Vascular Endothelial Growth Factor Inhibitors Research Articles

Risk factors for thromboembolism during first-line treatment of patients with unresectable advanced or recurrent colorectal cancer: a retrospective short study

BackgroundWhile cancer is a risk factor for developing thromboembolism, so is the use of molecularly targeted therapies. This study aimed to determine whether thromboembolism incidence differed between vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitor use in patients with unresectable advanced or recurrent colorectal cancer, and to compare the risk of thromboembolism caused by cancer and the use of molecular targeted therapy drugs.Main bodyWe retrospectively evaluated patients with unresectable advanced or recurrent colorectal cancer who were treated with a cytotoxic anticancer drug and a VEGF or EGFR inhibitor combination between April 2016 and October 2021. Patients were compared in terms of the regimen administered, thromboembolism occurrence during the first-line treatment period, patient background, and clinical laboratory values. Of the 179 included patients, 12 of 134 (8.9%) in the VEGF-inhibitor group and 8 of 45 (17.8%) in the EGFR-inhibitor group developed thromboembolism, with no significant difference between the groups (P = 0.11). There was no significant difference in time to thromboembolism between patients in the VEGF- inhibitor group and patients in the EGFR-inhibitor group (P = 0.206). The cutoff value determined by a receiver operating characteristic analysis for the occurrence of thromboembolism was one point. Multivariate analysis using the occurrence of thromboembolism as the response variable identified at least one risk factor for thromboembolism (odds ratio = 4.17, P = 0.006, 95% confidence interval = 1.51–11.50). Molecular targeted therapies were not identified as a risk factor.ConclusionsAlthough the small sample size, there was no difference in the incidence of thromboembolism between the two molecular-targeted therapies in first-line treatment of patients with unresectable advanced or recurrent colorectal cancer. Our results suggest that risk factors for thromboembolism may be more strongly influenced by cancer itself than by the use of molecularly targeted therapies.

Effect of Extracellular Ribonucleic Acids on Neurovascularization in Osteoarthritis.

Osteoarthritis is a degenerative disease characterized by abnormal neurovascularization at the osteochondral junctions, the regulatory mechanisms of which remain poorly understood. In the present study, a murine osteoarthritic model with augmented neurovascularization at the osteochondral junction is used to examine this under-evaluated facet of degenerative joint dysfunction. Increased extracellular RNA (exRNA) content is identified in neurovascularized osteoarthritic joints. It is found that the amount of exRNA is positively correlated with the extent of neurovascularization and the expression of vascular endothelial growth factor (VEGF). In vitro binding assay and molecular docking demonstrate that synthetic RNAs bind to VEGF via electrostatic interactions. The RNA-VEGF complex promotes the migration and function of endothelial progenitor cells and trigeminal ganglion cells. The use of VEGF and VEGFR2 inhibitors significantly inhibits the amplification of the RNA-VEGF complex. Disruption of the RNA-VEGF complex by RNase and polyethyleneimine reduces its in vitro activities, as well as prevents excessive neurovascularization and osteochondral deterioration in vivo. The results of the present study suggest that exRNAs may be potential targets for regulating nerve and blood vessel ingrowth under physiological and pathological joint conditions.

Outcomes of switching from proactive to reactive treatment after developing advanced central neovascular age-related macular degeneration.

We assessed outcomes of eyes with neovascular age-related macular degeneration (nAMD) that switched from proactive (treat-and-extend) to reactive (pro re nata) treatment regimen after developing macular atrophy (MA) or submacular fibrosis (SMFi). Data were collected from a retrospective analysis of a prospectively designed, multinational registry of "real-world" nAMD treatment outcomes. Eyes without MA or SMFi when starting treatment with a vascular endothelial growth factor inhibitor regimen that subsequently developed MA or SMFi were included. Macular atrophy developed in 821 and SMFi in 1166 eyes. Seven percent of eyes that developed MA, and 9% of those that developed SMFi, were switched to reactive treatment. Vision was stable at 12 months for all eyes with MA and inactive SMFi eyes. Active SMFi eyes that switched to reactive treatment had significant vision loss. No eyes that continued proactive treatment developed ≥15 letter loss, but 8% of all eyes that switched to a reactive regimen, and 15% of active SMFi eyes did. Eyes that switch from proactive to reactive treatment after developing MA and inactive SMFi, can have stable visual outcomes. Physicians should be aware of the risk of a significant loss of vision in eyes with active SMFi that switch to reactive treatment.

Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment

BackgroundInteractions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by interspecies differences between human and...

Comparison of Bevacizumab and Aflibercept for Suppression of Angiogenesis in Human Retinal Microvascular Endothelial Cells.

Bevacizumab (Avastin) is a vascular endothelial growth factor (VEGF) inhibitor that is widely used for aggressive posterior retinopathy of prematurity (APROP). Its use is associated with multiple adverse effects. Aflibercept (Eylea) is a VEGFR-1 analogue that is approved for ocular use, but its efficacy for APROP is less studied. We tested the hypothesis that Eylea is as effective as Avastin for suppression of intermittent hypoxia (IH)-induced angiogenesis. Human retinal microvascular endothelial cells (HRECs) were treated with Avastin and low- or high-dose Eylea and exposed to normoxia, hyperoxia (50% O2), or neonatal IH for 24, 48, or 72 h. Cells were assessed for migration and tube formation capacities, as well as biomarkers of angiogenesis and oxidative stress. Both doses of Eylea suppressed migration and tube formation in all oxygen environments, although the effect was not as robust as Avastin. Furthermore, the lower dose of Eylea appeared to be more effective than the higher dose. Eylea induced soluble VEGFR-1 (sVEGFR-1) coincident with high IGF-I levels and decreased Notch/Jagged-1, demonstrating a functional association. Given the role of VEGFR-1 and Notch as guidance cues for vascular sprouting, these data suggest that Eylea may promote normal vascular patterning in a dose-dependent manner.

Aortic dissection induced by vascular endothelial growth factor inhibitors.

Vascular endothelial growth factor (VEGF) contributes to angiogenesis and vasculogenesis. The occurrence and progression of tumors are accompanied by angiogenesis. Vascular endothelial growth factor inhibitors (VEGFI) have been used in anti-tumor treatment. However, aortic dissection (AD) is one of the VEGFI-associated adverse reactions with cute onset, rapid progression, and high case fatality rate. We collected case reports of VEGFI related to aortic dissection in PubMed and CNKI (China National Knowledge Infrastructure) from inception to 28 April 2022. Seventeen case reports were selected. The medication included sunitinib, sorafenib, pazopanib, axitinib, apatinib, anlotinib, bevacizumab, and ramucirumab. This review discusses the pathology, risk factors, diagnosis, and treatment of AD. Vascular endothelial growth factor inhibitors are related to aortic dissection. Although current literature lacks clear statistical evidence on the population, we offer points to encourage further confirmation of the best methods of care for these patients.

Impact of an immersive, interactive medical education initiative on guideline-based retinal disease management knowledge/competence and effectual practice change

BackgroundRetinal diseases, including wet or dry age-related macular degeneration, diabetic macular edema, and diabetic retinopathy (DR), are underdiagnosed and undertreated in the United States. Clinical trials support the effectiveness of anti-vascular endothelial growth factor (anti-VEGF) therapies for several retinal conditions, but real-world data suggest underuse by clinicians, resulting in patients experiencing poorer visual outcomes over time. Continuing education (CE) has demonstrated effectiveness at changing practice behaviors, but more research is needed to understand whether CE can help address diagnostic and treatment gaps.MethodsThis test and control matched pair analysis examined pre-/post-test knowledge of retinal diseases and guideline-based screening and intervention among 10,786 healthcare practitioners (i.e., retina specialists, ophthalmologists, optometrists, primary care providers, diabetes educators, pharmacists/managed care specialists, and other healthcare providers, such as registered nurses, nurse practitioners, and physician assistants) who participated in a modular, interactive CE initiative. An additional medical claims analysis provided data on practice change, evaluating use of VEGF-A inhibitors among retina specialist and ophthalmologist learners (n = 7,827) pre-/post-education, compared to a matched control group of non-learners. Outcomes were pre-/post-test change in knowledge/competence and clinical change in application of anti-VEGF therapy, as identified by the medical claims analysis.ResultsLearners significantly improved knowledge/competence scores on early identification and treatment, identifying patients who could benefit from anti-VEGF agents, using guideline-recommended care, recognizing the importance of screening and referral, and recognizing the importance of early detection and care for DR (all P-values = 0.003 to 0.004). Compared with matched controls, learners’ incremental total injections for anti-VEGF agents for retinal conditions increased more after the CE intervention (P < 0.001); specifically, there were 18,513 more (new) anti-VEGF injections prescribed versus non-learners (P < 0.001).ConclusionsThis modular, interactive, immersive CE initiative resulted in significant knowledge/competence gains among retinal disease care providers and changes in practice-related treatment behaviors (i.e., appropriate consideration and greater incorporation of guideline-recommended anti-VEGF therapies) among participating ophthalmologists and retina specialists compared to matched controls. Future studies will utilize medical claims data to show longitudinal impact of this CE initiative on treatment behavior among specialists and impact on diagnosis and referral rates among optometrists and primary care providers who participate in future programming.

Интравитреальное введение ингибиторов ангиогенеза пациентам с лучевой ретинопатией при увеальной меланоме

Relevance. Radiation retinopathy and maculopathy are the most common causes of visual impairment in patients with uveal melanoma treated with plaque radiotherapy. There are no standards of medical care for such patients, and various therapeutic methods of treatment are limited by rather poor results. The use of vascular endothelial growth factor inhibitors is proposed worldwide to improve visual acuity or stabilize one's with the development of post-radiation retinopathy, even though today the use of such methods is «off label». Purpose. To analyze the development of radiation maculopathy in patients with uveal melanoma treated with plaque radiotherapy and its intravitreal anti–vascular endothelial growth factor treatment. Material and methods. To perform the review, a search was carried out for literature sources on the Pubmed and Scopus reference databases for the period up to 2022 inclusive using the following keywords: «uveal melanoma», «radiation maculopathy», «anti-vascular endothelial growth factor», «plaque therapy complications». A total of 39 articles related to the review topic were selected. Results. It can be concluded that intravitreal anti-vascular endothelial growth factor treatment of uveal melanoma shows its effectiveness in reducing the height of macular edema and in improving visual acuity. Conclusion. This method of therapy certainly necessitates repeated treatment, since with single injections it is not possible to achieve a positive result. However, it is impossible to predict how much vision will improve and how many injections of drugs each individual patient will need today. Key words: uveal melanoma, radiation maculopathy, anti-vascular endothelial growth factor, plaque therapy

Chondroitin/Lactoferrin-dual functionalized pterostilbene-solid lipid nanoparticles as targeted breast cancer therapy

Breast cancer remains the leading cause of cancer-associated mortality in women. Research investigating novel therapeutic approaches is thus crucial, including phytotherapeutics. Pterostilbene (PTS) is a phytochemical agent with promising efficacy against breast cancer. Poor solubility, low bioavailability and chemical instability are major drawbacks compromising PTS functionality. Herein, novel PTS-loaded solid lipid nanoparticles (PTS-SLNs) were fabricated using the ultrasonication technique. Dual-functionalization with lactoferrin (Lf) and chondroitin-sulfate (CS; CS/Lf/PTS-SLNs) was adopted as active-targeting approach. CS/Lf/PTS-SLNs demonstrated nanoparticle-size (223.42 ± 18.71 nm), low PDI (0.33 ± 0.017), acceptable zeta potential (-11.85 ± 0.07 mV) and controlled release (72.93 ± 2.93% after 24 h). In vitro studies on triple-negative MDA-MB-231 revealed prominent cytotoxicity of CS/Lf/PTS-SLNs (2.63-fold IC50 reduction), higher anti-migratory effect and cellular uptake relative to PTS-solution. The in vivo anti-tumor efficacy in an orthotopic cancer model verified the superiority of CS/Lf/PTS-SLNs; achieving 2.4-fold decrease in tumor growth compared to PTS-solution. On the molecular level, CS/Lf/PTS-SLNs enhanced suppression of VEGF, down-regulated cyclin D1 and upregulated caspase-3 and BAX, compared to PTS-solution. Also, immunohistochemical assay confirmed the higher anti-tumorigenic effect of CS/Lf/PTS-SLNs (5.87-fold decrease in Bcl-2 expression) compared to PTS-solution. Our findings highlight CS/Lf/PTS-SLNs as a promising nanoplatform for phytotherapeutic targeted-breast cancer therapy.

#4220 NOT JUST AIN? OTHER IMMUNE-CHECKPOINT INHIBITOR LESIONS: A SINGLE INSTITUTION'S EXPERIENCE OVER 12 YEARS

Abstract Background and Aims Immune-checkpoint inhibitors (ICI) are antineoplastic therapies that unleash the immune-system and have revolutionized cancer outcomes. Though they are a drug class with great potential, their effects are not always limited to the malignant cells and can cause a spectrum of immune-related adverse events (irAEs). Roughly 5% of patients will experience acute kidney injury (AKI) with acute interstitial nephritis (AIN) being the predominant pathologic lesion. Glomerular and vascular lesions are thought to be rare and, as a result, not well-defined. We aim to document glomerular and vascular pathology in this context at our institution. Method We performed a retrospective review of internal native renal biopsies from 2010-2022 that had known ICI treatment. Standard processing of renal biopsies included light microscopy (LM), immunofluorescence (IF), and electron microscopy (EM). We reviewed the biopsies and pathology reports, as well as clinical data from patient electronic medical records. Results Our search yielded 32 kidney biopsies; of those, most had AIN (27/32), 8 cases had glomerular pathology, and 1 case had arterial endotheliitis. Of the cases with glomerular pathology, 4 had subacute glomerular thrombotic microangiopathy (TMA). Among the cases with TMA, 2 were also treated with vascular endothelial growth factor inhibitor (VEGFi),1 with gemcitabine, and 1 with BRAF-inhibitor therapy. Further, only one of these patients had complement testing, which did not reveal definitive deficiency. One patient had proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), IgG-κ. One patient had IgA nephropathy (IgAN) and another had membranous nephropathy (MN). Most patients were biopsied for rising serum creatinine (SCr) (median: 1.6 mg/dL; range: 0.55-5.5); 1 had nephrotic-range proteinuria (median urine protein/creatinine ratio (UPCR): 0.3; range: 0.12-5.64). One, with thin basement membrane disease, had significant hematuria (&amp;gt;100 RBC/hpf). Five patients had irAEs in other organs. 7/9 patients died or entered hospice care (median: 14 months post-biopsy; range: 2-48 months) due to malignancy progression. Of the deceased patients, 2 were dialysis-dependent. Of the living patients, 1 has dialysis-independent chronic kidney disease (CKD). Conclusion Overall, glomerular and vascular pathology due to ICI-use appears rare though difficult to isolate since other drugs and neoplasia can cause similar lesions. In our cohort, TMA was the most common glomerular lesion, though direct causation due to ICI is difficult to prove. In all patients with TMA, we identified concurrent use of other known causative drugs. IgAN and MN have been reported in association with neoplasia. PGNMID has been reported in a variety of malignant and nonmalignant conditions, and ICI-use could be a triggering factor. In conclusion, the patterns of glomerular injury seen in our cohort may be secondary to other concurrent risk factors other than ICI use. Arterial endotheliitis appears to be a rare but significant secondary effect to ICI-use.

The Oncolytic herpes simplex virus type-1 (HSV-1) vaccine strain VC2 causes intratumor infiltration of functionally active T cells and inhibition of tumor metastasis and pro-tumor genes VEGF and PDL1 expression in the 4T1/Balb/c mouse model of stage four breast cancer.

Introduction: Oncolytic viruses (OVs) provide new modalities for cancer therapy either alone or in combination with synergistic immunotherapies and/or chemotherapeutics. Engineered Herpes Simplex Virus Type-1 (HSV-1) has shown strong promise for the treatment of various cancers in experimental animal models as well as in human patients, with some virus strains licensed to treat human melanoma and gliomas. In the present study we evaluated the efficacy of mutant HSV-1 (VC2) in a late stage, highly metastatic 4T1 murine syngeneic. Method: VC2 was constructed VC2 using double red recombination technology. For in-vivo efficacy we utilized a late stage 4T1 syngeneic and immunocompetent BALB/cJ mouse model breast cancer model which exhibits efficient metastasis to the lung and other organs. Results: VC2 replicated efficiently in 4T1 cells and in cell culture, achieving titers similar to those in African monkey kidney (Vero) cells. Intra-tumor treatment with VC2 did not appreciably reduce average primary tumor sizes but a significant reduction of lung metastasis was noted in mice treated intratumorally with VC2, but not with ultraviolet-inactivated VC2. This reduction of metastasis was associated with increased T cell infiltration comprised of CD4+ and CD4+CD8+ double-positive T cells. Characterization of purified tumor infiltrating T cells revealed a significant improvement in their proliferation ability compared to controls. In addition, significant T cell infiltration was observed in the metastatic nodules associated with reduction of pro-tumor PD-L1 and VEGF gene transcription. Conclusion: These results show that VC2 therapy can improve anti-tumor response associated with a better control of tumor metastasis. improve T cell responses and reduce pro-tumor biomarker gene transcription. VC2 holds promise for further development as an oncolytic and immunotherapeutic approach to treat breast and other cancers.

Development of a Silk Fibroin-Small Intestinal Submucosa Small-Diameter Vascular Graft with Sequential VEGF and TGF-β1 Inhibitor Delivery for In Situ Tissue Engineering.

Proper endothelialization and limited collagen deposition on the luminal surface after graft implantation plays a crucial role to prevent the occurrence of stenosis. To achieve these conditions, a biodegradable graft with adequate mechanical properties and the ability to sequentially deliver therapeutic agents isfabricated. In this study, a dual-release system is constructed through coaxial electrospinning by incorporating recombinant human vascular endothelial growth factor (VEGF) and transforming growth factor β1 (TGF-β1) inhibitor into silk fibroin (SF) nanofibers to form a bioactive membrane. The functionalized SF membrane as the inner layer of the graft is characterized by the release profile, cell proliferation and protein expression. It presents excellent biocompatibility and biodegradation, facilitating cell attachment, proliferation, and infiltration. The core-shell structure enables rapid VEGF release within 10 days and sustained plasmid delivery for 21 days. A 2.0-mm-diameter vascular graft is fabricated by integrating the SF membrane with decellularized porcine small intestinal submucosa (SIS), aiming to facilitate the integration process under a stable extracellular matrix structure. The bioengineered graft is functionalized with the sequential administration of VEGF and TGF-β1, and with the reinforced and compatible mechanical properties, thereby offers an orchestrated solution for stenosis with potential for in situ vascular tissue engineering applications.

Delineating effects of angiopoietin-2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia/reperfusion.

Clinical trials demonstrated that co-targeting angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF-A) with faricimab controls anatomic outcomes and maintains vision improvements, with strong durability, through 2 years in patients with neovascular age-related macular degeneration and diabetic macular edema. The mechanism(s) underlying these findings is incompletely understood and the specific role that Ang-2 inhibition plays requires further investigation. We examined the effects of single and dual Ang-2/VEGF-A inhibition in diseased vasculatures of JR5558 mice with spontaneous choroidal neovascularization (CNV) and in mice with retinal ischemia/reperfusion (I/R) injuries. In JR5558 mice, Ang-2, VEGF-A, and dual Ang-2/VEGF-A inhibition reduced CNV area after 1 week; only dual Ang-2/VEGF-A inhibition decreased neovascular leakage. Only Ang-2 and dual Ang-2/VEGF-A inhibition maintained reductions after 5 weeks. Dual Ang-2/VEGF-A inhibition reduced macrophage/microglia accumulation around lesions after 1 week. Both Ang-2 and dual Ang-2/VEGF-A inhibition reduced macrophage/microglia accumulation around lesions after 5 weeks. In the retinal I/R injury model, dual Ang-2/VEGF-A inhibition was statistically significantly more effective than Ang-2 or VEGF-A inhibition alone in preventing retinal vascular leakage and neurodegeneration. These data highlight the role of Ang-2 in dual Ang-2/VEGF-A inhibition and indicate that dual inhibition has complementary anti-inflammatory and neuroprotective effects, suggesting a mechanism for the durability and efficacy of faricimab in clinical trials.

Impact of Renal Function on the Prognosis of Patients Receiving Atezolizumab/Bevacizumab Combination Therapy and Lenvatinib Monotherapy for Unresectable Hepatocellular Carcinoma

Introduction: Several studies have reported kidney injury caused by immune checkpoint inhibitors, and proteinuria caused by vascular endothelial growth factor inhibitors for unresectable hepatocellular carcinoma (u-HCC). We investigated the relationship between renal function and prognosis in patients with u-HCC receiving atezolizumab and bevacizumab (AB) and lenvatinib (LEN) therapy. Methods: Fifty-one patients who received AB and 50 patients who received LEN therapy were included. We analyzed prognostic factors related to the overall survival (OS), and characteristics related to renal function. Results: In patients with AB therapy, OS was shorter in patients with baseline proteinuria of 1+ or higher, as assessed by urine dipstick test, compared to those with –/± (p = 0.024). There were many cases with two or more drugs with a high risk of renal dysfunction (p = 0.019) in patients with 1+ or higher. Furthermore, OS was shorter in the group with estimated glomerular filtration rate (eGFR) grade deterioration without urinary protein-creatinine ratio (UPCR) of 2 g/g·Cre or higher than in the other groups (p = 0.027). In the group where eGFR worsened without an increase in UPCR, there were many cases with a daily salt intake of 10 g or more (p = 0.027), three or more drugs with a high risk of renal dysfunction (p = 0.021), and a history of arteriosclerosis (p = 0.021). On the other hand, in patients with LEN therapy, OS tends to be shorter in patients with proteinuria of ± or higher, compared to those without (p = 0.074). There were many cases with a daily salt intake of 10 g or more in patients with ± or higher (p = 0.002). Conclusion: In patients receiving AB and LEN therapy, baseline proteinuria was associated with OS. Renal function deterioration without proteinuria was associated with a poor prognosis in AB therapy. Excessive salt intake, preexisting atherosclerotic disease, and drug with a high risk of renal dysfunction were risk factors for renal deterioration.

Long-term Outcomes of Bevacizumab and Chemoradiation for Locoregionally Advanced Nasopharyngeal Carcinoma

The long-term outcomes associated with adding bevacizumab, a vascular endothelial growth factor inhibitor, to standard chemoradiation have continued to be favorable for a group of patients with locoregionally advanced nasopharyngeal carcinoma (NPC). To assess long-term toxic effects and clinical outcomes associated with chemotherapy, radiation therapy (RT), and bevacizumab for NPC. This single-arm phase II nonrandomized controlled trial was conducted by the National Cancer Trials Network group and NRG Oncology (formerly Radiation Therapy Oncology Group), with accrual from December 13, 2006, to February 5, 2009, and data analysis from June 26 to July 1, 2019. The study was conducted at 19 cancer centers with a median (IQR) follow-up of 9.0 (7.7-9.3) years. Included patients were adults (aged ≥18 years) with NPC that was World Health Organization (WHO) histologic grade I to IIb or III, American Joint Committee on Cancer stage IIB or greater, and with or without lymph node involvement. Patients received 3 cycles of bevacizumab (15 mg/kg) concurrently with standard cisplatin (100 mg/m2) and RT (69.96 Gy) followed by 3 cycles of adjuvant bevacizumab (15 mg/kg) given concurrently with cisplatin (80 mg/m2) and fluorouracil (1000 mg/m2/d). The primary end point was grade 4 hemorrhage or grade 5 adverse events in the first year. Secondary end points were locoregional progression-free (LRPF) interval, distant metastasis-free (DMF) interval, progression-free survival (PFS), overall survival (OS), and other adverse events. Long-term toxic effects and clinical outcomes were reported due to the limited follow-up in the initial report for this trial and the importance of long-term outcomes when combining bevacizumab with chemoradiation. Among 46 patients with NPC who were enrolled, 44 patients were analyzed (29 males [65.9%]; 23 Asian [52.3%], 2 Black [4.5%], and 16 White [36.4%]; 38 not Hispanic [86.4%]; median [IQR] age, 48.5 [39.0-56.0] years). There were 33 patients with a Zubrod performance status of 0, indicating that they were fully functional and asymptomatic (75.0%); 32 patients with a WHO histologic grade of IIb or III (72.7%); and 39 patients with stage III or IVB disease (88.6%). Among analyzed patients, 42 individuals received radiation therapy of 69.96 Gy or greater (95.5%; dose range, 65.72-70.00 Gy); 30 patients received 3 cycles of cisplatin (68.2%) with RT, and 31 patients received 3 cycles of bevacizumab with RT (70.5%); this was followed by 3 cycles of adjuvant cisplatin in 21 patients (47.7%), fluorouracil in 24 patients (54.5%), and bevacizumab in 23 patients (52.3%). No grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter. Late grade 3 AEs occurred in 16 patients (36.4%), including 7 patients with dysphagia (15.9%), 6 patients with hearing impairment (13.6%), and 2 patients with dry mouth (4.5%). The 1- and 5-year rates of feeding tube use were 5 of 41 patients (12.2%) and 0 of 27 patients, respectively. There were 19 patients (43.2%) who progressed or died without disease progression (6 patients with locoregional progression [13.6%], 8 patients with distant progression [18.2%], and 5 patients who died without progression [11.4%]). The 5- and 7-year rates were 79.5% (95% CI, 67.6%-91.5%) and 69.7% (95% CI, 55.9%-83.5%) for OS, 61.2% (95% CI, 46.8%-75.6%) and 56.3% (95% CI, 41.5%-71.1%) for PFS, 74.9% (95% CI, 61.4%-86.6%) and 72.3% (95% CI, 58.4%-84.7%) for LRPF interval, and 79.5% (95% CI,66.4%-90.0%) for both times for DMF interval. Among 13 patients who died, death was due to disease in 8 patients (61.5%). In this nonrandomized controlled trial, no grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter among patients with NPC receiving bevacizumab combined with chemoradiation. The rate of distant metastasis was low although 89% of patients had stage III to IVB disease, suggesting that further investigation may be warranted. ClinicalTrials.gov Identifier: NCT00408694.

Adverse events (AEs) of immune checkpoint therapy (ICT) combined with vascular endothelial growth factor inhibitors (VEGFi) vs. ICT alone: A pooled meta-analysis of 1735 patients.

e14667 Background: ICT combined with VEGFi are established as approved therapies for multiple malignancies. However, added toxicities remain unclear. We hypothesized that the combination of ICT + VEGFi has higher treatment-related AEs (TRAEs) and immune-related AEs (irAEs) compared with ICT alone. Methods: We performed a meta‐analysis to identify studies evaluating toxicity profile of ICT + VEGFi as compared to ICT. Systemic search was performed across all cancer types and major databases until August 10, 2022. Search structures, subject headings, and keywords were tailored to databases by medical research librarian. Screening of studies was done by two investigators. Inclusion criteria consisted of prospective phase II or III clinical studies which included at least one arm of patients treated with ICT + VEGFi and one arm treated with ICT alone. Restricted maximum likelihood fixed effects model was used to pool AEs data; I2 was used for heterogeneity. Results: From a total of 9366 studies found, seven met inclusion criteria. A total of 808 patients were treated with ICT while 927 were treated with ICT + VEGFi. Only one study reported irAEs. Therefore, we restricted our analysis to TRAEs. The total number of TRAEs (including grade 5) was significantly higher in ICT + VEGFi group with more frequent treatment withdrawals attributed to TRAEs. The list of TRAEs and specific effect sizes are summarized. The highest TRAE effect size increases with ICT + VEGFi were noted for rash (RR 6.50), hypertension (RR 6.07), hypothyroidism (RR 5.02), and diarrhea (RR 4.94). Conclusions: Combination therapy with ICT + VEGFi confers increased risk of specific TRAEs in comparison to ICT. Clinicians should be particularly mindful of the increased risk for rash, hypertension, hypothyroidism, diarrhea, nausea, anorexia, and proteinuria with ICT + VEGFi therapies. There are insufficient data on irAEs and future trials should provide more granular details on the AE cause. [Table: see text]

VEGF INHIBITION-INDUCED PARP OVERACTIVATION LEADS TO ENDOTHELIAL DYSFUNCTION AND INFLAMMATION: ROLE OF SIRTUIN 1 SIGNALLING

Objective: Hypertension is a common unwanted effect of VEGF inhibitors (VEGFi), which are used as anti-angiogenic drugs in cancer treatment. Clinical observations indicate that the magnitude of blood pressure elevation is lower in patients with cancer who are treated with combination VEGFi and olaparib (PARP inhibitor [PARPi]), versus monotherapy. However putative vascular mechanisms are unknown. PARP plays major role in the activation of TRPM2, a redox-sensitive Ca2+ channel, which is associated with hypertension-induced vascular dysfunction. PARP also regulates sirtuin deacetylases activity, especially sirtuin 1 (SIRT1), which is involved in vascular homeostasis and diseases. Here our aim is to investigate whether VEGFi, via PARP activation, leads to vascular dysfunction through disruption of SIRT1 signalling. Design and method: Human aortic endothelial cells (HAEC) and mouse mesenteric arteries were studied. Cells were exposed to axitinib (VEGFi; 1uM) alone or in combination with olaparib (PARPi; 1uM) in the presence or absence of a SIRT1 activator (SRT1720; 2uM). Wire myograph was used to assess vascular function. Results: Axitinib increased PARP activity in a ROS-dependent manner in HAEC (au: [Veh]0.31 vs. [Axi]0.55; [Tiron+Axi] 0.38] whereas SIRT1 activity was reduced by VEGF inhibition (au: [Veh]33760 vs. [Axi]23367), which was prevented by olaparib. This was followed by an increase in expression of acetyl-p53. Activation of SIRT1 decreased levels of MCP-1 and IL-6 and VCAM-1 and ICAM-1 mRNA levels in HAEC exposed to axitinib, which, similarly to olaparib, was accompanied by a reduction in monocytes adhesion to HAEC. U46619- and ET-1-induced vasoconstriction were increased by axitinib, an effect not observed with axitinib plus Olaparib. Pre-incubation with SRT1720 exacerbated the anti-contractile effects of olaparib. Axitinib impaired ACh-induced vasodilation (% relaxation: 70.5 [Ct] vs. 34.8 [Axi]), which was blocked by olaparib and SRT1720. Phosphorylation of the inhibitory site of eNOS was also increased in HAEC (au: [Veh] 0.18 vs. [Axi] 0.37) and restored by SRT1720. Conclusions: Our data indicate that VEGF inhibition-induced PARP overactivation leads to endothelial dysfunction and inflammatory responses via disruption of SIRT1 signalling. We define a putative vasoprotective effect of olaparib that may ameliorate vascular injury induced by VEGFi in cancer treatment.

Association of neutrophil/lymphocyte ratio and IFN-γ with clinical response and survival in patients with MSS/pMMR mCRC treated with anti-PD-1 and VEGF inhibitors.

e14610 Background: The findings on the clinical effect of the therapy with anti-PD-1 Abs plus angiogenic receptor inhibitors in the treatment of MSS/pMMR mCRC have been inconsistent. The aim of this study was to evaluate the prognostic and predictive role of NLR and IFN-γ in mCRC treated with anti-PD-1 and angiogenic receptor inhibitors. Methods: A total number of 35 patients with MSS/pMMR colorectal cancer treated with anti-PD-1 and angiogenic receptor inhibitors at Shanghai Tenth People’s Hospital (Shanghai, China) between December 2019 and January 2023 were retrospectively evaluated. We reviewed the tumor response and progression-free survival (PFS), and evaluated the associations among neutrophil-to-lymphocyte ratio (NLR), cytokines, and outcomes in the treatment of MSS/pMMR mCRC. A cut-off value of 3 was adopted to discriminate patients with low (NLR &lt; 3) versus high (NLR &gt; 3) NLR. A cut-off value of 2.7 was employed to discriminate patients with low (IFN-γ &lt; 2.7) versus high (IFN-γ &gt; 2.7) IFN-γ. Tissue samples from the mCRC patients were stained with CD4, CD8 to establish the immune status. Results: Of the remaining 25 mCRC patients, 14 received sintilimab and fruquintinib, 3 received sintilimab and regorafenib, 6 received camrelizumab and fruquintinib, and 2 received raltizumab and fruquintinib. Two patients were treated with PEG-rhG-CSF, and one patient had myelosuppression after previous chemotherapy. Thus, the NLR ratio could not be calculated in these three patients. Meanwhile, among the 25 patients, 4 patients no cytokine test had been performed before the treatment with anti-PD-1 and VEGF inhibitors. Thus, cytokine analyses were conducted only in the remaining 21 patients. Partial response and stable disease were found in 5 (20%) and 8 (32%) patients, respectively. The disease control rate was 52%. The pretreatment NLR ratio and IFN-γ level of the responder and stable patients were higher than those in progressive patients ( P = 0.0010, n = 22; P = 0.0267, n = 21, respectively). Higher baseline levels of NLR ratio and IFN-γ was associated with longer progression-free survival in mCRC patients receiving anti-PD-1 and angiogenic receptor inhibitors. NLR and IFN-γ were also positively correlated with PFS (R2 = 0.3334, P = 0.0049; R2 = 0.4063, P = 0.0019) respectively. Patients getting clinical benefits (PR+SD) were found CD4+ T cells infiltrated (P = 0.0074). Conclusions: Higher NLR ratio and IFN-γ level are prognostic factors associated with longer progression-free survival and better response of MSS/pMMR mCRC patients to anti-PD-1 and angiogenic receptor inhibitors. NLR ratio and IFN-γ level pretreatment could be predictive factors of the response to anti-PD-1 and angiogenic receptor inhibitors in MSS/pMMR mCRC patients. Clinical trial information: ChiCTR2300067767 .

Outcomes with bevacizumab for radiation induced-brain necrosis.

e14006 Background: Radiation necrosis (RN) is post-radiation complication that leads to increased permeability and disruption of the blood brain barrier (BBB). This in turn leads to a pro-inflammatory state and an increased production of vascular-endothelial growth factor (VEGF). Bevacizumab is a monoclonal antibody against VEGF and is a potential treatment for RN. The objective of the study is to assess effectiveness of bevacizumab (BEV) for the treatment of brain RN in adults. Methods: Retrospective chart review of 22 patients with various solid malignancies including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), metastatic melanoma and breast cancer with clinical or radiographic diagnosis of RN seen at Memorial Cancer Institute (MCI) in a 3-year period, from January 1st, 2019 to January 1st, 2023. Radiation doses ranged from 18-24 Gy (single fraction) or 24-27 Gy (3-fraction) for radiosurgery and 30-37.5 Gy for whole brain radiotherapy. Patients were identified that developed RN and VEGF inhibitors were subsequently given to assess effectiveness in the treatment of the condition. We evaluated the dose, frequency, number of treatments received, adverse effects and therapeutic benefits of BEV. Therapeutic benefit was defined as patients that received bevacizumab had a radiological and clinical improvement of the RN (clinical benefit). Brain imaging with MRI or PET/CT scan was completed both pre and post treatment to evaluate efficacy of treatment. Patients were initially given 4 cycles with a subsequent 4 more cycles if it was beneficial and tolerated treatment. Results: 22 patients were included in the study, 9 were males (41%) and median age 66 (range 31-81). 91% (20/22) had a diagnosis of lung cancer. 1 patient had a diagnosis of SCLC, while 19 were diagnosed with NSCLC. The study had a good representation of different races including Non-Hispanic Whites 7 (32%), Hispanics 10 (45%), Blacks 13% (3) and Asians 10% (2). Over 95% (21/22) of patients achieved a clinical benefit, while one patient did not (5%). Patients experienced improvement in cognitive function, headaches, dizziness, weakness, and other symptoms with BEV. MRIs showed improvement in edema and a reduction/stabilization of brain lesions. The most frequent dosing regimen used was BEV 10 mg/kg every two weeks. The median number of cycles given was 4 cycles (1-12). The most common adverse events were hypertension, minor nose bleeding, an occasional protein found in urine. There were no severe AEs or discontinuation of therapy with bevacizumab. Conclusions: This study demonstrated treatment with BEV 10 mg/kg every two weeks for a total of 12 cycles is well tolerated and has potential clinical benefit in RN in lung cancer patients with CNS metastasis. The therapeutic effects of VEGF inhibitors were seen in our small population study but warrants further investigation in a larger population study.

NRG-GU012: Randomized phase II stereotactic ablative radiation therapy (SABR) for patients with metastatic unresected renal cell carcinoma (RCC) receiving immunotherapy (SAMURAI).

TPS4604 Background: The treatment for patients with metastatic RCC is evolving. The current standard of care for patients presenting with de novo metastatic disease is combination immunotherapy (IO)-based treatment. At the time of this shift in the systemic treatment strategy, the role of immediate cytoreductive nephrectomy has also been in flux. For patients with de novo disease, there has been a shift towards initiation of upfront systemic rather than immediate cytoreductive nephrectomy. SABR is a highly focused radiation technique that delivers a high dose of radiation over a limited number of fractions. The SAMURAI trial seeks to evaluate SABR as an alternative approach to treat the primary tumor in patients with metastatic RCC receiving IO, who are not recommended for surgery, or who decline surgery. Methods: This is a randomized phase II trial for patients with metastatic RCC with an intact primary tumor. Eligible patients include those with any histology RCC who are candidates to receive standard IO combination treatment and are those not recommended for upfront surgery or decline surgery. Patients will be randomized to SABR + IO combination versus IO combination alone. The primary objective of the study is to determine whether the addition of SABR to the primary tumor in combination with IO improves outcomes compared to IO alone in patients with metastatic, unresected, RCC. The primary endpoint is nephrectomy and radiographic progression-free survival (nrPFS) with progression determined as per iRECIST criteria. Patients are eligible if they are not recommended for upfront surgery, have a primary tumor treatable with SABR, and are candidates for IO. Choice of IO combination regimen will be at the discretion of the treating physician and will include either IO-IO or regimens of IO in combination with a VEGF inhibitor (IO-VEGF). 240 patients will be randomized in a 2:1 ratio favoring SABR plus IO combination (n=160) as compared to standard of care IO combination alone (n=80). The sample size will provide 90% power at a one-sided alpha level of 0.05 to detect a hazard ratio for nrPFS of 0.62, i.e., an approximate 40% reduction in the rate of events. Secondary endpoints include objective response rate by iRECIST and RECIST, radiographic progression free survival by RECIST and iRECIST, time to second line therapy, rate of cytoreductive nephrectomy, treatment free survival, and overall survival. Exploratory analyses will assess potential prognostic and predictive biomarkers. The trial is currently open and accruing through the NRG oncology cooperative group (NCT05327686) and study information can be found through the Cancer Trials Support Unit website www.ctsu.org . Clinical trial information: NCT05327686 .