib was well tolerated but did not significantly improve 6-month PFS rate, PFS, or OS for patients with rGBM over bevacizumab alone. The shorter PFS in the experimental arm with a hazard ratio of 1.51 (P = .04) suggests that the addition of trebananib to bevacizumab is detrimental. [ABSTRACT FROM AUTHOR]

Aggressive hepatocellular carcinoma (HCC) overexpressing Angiopoietin-2 (ANG-2) (a protein linked with angiogenesis, proliferation, and epithelial-mesenchymal transition (EMT)), shares 95% of up-regulated genes and a similar poor prognosis with the proliferative subgroup of intrahepatic cholangiocarcinoma (iCCA). We analyzed the pro-invasive effect of ANG-2 and its regulator vascular endothelial growth factor (VEGF) on HCC and CCA spheroids to uncover posUsible common ways of response. Four cell lines were used: Hep3B and HepG2 (HCC), HuCC-T1 (iCCA), and EGI-1 (extrahepatic CCA). We treated the spheroids with recombinant human (rh) ANG-2 and/or VEGF and then observed the changes at the baseline, after 24 h, and again after 48 h. Proangiogenic stimuli increased migration and invasion capability in HCC- and iCCA-derived spheroids and were associated with a modification in EMT phenotypic markers (a decrease in E-cadherin and an increase in N-cadherin and Vimentin), especially at the migration front. Inhibitors targeting ANG-2 (Trebananib) and the VEGF (Bevacizumab) effectively blocked the migration ability of spheroids that had been stimulated with rh-ANG-2 and rh-VEGF. Overall, our findings highlight the critical role played by ANG-2 and the VEGF in enhancing the ability of HCC- and iCCA-derived spheroids to migrate and invade, which are key processes in cancer progression.

Aims Trebananib, a peptide-Fc fusion protein, inhibits angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. This randomised, double-blind, placebo-controlled phase 3 study evaluated whether trebananib plus pegylated liposomal doxorubicin (PLD) improved progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer. Methods Women with recurrent ovarian cancer (platinum-free interval ≤12 months) were randomised to intravenous PLD 50 mg/m 2 once every 4 weeks plus weekly intravenous trebananib 15 mg/kg or placebo. PFS was the primary end-point; key secondary end-points were objective response rate (ORR) and duration of response (DOR). Owing to PLD shortages, enrolment was paused for 13 months; the study was subsequently truncated. Results Two hundred twenty-three patients were enrolled. Median PFS was 7.6 months (95% CI, 7.2–9.0) in the trebananib arm and 7.2 months (95% CI, 4.8–8.2) in the placebo arm, with a hazard ratio of 0.92 (95% CI, 0.68–1.24). However, because the proportional hazards assumption was not fulfilled, the standard Cox model did not provide a reliable estimate of the hazard ratio. ORR in the trebananib arm was 46% versus 21% in the placebo arm (odds ratio, 3.43; 95% CI, 1.78–6.64). Median DOR was improved (trebananib, 7.4 months [95% CI, 5.7–7.6]; placebo, 3.9 months [95% CI, 2.3–6.5]). Adverse events with a greater incidence in the trebananib arm included localised oedema (61% versus 32%), ascites (29% versus 9%) and vomiting (45% versus 33%). Conclusions Trebananib demonstrated anticancer activity in this phase 3 study, indicated by improved ORR and DOR. Median PFS was not improved. No new safety signals were identified. Trial registration: ClinicalTrials.gov , NCT01281254 [ABSTRACT FROM AUTHOR]

In addition to the monoclonal vascular endothelial growth factor (VEGF) antibody bevacizumab, several alternative anti-angiogenic treatment strategies for ovarian cancer patients have been evaluated in clinical trials. Apart from targeting extracellular receptors by the antibody aflibercept or the peptibody trebananib, the multikinase inhibitors pazopanib, nintedanib, cediranib, sunitinib, and sorafenib were developed to interfere with VEGF receptors and multiple additional intracellular pathways. Nintedanib and pazopanib significantly improved progression-free survival in two positive phase III trials for firstline therapy. A reliable effect on overall survival could, however, not be observed for any anti-angiogenic firstline therapies so far. In terms of recurrent disease, two positive phase III trials revealed that trebananib and cediranib are effective anti-angiogenic agents for this indication. Patient selection and biomarker guided prediction of response seems to be a central aspect for future studies. Combining anti-angiogenics with other targeted therapies to possibly spare chemotherapy in certain constellations, represents another very interesting future perspective for clinical trials. This short review gives an overview of current clinical trials for anti-angiogenic treatment strategies beyond bevacizumab. In this context, possible future perspectives combining anti-angiogenics with other targeted therapies and the need for specific biomarkers predicting response are elucidated.

Background: To evaluate the influence of treatment on health-related quality of life (HRQoL) in 919 women with recurrent ovarian cancer enrolled in the TRINOVA-1 study, a randomized, placebo-controlled phase III study that demonstrated that trebananib 15 mg/kg QW plus weekly paclitaxel significantly improved progression-free survival (PFS) compared with placebo plus weekly paclitaxel (7.2 versus 5.4 months; hazard ratio, 0.66; 95% confidence interval 0.57-0.77; P < 0.001). Patients and methods: HRQoL was assessed with the Functional Assessment of Cancer Therapy-Ovary [FACT-O; comprising FACT-G and the ovarian cancer-specific subscale (OCS)] and EuroQOL EQ-5D instruments before treatment on day 1 of weeks 1, 5, 9, 13, 17, and every 8 weeks thereafter and at the safety follow-up visit. A pattern-mixture model was used to evaluate the influence of patient dropout on FACT-O and OCS scores over time. Results: Of 919 randomized patients, 834 (91%) had a baseline and ≥1 post-baseline HRQoL assessment. At baseline, scores for all instruments were similar for both arms. At 25 weeks, mean ± SD changes from baseline were negligible, with mean ± SD changes typically <1 unit from baseline: -2.4 ± 16.6 in the trebananib arm and -1.6 ± 15.2 in the placebo arm for FACT-O, -0.71 ± 5.5 in the trebananib arm and -0.86 ± 4.9 in the placebo arm for OCS, and -0.02 ± 0.22 in the trebananib arm and 0.02 ± 0.19 in the placebo arm for EQ-5D. Distribution of scores was similar between treatment arms at baseline and over the course of the study. In pattern-mixture models, there was no evidence that patient dropout affected differences in mean FACT-O or OCS scores. Edema had limited effect on either FACT-O or OCS scores in patients with grade ≥2 edema or those with grade 1 or no edema. Conclusions: Our results demonstrate that the improvement in PFS among patients in the trebananib arm in the TRINOVA-1 study was achieved without compromising HRQoL. [ABSTRACT FROM AUTHOR]

Angiogenesis plays a pivotal role in normal ovarian physiology as well as in the progression of ovarian cancer through ascites formation and metastatic spread. Bevacizumab (Avastin®, Genentech; South San Francisco, CA, USA), a humanized antivascular endothelial growth factor (VEGF) monoclonal antibody, is the most widely studied anti-angiogenesis agent both across tumor types and specifically in epithelial ovarian cancer. In 2005, single-agent bevacizumab at 15 mg/kg (IV) every 3 weeks was first reported to be active in a case of recurrent high-grade serous ovarian cancer after failing 11th line cytotoxic treatment. Since then, many case series, phase II and phase III trials have confirmed these results leading to regulatory approval in most countries including the US Food and Drug Administration in 2014. Guidelines now give clear recommendations as to when and how bevacizumab should be integrated into the ovarian cancer treatment paradigm. Other anti-VEGF agents such as the VEGF receptor (VEGFR) tyrosine kinase inhibitors have not shown increased activity or reduced toxicity relative to bevacizumab. However, anti-angiogenics other than anti-VEGF/VEGFR agents such as those targeting Angiopoietin-1 and -2 are in development as well as novel combinations with vascular disrupting agents (VDAs), PARP inhibitors and immune checkpoint inhibitors. Clearly, the benefits of anti-angiogenic agents such as bevacizumab must be carefully weighed against the cost and associated toxicities. Although almost all patients with ovarian cancer will receive an anti-angiogenic compound, cures are not increased. Predictive biomarkers are an urgent unmet need. [ABSTRACT FROM AUTHOR]

In addition to the monoclonal vascular endothelial growth factor (VEGF) antibody bevacizumab, several alternative anti-angiogenic treatment strategies for ovarian cancer patients have been evaluated in clinical trials. Apart from targeting extracellular receptors by the antibody aflibercept or the peptibody trebananib, the multikinase inhibitors pazopanib, nintedanib, cediranib, sunitinib, and sorafenib were developed to interfere with VEGF receptors and multiple additional intracellular pathways. Nintedanib and pazopanib significantly improved progression-free survival in two positive phase III trials for first-line therapy. A reliable effect on overall survival could, however, not be observed for any anti-angiogenic first-line therapies so far. In terms of recurrent disease, two positive phase III trials revealed that trebananib and cediranib are effective anti-angiogenic agents for this indication. Patient selection and biomarker guided prediction of response seems to be a central aspect for future studies. Combining anti-angiogenics with other targeted therapies to possibly spare chemotherapy in certain constellations represents another very interesting future perspective for clinical trials. This short review gives an overview of current clinical trials for anti-angiogenic treatment strategies beyond bevacizumab. In this context, possible future perspectives combining anti-angiogenics with other targeted therapies and the need for specific biomarkers predicting response are elucidated. [ABSTRACT FROM AUTHOR]

Objectives Ang1 & 2 (angiopoietin-1; − 2) interact with Tie2 receptors on endothelial cells to mediate vascular remodeling in an angiogenesis signaling pathway distinct from the VEGF axis. Trebananib is a peptide Fc fusion protein that binds Ang1 and 2 and prevents interaction with Tie2. The efficacy of trebananib in recurrent/persistent endometrial cancer (EC) was studied. Methods The primary objective was to determine the frequency of patients with objective tumor responses (ORR) and event-free survival for ≥ 6 months (6-month EFS) and determine toxicity of trebananib at a dose and schedule of 15 mg/kg, IV QW. Recurrent/persistent EC, measurable disease, and ≤ 2 prior chemotherapy lines were required. Results Thirty-two patients were eligible and treated. The most common histologies were G1/2 endometrioid (31%), G3 endometrioid (28%) and serous (31.3%). 78% of patients had 1 prior regimen. Patients received 1–9 + cycles of trebananib; 24 patients (75%) received ≤ 2 cycles. One patient had a partial response (3.1%); 8 patients had stable disease (25%) and 5 patients (15.6%) had 6 month EFS. Median progression-free survival and overall-survival were 1.97 months (90% CI 1.77–2.1) and 6.6 months (90% CI 4.01–14.75), respectively. Most common adverse events (AEs) were fatigue, anemia, and GI issues. Grade 3 and 4 AEs were: GI 31 and 0%; vascular 22 and 0%; metabolism/nutrition 19 and 3%; and general (including edema) 16 and 0%. Conclusions Trebananib has insufficient single agent activity in recurrent EC to warrant further investigation at this dose/schedule. [ABSTRACT FROM AUTHOR]

Ovarian cancer is a multifaceted and genomically complex disease and has emerged as leading cause of death among gynecological malignancies. Gold-standard treatment consisted of cytoreductive surgery and paclitaxel–carboplatin chemotherapy. Recently, promising results of randomized trials have definitively confirmed the importance of angiogenesis in oncogenesis and ovarian cancer behavior, by showing a significant prolongation of progression-free survival with the addiction of an angiogenesis inhibitor to standard treatment in the first and second line setting. Research over the years has sequentially provided a rapidly broadening signaling landscape and many drugs targeting different signaling pathways of angiogenesis have been developed and investigated. Recently accumulating scientific evidence has started to shed light on the efficacy of AMG 386, a new peptibody reported to neutralize the interaction between angiopoietins (Ang1/2) and their Tie2 receptors, thus representing a promising alternative, both in terms of efficacy and toxicity profile and is considerably under investigation. The aim of this review is to summarize the recent researches and clinical progresses of AMG 386 as a novel target agent in ovarian cancer. [ABSTRACT FROM AUTHOR]