Anti-vascular Endothelial Growth Factor Research Articles

Atezolizumab Plus Chemotherapy With or Without Bevacizumab in Advanced Biliary Tract Cancer: Clinical and Biomarker Data From the Randomized Phase II IMbrave151 Trial.

Biliary tract cancers (BTCs) harbor an immunosuppressed tumor microenvironment and respond poorly to PD-1/PD-L1 inhibitors. Bevacizumab (anti-vascular endothelial growth factor) plus chemotherapy can promote anticancer immunity, augmenting response to PD-L1 inhibition. This randomized, double-blind, proof-of-concept phase II study enrolled patients (n = 162) with previously untreated advanced BTC (IMbrave151; ClinicalTrials.gov identifier: NCT04677504). Patients were randomly assigned 1:1 to receive cycles of atezolizumab (1,200 mg) plus bevacizumab (15 mg/kg) or atezolizumab plus placebo once every 3 weeks until disease progression or unacceptable toxicity. All patients received cisplatin (25 mg/m2) plus gemcitabine (1,000 mg/m2; cisplatin plus gemcitabine [CisGem]) on days 1 and 8 once every 3 weeks for up to eight cycles. Stratification of patients was by disease status, geographic region, and primary tumor location. The primary end point was progression-free survival (PFS). No formal hypothesis testing was performed. Exploratory correlative biomarker analysis was undertaken using transcriptome analysis (n = 95) and mutation profiling (n = 102) on baseline tumor samples. Between February and September 2021, 162 patients were enrolled. Median PFS was 8.3 months in the bevacizumab arm and 7.9 months in the placebo arm (stratified hazard ratio [HR], 0.67 [95% CI, 0.46 to 0.95]). Median overall survival (OS) was 14.9 and 14.6 months in the bevacizumab and placebo arms, respectively (stratified HR, 0.97 [95% CI, 0.64 to 1.47]). The incidence of grade 3 or 4 adverse events was 74% in both arms. High VEGFA gene expression was associated with improved PFS (HR, 0.44 [95% CI, 0.23 to 0.83]) in the bevacizumab arm versus placebo. In unselected patients with advanced BTC, adding bevacizumab to atezolizumab plus CisGem modestly improves PFS but not OS. High VEGFA gene expression may represent a predictive biomarker of benefit from atezolizumab/bevacizumab, warranting further investigation.

Systemic counterregulatory response of angiopoietin-2 after intravitreal injections with faricimab for nAMD.

Recently, a systemic counterregulatory response of angiopoietin-2 after intravitreal application of the anti vascular endothelial growth factor (anti-VEGF) drug aflibercept in neovascular age-related macular degeneration (nAMD) has been described. The aim of the study was to find out wether faricimab, a combined anti-VEGF/angiopoietin-2 drug, had an effect on systemic cytokine levels. 20 women and 11 men (mean age 79.5 ± 7.3 years) were included into this cohort study. Plama levels of VEGF-A and angiopoietin-2 were determined before and after intravitreal application of faricimab (6mg/0.05ml/eye) using ELISA-technique. These results were correlated with central macular thickness (CMT). Responders were defined as having had CMT thinning ≥ 50μm. CMT decreased from 384.8 ± 108.8μm prior to intravitreal injection (IVI) to 286.1 ± 63μm one month after IVI (p < 0.0001). Angiopoietin-2 levels increased from 526.9 ± 129 pg/ml to 597.2 ± 174.8 pg/ml (p = 0.0087) one week after IVI and dropped to 547.4 ± 165 pg/ml (ns) four weeks after IVI. Responders revealed higher angiopoietin-2 (p = 0.0035) as well as higher VEGF-A (p = 0.0248) levels throughout the study period compared to non-responders. Initial CMT revealed to be the only independent factor influencing CMT 4 weeks after IVI in linear regression models with a positive correlation between initial thickness and effect size. The trending increase in systemic angiopoietin-2 levels, may be interpreted as an escape mechanism of the concomitant anti-VEGF component of therapy. Angiopoietin-2 levels could serve as a positive predictive factor of therapy response in the future. Further research regarding this effect as well as differences between responders and non-responders is mandatory. What is known Bispecific antibodies may be more beneficial compared to monospecific antibodies in neovascular age related macular degeneration (nAMD). For monospecific antibodies, there are systemic effects on systemic vascular endothelial growth factor (VEGF) levels. What is new The knew bispecific antibody faricimab entails an increase in systemic angiopoietin-2 levels, as well as a decrease in VEGF levels. The increase in systemic angiopoietin-2 may be interpreted as a counterregulatory effect. The decrease in systemic VEGF levels resembles the effects of monospecific antibodies.

Silicone Oil Droplets in the Vitreous After an Anti-vascular Endothelial Growth Factor (VEGF) Injection: A Complication of Syringe Lubrication

Silicone Oil Droplets in the Vitreous After an Anti-vascular Endothelial Growth Factor (VEGF) Injection: A Complication of Syringe Lubrication

A Markov model assessing the cost-effectiveness of various anti-vascular endothelial growth factor drugs and panretinal photocoagulation for the treatment of proliferative diabetic retinopathy.

Proliferative diabetic retinopathy (PDR) may lead to vision loss and blindness. The cost-effectiveness of various anti-vascular endothelial growth factor (anti-VEGF) drugs and panretinal photocoagulation (PRP) was assessed to supplement the NICE guideline for treating PDR. A Markov model including eight levels of visual acuity (ranged between >85 and ≤25 letters) was developed to compare the cost-effectiveness of ranibizumab, aflibercept and bevacizumab with PRP (alone or in combination). Clinical inputs in the model were based on literature, while a published network meta-analysis (NMA) informed visual outcomes. Costs were estimated from a UK NHS perspective. Assuming initial treatment effects from the NMA continued to be applied for the remainder of lifetime, the probabilistic analysis resulted in bevacizumab plus PRP producing the highest net monetary benefit (NMB [95% CI]) of £221,374 [£203,941-£238,388] at £20,000 per quality-adjusted life-year. However, assuming initial treatment effects stabilised over time resulted in PRP alone producing the highest NMB of £223,416 [£209,318-£236,866]. Results were associated with large uncertainty due to wide confidence intervals around vision-based treatment effects of anti-VEGFs versus PRP, particularly for bevacizumab as data were drawn from trials with small sample size and high risk of bias. Using confidential prices for aflibercept and ranibizumab did not change the overall findings. PRP is likely to be more cost-effective than anti-VEGFs for PDR. However, the results should be interpreted with caution given the scarcity of long-term visual outcomes with anti-VEGFs in this population. Further research on long-term visual outcomes may resolve these uncertainties.

Ref-1 redox activity regulates retinal neovascularization by modulating transcriptional activation of HIF-1α.

Retinal neovascularization impairs visual function and is a hallmark of several neovascular eye diseases, including retinopathy of prematurity (ROP) and proliferative diabetic retinopathy (PDR). Current treatments include intravitreal injections of anti-vascular endothelial growth factor (VEGF) biologics, but these therapeutics are often accompanied by high treatment burden and resistance to therapy. Prior studies indicate that APE1/Ref-1, a multifunctional protein with both endonuclease (APE1) and redox-mediated transcriptional regulatory activity (Ref-1), activates multiple pro-angiogenic and pro-inflammatory signaling pathways by chemically reducing key cysteine residues in transcription factors, thereby activating them. Here, we investigated the previously unexplored role of Ref-1 in retinal neovascularization. We demonstrate that Ref-1 is highly expressed in endothelial cells in human PDR and in the oxygen-induced retinopathy (OIR) mouse model of retinal neovascularization. Ref-1 is also highly expressed in microglia and astrocytes in OIR. A small molecule Ref-1 redox inhibitor, APX2009, decreased retinal neovascularization in OIR after systemic delivery. Invitro, hypoxic endothelial cells did not exhibit upregulation of Ref-1 but rather increased Ref-1 nuclear localization. APX2009 decreased hypoxic endothelial cell proliferation and HIF-1α transcriptional activation. Thus, Ref-1 redox activity may be a novel therapeutic target for the treatment of retinal neovascularization, making APX2009 a promising systemic therapeutic approach for the treatment of vascular retinopathies such as ROP and PDR.

To Treat or Not to Treat? Resolving the Question of Subretinal and Intraretinal Fluid in Age-Related Macular Degeneration: A Narrative Review.

Neovascular age-related macular degeneration (nAMD) is associated with considerable quality of life and economic burden. nAMD is characterized by pathological neovascularization, leading to the accumulation of retinal fluid. Intraretinal fluid (IRF) is a major contributor to vision loss and may predict response to treatment. In contrast, the role of subretinal fluid (SRF) is less clear. Nevertheless, complete resolution of retinal fluid accumulation is often stated to be a key goal of therapy for nAMD, even though some eyes may never achieve a fluid-free macula despite regular anti-vascular endothelial growth factor treatment. In this article, we review the current literature regarding the role of retinal fluid in nAMD disease outcomes and assess whether and when it may be beneficial to leave retinal fluid untreated. In this context, we highlight the importance of correctly identifying retinal fluid types in nAMD and avoiding confusion with other optical coherence tomography signs that may respond differently to therapy, such as subretinal pseudocysts. Current evidence shows that IRF is associated with poor outcomes and an increased risk of developing atrophy and fibrosis; resolution of this retinal fluid type should remain a treatment target. However, the literature around SRF indicates that low levels of this fluid type, potentially up to 150-200µm in thickness, may be tolerated with minimal impact on vision, and that SRF could be protective against the development and progression of macular atrophy and fibrosis. Although mild SRF may be protective in nAMD, cause and effect between SRF and reduced or slowed atrophy has not yet been proven and requires further research. Treatment should be given for the most aggressive component; when both IRF and SRF are present, treatment should be given for IRF.

Proliferative Diabetic Retinopathy in Nigerians: Treatment Methods, Visual Outcomes, and Predictors of Poor Outcomes

Abstract Objective: To investigate demographics, treatment methods, pre- and post-treatment vision of proliferative diabetic retinopathy (PDR) patients, and predictors of poor visual outcomes. Materials and Methods: This is a multicentre chart review of consecutive PDR eyes, investigating vision, presence of vitreous haemorrhage (VH), tractional retinal detachment (TRD), diabetic macular edema (DME), and rubeosis. Rates of good vision (6/60+) and poor vision (&lt; 6/60) and rates of worse, same, or improved vision were the primary outcomes. The secondary outcome was the number of eyes in each treatment category. Results: A total of 640 PDR eyes/473 patients were evaluated [334 bilateral eyes (52.2%)/167 patients (35.3%)]. Mean age: 58.9/SD 10.97 years (17–95). Mean symptom duration: 12.8 months. Rates of DME, TRD, VH, TRD with VH , and rubeosis were 12%, 3%, 25.6%, 2.5%, and 15%, respectively. The five treatment categories include intravitreal antivascular endothelial growth factor injections (IVI) alone (392 eyes/61.25%), IVI + retinal laser photocoagulation (86 eyes/13.45%), IVI + cataract surgery (CS) (24 eyes/3.76%), IVI + vitrectomy (V) (109 eyes/17.0%), and IVI + CS + vitrectomy (29 eyes/4.54%). IVI + CS had the highest mean number of intravitreal anti-VEGF use (2.96/SD 4.56) and highest rate of improved vision (62.5%). IVI + vitrectomy had the highest worse vision (29%). IVI alone and IVI + CS had the highest pre- and post-treatment best corrected visual acuity (BCVA). TRD, rubeosis, VH, and no DME eyes had poor mean pretreatment BCVA (&lt; 6/60). Post-treatment mean BCVA improved significantly in VH and DME. Poor pretreatment BCVA, TRD, TRD with VH, and rubeosis were predictors of poor outcomes. Conclusion: PDR is a cause of poor vision and associated poor treatment outcomes in Nigerians. Systematic, effective DR screening and retinal laser treatment of high-risk eyes is urgently needed.

Optical Coherence Tomography Angiography Flow Signal in Non-Treatment-Naïve Patients with Neovascular Age-Related Macular Degeneration Treated with Faricimab

Background and Objectives: Age-related macular degeneration (AMD) remains a leading cause of legal blindness. Anti-Vascular Endothelial Growth Factor (VEGF) agents are the first-line treatment for neovascular AMD (nAMD). The choroid plays a key role in AMD and is affected by the anti-VEGF treatment. Faricimab, a bispecific antibody additionally targeting angiopoietin 2 (Ang2), was recently approved for nAMD treatment. This study investigates the effect of Faricimab on choroidal flow signal. Materials and Methods: Optical coherence tomography angiography images of 29 nAMD eyes were examined retrospectively. Patients had received treatment with other anti-VEGF agents before Faricimab application. The flow signal in the choroid was measured before, after one and after a series of ≥2 Faricimab injections. Results: The flow signal decreased significantly (p = 0.026) at the choriocapillaris (CC) level after ≥2 injections. The flow signal did not show a significant change in Haller’s layer but increased slightly in Sattler’s layer (p = 0.034). Conclusions: In conclusion, our results show that the flow signal, especially at the CC level, changed during treatment. Despite the known influence of anti-VEGF treatment on the choroid, auxiliary inhibition of Ang2 might enhance this effect. Due to the retrospective nature, moderate sample size and non-treatment, naïve patients, care must be taken while interpreting our observations. Prospective studies with larger sample sizes and treatment-naïve patients will be needed.

Treatment Interval Progression and Adherence to Observe-and-Plan Regimen for Neovascular Age-Related Macular Degeneration Treated with Aflibercept 2mg.

Treatment burden of anti-vascular endothelial growth factor (VEGF) therapy for neovascular age-related macular degeneration (AMD) can be reduced with the Observe-and-Plan (O&P) regimen, which allows for an individualized treatment while reducing the number of injections and assessment visits. In this study, we evaluate detailed characteristics of treatment interval adjustment through individual follow-ups and evaluate adherence to the O&P regimen in a real-world setting in one of the largest centers in Europe. This was a retrospective cohort study of treatment-naïve eyes with neovascular AMD that were treated with intravitreal aflibercept 2mg in an O&P regimen who had persisting exudation after completion of loading dose. We evaluated decisions on adjustment of treatment intervals and adherence to the O&P regimen from a total of 5 follow-up visits. Data from visits and decision on treatment intervals were extracted from a treatment database. A total of 561 eyes were eligible for this study. Treatment intervals gradually increased from a 4-weeks interval (loading dose) to a wide distribution of intervals from 4-weeks to 12-weeks, and at the 5th follow-up 24.9% were followed without any treatment. In total, 209 eyes (49.5%) at the 5th follow-up (of 422 eyes present at the 5th follow-up) adhered to the treatment algorithm. Aflibercept 2mg in an O&P treatment regimen leads to a variety of treatment intervals, and some eyes may be overtreated. An important proportion of eyes deviate from the intended O&P treatment regimen. Our study contributes to understanding real-world implications of personalized treatment regimens.

Real-world evidence of anti-VEGF therapies in patients with neovascular age-related macular degeneration in Italy: The RADIANCE study.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss, particularly neovascular AMD (nAMD). This study aimed to investigate the real-world treatment patterns, effectiveness, and safety of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapies for anti-VEGF naïve nAMD patients in Italy. RADIANCE is a retrospective, observational, multicenter cohort study conducted at 13 clinical sites across Italy. The study enrolled all consecutive patients with nAMD, naïve to any intraocular anti-VEGF treatment and who initiated therapy with aflibercept, ranibizumab, or bevacizumab between January 2017 and November 2018. The primary objective of this study was to evaluate changes in visual acuity (VA) 52 weeks after initiating treatment with anti-VEGF. A total of 405 patients were enrolled; of these, 263 patients had at least two VA measurements and were included in the completer analysis (CA) set. At 52 weeks, the median VA change from baseline in the CA set was +1 letter, with 41.1% showing ≥ 5-letter improvement. Stratified by anti-VEGF agent, no statistically significant differences were observed. Overall, patients received a median of 5.0 (25th-75th percentile 3-6) injections of the initial anti-VEGF agent during the first year. Patients receiving ≥ 6 injections in the first year showed better VA outcomes. Undertreatment was evident at decreasing injection frequency over time. The results of the RADIANCE study suggest an overall moderate effectiveness after 1 year of treatment with anti-VEGF in naïve patients with nAMD in Italy. Real-world outcomes demonstrated suboptimal treatment with no significant differences among anti-VEGF agents.

The Optimized Lipid-Modified Prodrug for CNV Treatment.

Choroidal neovascularization (CNV) is a prevalent cause of vision impairment. The primary treatment for CNV involves intravitreal injections of anti-vascular endothelial growth factor antibodies. Nevertheless, this approach still faces numerous limitations like poor patient compliance, high therapy expenditure and lack of response in some individuals. Herein, a series of anti-neovascularization prodrugs, SU5402 (SU), modified with lipids of varying chain lengths (C12, C16, C20, C24, C28) is synthesized (SU-C12, SU-C16, SU-C20, SU-C24, SU-C28). 1% polyvinyl alcohol (PVA) is used as a stabilizer to create nanoformulations of five prodrugs named SU-C12 NPs, SU-C16 NPs, SU-C20 NPs, SU-C24 NPs, SU-C28 NPs. Among these, SU-C20 NPs significantly prolong the retention of bioactive drug in the eye for up to 70 d. Moreover, SU-C20 NPs demonstrate superior tissue permeability via enhanced cellular endocytosis and exocytosis. With its prolonged retention and improved penetration, SU-C20 NPs reduce the fluorescence intensity of fundus leakage by 42.5% and the fluorescence area by 51.5% in CNV mice after four weeks, effectively inhibiting the progression of CNV. Altogether, small molecule drug SU is innovatively modified to improve its effectiveness for treating fundus neovascular diseases, proposing an alternative therapy for wet age-related macular degeneration (wAMD).

Phase 2 randomized study evaluating safety, efficacy, and optimal dose of ABBV-400 in combination with fluorouracil, folinic acid, and bevacizumab in previously treated patients with metastatic colorectal cancer.

TPS308 Background: Colorectal cancer (CRC) is the third most common cancer. In the metastatic (m) setting, the 5-year relative overall survival is approximately 15%. Conventional treatment comprises fluorouracil (5-FU)–based chemotherapy. Recently, targeted therapies have been studied for specific molecular subtypes. c-Met overexpression frequently occurs in a variety of tumors, including CRC. ABBV-400 is a c-Met–directed antibody-drug conjugate composed of the monoclonal antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor payload. Preliminary data from the first-in-human study of ABBV-400 in patients with advanced solid tumors indicate encouraging efficacy of ABBV-400 monotherapy in patients with third-line or later mCRC. This phase 2 randomized study evaluates the safety, efficacy, and optimal dose of ABBV-400 in combination with 5-FU, folinic acid (FA), and bevacizumab (bev) in patients with mCRC with progression after first line (1L) treatment. Methods: Global, open-label, phase 2 randomized controlled study (NCT06107413). Eligible patients (≥18 years) have confirmed unresectable mCRC and measurable disease per RECIST v1.1, are microsatellite stable or mismatch repair proficient, BRAF V600E wild type, and have progression after 1L combination chemotherapy ± an anti-vascular endothelial growth factor or anti-epidermal growth factor receptor antibody. Primary objectives are (a) optimize ABBV-400 dose in combination with 5-FU, FA, and bev; (b) evaluate the efficacy of the combination, using objective response and progression-free survival as dual primary endpoints; (c) evaluate the safety and tolerability of the combination. Approximately 206 patients planned for enrollment in 2 stages: safety lead-in dose escalation (stage 1; n=30) and dose optimization (stage 2; n=176). In stage 1, patients receive escalating doses of ABBV-400 either every 2 weeks (Q2W; 0.8–2.4 mg/kg) or every 4 weeks (Q4W; 1.6–3.0 mg/kg) in combination with Q2W 5-FU (2400 mg/m 2 infusion), FA (200 mg/m 2 ), and bev (5 mg/kg) in 28-day cycles. Dose escalation of ABBV-400 uses a Bayesian optimal interval design, with target toxicity rate of 30%. Dose-limiting toxicities (DLT) are assessed during cycle 1, with ≥6 DLT evaluable patients required to declare a dose safe for the dose-optimization stage. In stage 2, patients are randomized to up to 4 ABBV-400 dose cohorts (2 with Q2W and 2 with Q4W ABBV-400 schedule; all in combination with Q2W 5-FU, FA, and bev) and a comparator cohort (irinotecan [180 mg/m 2 ] + 5-FU [400 mg/m 2 bolus and 2400 mg/m 2 infusion] + FA [200 mg/m 2 ] + bev [5 mg/kg]; all Q2W). Patients are treated until progression, unacceptable toxicity, or other discontinuation criteria are met. Enrollment was initiated in November 2023, with 3 patients enrolled as of January 4, 2024. Clinical trial information: NCT06107413 .

A real-world study of treatment patterns among patients (pts) with metastatic colorectal cancer (mCRC) receiving third-line (3L) or fourth-line (4L) treatment in the US.

64 Background: There are limited real-world data describing 3L and 4L treatments for pts with mCRC. However, the landscape is evolving with new options becoming available, including fruquintinib, a highly selective oral inhibitor of all 3 VEGF receptors, approved by the US FDA in November 2023. This study aimed to understand pt characteristics and real-world treatment patterns in 3L and 4L to characterize the standard of care, adherence to guidelines, and identify unmet needs among pts with mCRC in the US, prior to recent changes in the landscape. Methods: A retrospective study of adults with mCRC who had received ≥3L of therapy between 1/1/2018 and 3/31/2023 in the US-based Flatiron electronic health records database. In two cohorts, defined by initiating 3L and 4L systemic treatment, pt demographics, clinical characteristics, and treatment by line of therapy were summarized. Results: Overall, 5401 pts were included in the 3L cohort and 2868 pts in the 4L cohort: median age at baseline was 63 and 62 years (yrs), 56% and 56% were male, 43% and 43% had a KRAS variant, and 46% and 49% had liver metastasis, respectively. 96% of pts in the 3L cohort received standard chemotherapy (CT) +/- targeted therapy as 1L treatment (55% CT + anti-vascular endothelial growth factor [VEGF] therapy; 34% CT only; 7% CT + anti-epidermal growth factor receptor [EGFR] therapy). In 2L, 87% of pts had standard CT-containing regimens (53% CT + anti-VEGF therapy; 19% CT alone; 15% CT + anti-EGFR therapy). A similar treatment history was observed for the 4L cohort. Commonly used 3L regimens in the 3L cohort were trifluridine/tipiracil (TAS-102; 11%), regorafenib (rego; 10%), and standard CT-containing regimens (54%; including: 12% FOLFIRI + bevacizumab [bev], 7% FOLFOX + bev, 4% FOLFIRI, 3% FOLFOX, and 15% standard CT + anti-EGFR therapy). Approximately 47% (n=2513) of pts did not receive subsequent treatments after 3L. In the 4L cohort, use of TAS-102 (16%) and rego (15%) increased slightly in 4L, accompanied with a moderate decrease in CT-containing regimens (42%; including 6% FOLFOX + bev, 5% FOLFIRI + bev, 3% FOLFOX, 3% FOLFIRI, and 12% standard CT + anti-EGFR therapy). Approximately 4% of pts in the 3L and 4L cohorts received TAS-102 + bev in 3L and 4L, respectively. Pts receiving standard CT-containing regimens were slightly younger (&lt;65 yrs: 3L 57%, 4L 58%) and had better Eastern Cooperative Oncology Group performance status (ECOG PS; 0-1: 3L 77%, 4L 77%) vs pts receiving TAS-102 (&lt;65 yrs: 3L 54%, 4L 58%; ECOG PS 0-1: 3L 70%, 4L 68%) or rego (&lt;65 yrs: 3L 50%, 4L 53%; ECOG PS 0-1: 3L 68%, 4L 70%). Conclusions: Characterization of treatment patterns in US pts from 1/2018 to 3/2023 showed that standard CT +/- targeted therapy was used frequently in 3L and 4L, demonstrating an unmet need for additional therapies. Approval of novel treatments, such as fruquintinib, may help to address this need.

A phase II study of agenT-797 (invariant natural killer T-cells), botensilimab (Fc-enhanced CTLA-4 inhibitor) and balstilimab (anti-PD-1) in patients with advanced, refractory gastroesophageal adenocarcinoma.

TPS515 Background: Esophagogastric (EG) cancer, the fifth most common cancer worldwide and second leading cause of cancer-related mortality, results in 1.3 million deaths annually. Despite recent advances in frontline management, nearly all patients with metastatic disease experience progression, highlighting the urgent need for novel therapies. Botensilimab (BOT), an Fc-enhanced, multifunctional anti-CTLA-4 antibody, has shown promise in combination with balstilimab (BAL, anti-PD-1) across multiple treatment-refractory cancers. Additionally, agenT-797, an allogeneic off-the-shelf invariant Natural Killer T (iNKT) cell therapy, enhances immune responses, including in settings refractory to immune checkpoint inhibitors (ICI), without requiring HLA matching or lymphodepletion. In a cohort of 82 previously treated patients, agenT-797 demonstrated a favorable safety profile with no severe Cytokine Release Syndrome, Graft-versus-Host Disease, or immune effector cell-associated neurotoxicity syndrome. Notably, in patients with relapsed/refractory gastric cancer, agenT-797 plus anti-PD-1 showed important clinical activity that warrants further exploration. Given their complementary mechanisms of action in modulating anti-tumor immunity, we aimed to evaluate the safety and efficacy of combining BOT, BAL, and agenT-797 with standard ramucirumab (anti-vascular endothelial growth factor receptor-2 antibody) and paclitaxel chemotherapy in patients with advanced EG cancer who have progressed on frontline therapy. Methods: This is an investigator-initiated, single-arm phase II trial in adult patients (≥18 years) with esophageal, gastric, or gastro-esophageal junction (GEJ) adenocarcinoma who have received one prior line of therapy, performed at Memorial Sloan Kettering Cancer Center. Eligible patients receive a single infusion of agenT-797 on cycle 1 day 1, BOT 75 mg on day 1 of cycles 1 through 3, BAL 240 mg on days 1 and 15, ramucirumab 8 mg/kg on days 1 and 15, and paclitaxel chemotherapy 80 mg/m 2 on days 1, 8, and 15 of a 28-day cycle. Treatment is continued until disease progression (defined by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), unacceptable toxicity, or withdrawal of consent. The primary endpoint is overall response rate. The secondary endpoints are safety and tolerability, disease control rate, duration of response, progression-free survival, and overall survival. The regimen will be considered worthy of further investigation if at least 15 out of 37 patients achieve an objective response. To date, 12 patients have been enrolled and started on treatment. This trial is registered with ClinicalTrials.gov, NCT06251793. Clinical trial information: NCT06251793 .

Timing of vitrectomy for treatment of endophthalmitis after intravitreal anti-VEGF injection: a systematic literature review of case reports and series.

To perform a systematic literature review analyzing visual outcomes of immediate, early, and delayed vitrectomy in the treatment of acute endophthalmitis after intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. We conducted a literature search using the Ovid Medline, Embase.com, and Web of Science databases, and relevant articles were selected from original English papers published from 2005 to 2021. Inclusion criteria were studies reporting cases of acute post-anti-VEGF endophthalmitis, defined as occurring within 6 weeks of injection treatment. Exclusion criteria were pediatric cases and cases explicitly reported to be caused by injections of contaminated drugs. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal tool for case reports and case series. The study dataset for descriptive and statistical analysis comprised patient-level data extracted from included studies. The timing of vitrectomy compared were defined as (1) immediate vitrectomy as occurring within 24 h of endophthalmitis diagnosis; (2) early vitrectomy as occurring between 24 and 48 h of endophthalmitis diagnosis; (3) late vitrectomy as occurring after 48 h of endophthalmitis diagnosis. Primary outcome was final visual acuity following treatment with vitrectomy. Twenty-five articles were published that met our inclusion and exclusion criteria for a total of 86 cases. Thirty-seven were immediate vitrectomy, 25 were early, and 24 were late vitrectomy treatment groups, respectively. We observed differences in final visual outcomes and in improvement from diagnosis to final visual acuity, with patients receiving immediate and late vitrectomy to have better final visual outcomes than those patients receiving early vitrectomy (p < 0.005). Our results show that there may be an association between time to vitrectomy and visual outcomes. Immediate and late vitrectomy treatment groups had better visual outcomes than the early group. Our results were limited by the reliance on case reports and series and the paucity of data available specifying the timing of vitrectomy. Additional research is necessary to elucidate the effects of treatment timing in patients with endophthalmitis following anti-VEGF injection.

Anti-PD-L1 envafolimab combined with anti-VEGF suvemcitug in pretreated solid tumors and hepatocellular carcinoma: an open-label phase II study with safety run-in stage.

Immune checkpoint inhibitors (ICIs) combined with anti-vascular endothelial growth factor (VEGF) have been the standard first-line treatment of hepatocellular carcinoma (HCC). However, the efficacy of this combination in post-line treatment is still unknown. This study aimed to evaluate the efficacy and safety of the combination of anti-PD-L1 envafolimab and novel humanized anti-VEGF suvemcitug as second-line treatment for patients with HCC. This open-label, prospective phase II clinical study (NCT05148195) comprised safety run-in stage and dose expansion stage of HCC cohort. Eligible patients were aged ≥ 18 years and had undergone at least a prior line of treatment. Patients received fixed-dose envafolimab and suvemcitug until termination of disease progression, unacceptable toxicities, or withdrawal. The primary endpoint of safety run-in stage was recommended dose (RD), and dose expansion stage was objective response rate (ORR). As of August 10, 2023, no dose-limiting toxicity was observed in six patients in the safety-run-in stage, and 2 mg/kg dose every 3 weeks was declared the RD of suvemcitug. Among 20 patients with HCC, the median age was 54.5 (range, 42-70) years. Of these patients, 20 (100.0%) received ≥ one prior line treatment, with 20 (100%) received tyrosine kinase inhibitor (TKI) treatment and 8 (40.0%) received prior ICI treatment. The ORR was 10.0% (95% confidence interval (CI), 1.2-31.7), DCR was 65.0% (95% CI, 40.8-84.6), and DoR was not reached (NR). With a median follow-up of 13.9 months, the median progression-free survival (PFS) and median overall survival (OS) were 4.3 months (95% CI, 1.4-8.1) and 10.7 months (95% CI, 6.0-not evaluable [NE]), respectively. Treatment-related adverse events (TRAEs) of grade ≥ 3 occurred in 40% patients, with proteinuria (20.0%, 4/20) being the most frequent. The ORR of no lung metastasis, prior first-line treatment and IO naïve treatment subgroup was 16.7%. The combination of envafolimab and suvemcitug showed a tolerable safety profile and promising antitumor activity in HCC patients who failed later-line treatment.

A systematic review of the cost-effectiveness of anti-VEGF drugs for the treatment of diabetic retinopathy.

Non-proliferative and proliferative diabetic retinopathy are common complications of diabetes and a major cause of sight loss. Anti-vascular endothelial growth factor drugs represent a treatment option for people with diabetic retinopathy and are routinely used to treat various other eye conditions. However, anti-vascular endothelial growth factor drugs are expensive relative to current care options, and it is unclear whether this additional cost is justified when the immediate risk of vision loss is lower compared to patients with more aggressive ophthalmological conditions. To systematically review the evidence supporting the cost-effectiveness of alternative treatments for diabetic retinopathy. A systematic review of all comparative cost-effectiveness studies evaluating any treatment for diabetic retinopathy was conducted. Bibliographic searches were carried out to identify studies reporting on the cost-effectiveness of treatments for diabetic retinopathy; the latest searches were conducted on 28 April 2023. Included studies were synthesised narratively and evaluated with reference to UK decision-making. Studies were grouped by population into non-proliferative diabetic retinopathy and proliferative diabetic retinopathy. The review identified five studies in the proliferative diabetic retinopathy population, all of which examined the cost-effectiveness of anti-vascular endothelial growth factor treatments compared to pan-retinal photocoagulation. Results of these studies suggest that anti-vascular endothelial growth factor treatments offer some additional benefits in terms of preserved visual acuity but also incur substantial additional costs relative to pan-retinal photocoagulation. Most authors agreed that the additional costs outweigh the limited benefits, especially in certain patient subgroups without pre-existing oedema. As most of the identified evidence considered a US perspective, it is unclear how these results would translate to a UK setting. Two studies were identified in the non-proliferative diabetic retinopathy population. There was limited evidence to support the early use of anti-vascular endothelial growth factor treatment. However, one UK study suggested that early treatment of non-proliferative diabetic retinopathy with pan-retinal photocoagulation is cost-effective compared to delayed pan-retinal photocoagulation. Overall, there is a dearth of cost-effectiveness evidence considering the UK context. The identified studies raised doubts about the cost-effectiveness of anti-vascular endothelial growth factor treatments for proliferative diabetic retinopathy. No conclusions can be made regarding the cost-effectiveness of anti-vascular endothelial growth factor treatments for non-proliferative diabetic retinopathy. Future research should focus on developing rigorous model-based cost-effectiveness analyses integrating all available evidence. This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR132948.

From pro-re-nata to fixed-interval regimen: evolving real-world treatment paradigms in anti-VEGF therapy for neovascular AMD.

To evaluate the impact of evolving treatment paradigms for neovascular age-related macular degeneration (nAMD) by comparing outcomes between two patient cohorts treated with different anti-vascular endothelial growth factor (anti-VEGF) regimens over a decade apart. This retrospective cohort study included 200 treatment-naive nAMD patients divided into two cohorts. Cohort 1 (2009-2010) was treated with a pro re nata (PRN) regimen, involving three initial monthly injections followed by as-needed treatments based on monthly monitoring. Cohort 2 (2019-2021) received a fixed-interval regimen, consisting of three initial monthly injections followed by bimonthly maintenance doses. Primary outcomes included changes in best corrected visual acuity (BCVA) and central retinal thickness (CRT) at 12 months. Secondary outcomes included the number of injections, follow-up visits, and adherence to treatment schedules. Cohort 2 demonstrated significantly greater improvement in BCVA (+5.5 vs -2.0 ETDRS letters, p < 0.001) and CRT reduction (-101.7 vs -26.5 μm, p < 0.001) compared to Cohort 1. Patients in Cohort 2 received more injections (7.7 vs 4.8, p < 0.001) but required fewer monitoring visits (3.2 vs 5.1, p < 0.001). Adherence to treatment schedules was markedly higher in Cohort 2 (78% vs 0%, p < 0.001). The transition from a PRN to a fixed-interval anti-VEGF regimen significantly improved visual and anatomical outcomes in nAMD patients. Fixed-interval regimens not only enhanced treatment efficacy but also optimized resource utilization, suggesting a superior approach for managing nAMD in a real-world clinical setting.

Recent advances in pharmacological treatments of proliferative vitreoretinopathy.

Proliferative vitreoretinopathy (PVR) is a severe complication of retinal detachment and trauma, posing significant challenges to surgical success and visual prognosis. Despite advancements in vitreoretinal surgery, PVR incidence remains unchanged, this review presents a synthesis of the principal clinical and preclinical research findings from recent years. Recent research has focused on anti-inflammatory, antiproliferative, and antifibrotic agents. Corticosteroids, such as triamcinolone and dexamethasone, show promise in reducing inflammation but have inconsistent results. Methotrexate and mitomycin C demonstrate efficacy in preclinical and select clinical scenarios. Anti-vascular endothelial growth factor agents and immunotherapies, like infliximab, have shown limited clinical benefits despite promising preclinical data. Novel approaches, including CB2 receptor agonists, exosome-based drug delivery, and nuclear factor kappa B pathway inhibitors, are gaining traction. Additionally, RNA-based and multitargeted therapies highlight the importance of addressing inflammation, fibrosis, and proliferation simultaneously. Effective management of PVR requires multifaceted therapies targeting its complex pathogenesis. While current treatments are limited, ongoing research in precision drug delivery and combination therapies offers hope for improved outcomes. Future strategies should focus on translating promising preclinical findings into robust clinical applications.

Surgery in ophthalmology during pregnancy

The new Maternity Protection Act (MuSchG) enacted in 2018, is intended to enable pregnant employees to carry out their work, to protect the pregnant employee and the child and to counteract discrimination. Nevertheless, aban on surgical activities or even aban on employment is often issued, although the law first requires the workplace to be reorganized to enable the pregnant employee to continue working. In many cases, such bans are issued without the legally required risk assessment, which constitutes prohibited discrimination. In ophthalmology, the sedentary nature of the work and the short operating times mean that conditions are comparatively favorable to enable pregnant doctors to continue their surgical work. The procedures following notification of pregnancy by amember of staff as well as some innovations in the MuSChG are explained. Hazards in ophthalmology, such as infection risks and the handling of hazardous substances (e.g., mitomycinC or 5‑fluorouracil) are discussed in detail. The potential handling of anti-vascular endothelial growth factor (VEGF) drugs in intravitreal injections and the risks of needlestick injuries in relation to human immunodeficiency virus (HIV) and hepatitisC are also discussed. The nondiscriminatory requirements and support of female doctors during pregnancy are not only required by law but are also socially, organizationally and economically necessary in times of ashortage of doctors. This includes not only enabling surgical activities during pregnancy but also nondiscriminatory planning of the return to work in order to promote the training and further education of women during and after pregnancy.