Vascular Endothelial Growth Factor Inhibitors Research Articles

Understanding Loss to Follow-Up in AMD Patients Receiving VEGF Inhibitor Therapy: Associated Factors and Underlying Reasons.

In patients with wet age-related macular degeneration (AMD), loss to follow-up (LTFU) leads to unplanned interruptions in therapy and the risk of visual loss. This retrospective and prospective case-control cohort study compared AMD patients with (LTFU YES) and without (LTFU NO) LTFU during anti-VEGF treatment over 12 years. LTFU was defined as missing any treatment or monitoring visits, or not scheduling follow-ups for six months. Significant differences between LTFU NO (n = 298) and LTFU YES (n = 174) groups were age, treatment phase, baseline and final best-corrected visual acuity (BCVA), type of anti-VEGF drug, treatment switch, commuting distance, and escort during commuting. A multivariate logistic regression analysis identified the need for an escort during the commuting and treatment phase as the only significant difference. The four most common reasons for LTFU were general health worsening (21.8%), patient-missed appointments (16.7%), COVID-19-related issues (14.9%), and treatment dissatisfaction (8.6%). The factors associated with increased LTFU rates were older age, inactive treatment phase, lower baseline and final BCVA, bevacizumab treatment, monotherapy, longer travelling distance, and commuting with an escort. According to the multivariate logistic regression analysis, only the escort during the commuting and treatment phases was significant. These findings could direct research to explore social support in treatment adherence and highlight the importance of treatment phases in practice.

Effect of Intravitreal Anti-Endothelial Growth Factor Agents on Renal Function in Patients With Diabetes Mellitus

BackgroundIntravitreal administration of vascular endothelial growth factor inhibitors (anti-VEGF) is the treatment of choice in retinal pathology associated with type 2 diabetes mellitus (DM2). We aimed to analyze the effect on renal function in patients with DM2 after intravitreal anti-VEGF administration. MethodsSingle-center retrospective and observational study of patients with DM2 with and without chronic kidney disease (CKD). We analyzed the evolution of renal function after anti-VEGF onset, compared with a control group. ResultsWe included 45 patients (55.6% male) who received anti-VEGF therapy. Mean age was 74.4±11.5 (50-91) years. These were compared with 45 patients with similar characteristics. After 12-months, 76.3% had CKD with a mean reduction in estimate glomerular filtration rate (eGFR) of 19.4%. Nine patients (20%) had a >25% reduction in eGFR, and three patients (6.7%) had a >50% reduction in GFR. At 24-months, 80% of patients had CKD with a mean eGFR drop of 28%. The mean eGRF slope of patients who had received anti-VEGF treatment was 10 ml/min/year compared to 1,5 ml/min/year in the control group (p<0.05). After the first administration, five patients (17.2%) in the CKD group required renal replacement therapy during follow-up (mean time 22±12 months). Main risk factors for need of dialysis were age, presence of previous CKD, and baseline proteinuria. ConclusionIntravitreal anti-VEGF administration is a risk factor for CKD and rapid progression to end-stage kidney disease in patients with previous CKD. Knowing these drugs' implications is crucial to avoid CKD progression and opportunely limit their use in certain patients.

Retraction: Multimodal targeting of tumor vasculature and cancer stem-like cells in sarcomas with VEGF-A inhibition, HIF-1α inhibition, and hypoxia-activated chemotherapy.

Retraction: Multimodal targeting of tumor vasculature and cancer stem-like cells in sarcomas with VEGF-A inhibition, HIF-1α inhibition, and hypoxia-activated chemotherapy.

Evolving metastatic renal cell carcinoma (mRCC) treatment landscape in the post vascular endothelial growth factor (VEGF) and immune checkpoint inhibitor (IO) setting.

406 Background: IO and VEGF based therapies have transformed the front-line treatment paradigm for patients with mRCC. This study's objective is to describe treatment patterns and clinical outcomes among mRCC patients in the post IO and VEGF setting. Methods: Adult patients diagnosed with mRCC between Jan 2015 - Dec 2022 and received IO and VEGF (in combination or sequence) in the first three lines of therapy after mRCC diagnosis were identified from Optum’s de-identified Clinformatics® Data Mart Database, a large retrospective claims database. Index date was defined as the date of the first (index) treatment in the post IO and VEGF setting. Patients were required to have continuous enrollment of 6 months prior to index date. Patients were categorized into 3 cohorts based on lines of index treatment (2L, 3L, 4L). Treatment patterns were described and real world (rw) time on treatment (ToT), time to next treatment (TTNT), and overall survival (OS) were estimated by Kaplan Meier analysis. Results: A total of 664 patients were included (2L:186, 3L:429, 4L:49). 37% received IO and VEGF in combination prior to index line of therapy. Median age at mRCC diagnosis was 67.0 years, with 72.7% male and 68.1% White; 11.6% died and 7.4% disenrolled during index treatment. Post IO and VEGF, cabozantinib was the most used therapy across 3 cohorts (2L: 43.5%, 3L: 35.2%, 4L: 30.6%) (Table). Median rwToT and rwTTNT for 2L, 3L, and 4L cohorts were 4.4, 5.0, and 5.6 months and 10.7, 11.7, and 9.5 months, respectively. Median OS from mRCC diagnosis was similar across the 3 cohorts (2L: 41.6, 3L: 38.7, 4L: 40.6 months); median OS from index date decreased with advancement in LOT (2L: 20.6, 3L: 14.1, 4L: 10.3 months). Conclusions: Our study is one of the largest and comprehensive study giving a unique perspective into evolving treatment patterns and outcomes for mRCC patients in the post IO and VEGF setting. Post IO+VEGF, the most common treatments were tyrosine kinase inhibitor-based treatments, and the median ToT was less than 6 months. Hence, novel treatments are needed to improve clinical outcomes for mRCC patients in the post IO and VEGF setting. [Table: see text]

A phase II study of neoadjuvant tislelizumab and axitinib in patients with locally advanced non-metastatic clear cell renal cell carcinoma (accRCC).

420 Background: PD-1/PD-L1 combined with vascular endothelial growth factor (VEGF) inhibitors improves survival in patients with advanced renal cell carcinoma (RCC), but the role of perioperative application in patients with localized RCC has not been established. In this phase II trial, we investigate the safety and role of tislelizumab and axitinib in downsizing tumors in patients with non-metastatic clear cell RCC prior to surgical resection. Methods: In this investigator-initiated study, 20 patients with high-risk non-metastatic ccRCC (clinical stage T2a-4 and/or N1, M0 lesions) were enrolled to receive 12 weeks of neoadjuvant ticelizumab and axitinib prior to nephrectomy. The primary endpoint was the objective response rate (complete and partial response) after neoadjuvant treatment according to RECIST v1.1. Secondary endpoints were disease-free survival (DFS), overall survival (OS), surgical outcome and safety. Results: By September 2023,13 eligible pts were enrolled. 11 pts have completed neoadjuvant therapy, with a median age of 60 (range 45-73) years, among whom 9 pts underwent surgery as planned without any delay. One patient progressed during treatment and received further systemic therapy. In 9 pts evaluable for efficacy, the investigator-assessed confirmed ORR was 55.5%. The median reduction of primary renal tumor size was 26.2% (range 12.5-45%). Pathologic results showed that one patient (11.1%) achieved a complete response (CR) by RECIST 1.1 and four patients achieved a partial response (PR). One patient who was considered unresectable became resectable at the end of treatment. Two patients were converted from radical to partial nephrectomy. The most common neoadjuvant therapy-related AEs were hematologic toxicity, hypothyroidism, nausea, vomiting, decreased appetite, fatigue, diarrhea, and elevated ALT/AST. There were no Gr4/Gr5 TRAEs. No direct intraoperative complications and no drug-related surgical complications postoperatively. Conclusions: As a neoadjuvant therapy for accRCC, the combination of tislelizumab and axitinib has clinical efficacy and a manageable safety profile. Clinical trial information: NCT05172440 .

Analysis of the Potential Angiogenic Mechanisms of BuShenHuoXue Decoction against Osteonecrosis of the Femoral Head Based on Network Pharmacology and Experimental Validation.

Osteonecrosis of the femoral head (ONFH) is a common orthopedic disease with a high disability rate. The clinical effect of BuShenHuoXue decoction (BSHX) for ONFH is satisfactory. We aimed to elucidate the potential angiogenic mechanisms of BSHX in a rat femoral osteonecrosis model and bone marrow mesenchymal stem cells (BMSCs). With in vivo experiments, we established the steroid-induced osteonecrosis of the femoral head (SONFH) model using Sprague-Dawley (SD) rats (8-week-old). The rats were randomly divided into five group of 12 rats each and given the corresponding interventions: control, model (gavaged with 0.9% saline), BSHX low-, medium- and high-dose groups (0.132 3, 0.264 6, and 0.529 2 g/mL BSHX solution by gavage). After 12 weeks, haematoxylin and eosin (H&E) staining was preformed to evaluate rat osteonecrosis. the expression of angiogenic factors (CD31, VEGFA, KDR, VWF) in rat femoral head was detected by immunohistochemistry, qPCR and western blotting. In cell experiment, BMSCs were isolated and cultured in the femoral bone marrow cavity of 4-week-old SD rats. BMSCs were randomly divided into eight groups and intervened with different doses of BSHX-containing serum and glucocorticoids: control group (CG); BSHX low-, medium-, and high-dose groups (CG + 0.661 5, 1.323, and 2.646 g/kg BSHX gavage rat serum); dexamethasone (Dex) group; and Dex + BSHX low-, medium-, and high-dose groups (Dex + 0.661 5, 1.323, and 2.646 g/kg BSHX gavaged rat serum), the effects of BSHX-containing serum on the angiogenic capacity of BMSCs were examined by qPCR and Western blotting. A co-culture system of rat aortic endothelial cells (RAOECs) and BMSCs was then established. Migration and angiogenesis of RAOECs were observed using angiogenesis and transwell assay. Identification of potential targets of BSHX against ONFH was obtained using network pharmacology. BSHX upregulated the expression of CD31, VEGFA, KDR, and VWF in rat femoral head samples and BMSCs (p < 0.05, vs. control group or model group). Different concentrations of BSHX-containing serum significantly ameliorated the inhibition of CD31, VEGFA, KDR and VWF expression by high concentrations of Dex. BSHX-containing serum-induced BMSCs promoted the migration and angiogenesis of RAOECs, reversed to some extent the adverse effect of Dex on microangiogenesis in RAOECs, and increased the number of microangiogenic vessels. Furthermore, we identified VEGFA, COL1A1, COL3A1, and SPP1 as important targets of BSHX against ONFH. BSHX upregulated the expression of angiogenic factors in the femoral head tissue of ONFH model rats and promoted the angiogenic capacity of rat RAOECs and BMSCs. This study provides an important basis for the use of BSHX for ONFH prevention and treatment.

MicroRNA-34a-Dependent Attenuation of Angiogenesis in Right Ventricular Failure.

The right ventricle (RV) is at risk in patients with complex congenital heart disease involving right-sided obstructive lesions. We have shown that capillary rarefaction occurs early in the pressure-loaded RV. Here we test the hypothesis that microRNA (miR)-34a, which is induced in RV hypertrophy and RV failure (RVF), blocks the hypoxia-inducible factor-1α-vascular endothelial growth factor (VEGF) axis, leading to the attenuated angiogenic response and increased susceptibility to RV failure. Mice underwent pulmonary artery banding to induce RV hypertrophy and RVF. Capillary rarefaction occurred immediately. Although hypoxia-inducible factor-1α expression increased (0.12±0.01 versus 0.22±0.03, P=0.05), VEGF expression decreased (0.61±0.03 versus 0.22±0.05, P=0.01). miR-34a expression was most upregulated in fibroblasts (4-fold), but also in cardiomyocytes and endothelial cells (2-fold). Overexpression of miR-34a in endothelial cells increased cell senescence (10±3% versus 22±2%, P<0.05) by suppressing sirtulin 1 expression, and decreased tube formation by 50% via suppression of hypoxia-inducible factor-1α, VEGF A, VEGF B, and VEGF receptor 2. miR-34a was induced by stretch, transforming growth factor-β1, adrenergic stimulation, and hypoxia in cardiac fibroblasts and cardiomyocytes. In mice with RVF, locked nucleic acid-antimiR-34a improved RV shortening fraction and survival half-time and restored capillarity and VEGF expression. In children with congenital heart disease-related RVF, RV capillarity was decreased and miR-34a increased 5-fold. In summary, miR-34a from fibroblasts, cardiomyocytes, and endothelial cells mediates capillary rarefaction by suppressing the hypoxia-inducible factor-1α-VEGF axis in RV hypertrophy/RVF, raising the potential for anti-miR-34a therapeutics in patients with at-risk RVs.

Transthyretin-Regulated Diabetic Retinopathy Through the VEGFA/PI3K/AKT Pathway.

Transthyretin (TTR) plays a regulatory role in a variety of diabetes-related diseases. The objective of this work was to probe whether TTR affects diabetic retinopathy (DR) through the VEGFA/PI3K/AKT pathway. High glucose (HG, 25mM) was used to treat human retinal microvascular endothelial cells (hRMECs) and C57BL/6J mice were intraperitoneally injected with STZ (50mg/kg) to construct a DR model. In vitro, the effect of TTR on DR was evaluated by measuring hRMEC proliferation, migration, and angiogenesis. The changes in retinal tissue were observed by hematoxylin and eosin staining in vivo. ELISA, immunohistochemistry, and immunofluorescence staining were used to measure VEGFA or CD31 levels. The levels of all proteins were evaluated through Western blot. The increase of proliferation, migration, and angiogenesis and decrease of apoptosis in hRMECs caused by HG were notably reversed by TTR. TTR greatly impeded HG-raised VEGFA, PI3K p-p85, and p-AKT in hRMECs. Inhibition of TTR further exacerbated the effect of HG-induced hRMECs. Inhibition of VEGFA reversed the effect of HG-induced hRMECs. VEGFA neutralized the function of TTR on cell proliferation, apoptosis, migration, and angiogenesis in HG-triggered hRMECs. It was further confirmed in vivo that TTR can alleviate the occurrence of DR in diabetic mice models. TTR significantly restrained the progression of DR via molecular modulation of the VEGFA/PI3K/AKT axis.

Cancer drugs and diabetic retinopathy: a dangerous, underestimated association

The worldwide growing prevalence of diabetes and cancer led to an increase in subjects affected by both these diseases that share several of the involved risk factors and have a complex, multifactorial etiopathogenesis. Cancer therapies could have harmful effects on several organs, particularly in subjects also affected by diabetes and its related comorbidities. Moreover, cancer diagnosis often monopolizes the attention of both patients and caregivers, thus reducing the attention to pre-existent diseases. Retinopathy is one of the most frequent microvascular complications of diabetes, accounting for about 5% of legal blindness worldwide. The retinal neurovascular unit is dysfunctional in diabetes and could represent a frail site when cancer therapies are administered. Nevertheless, the short- and long-term effects of the different anticancer molecules on retinal tissue, especially in diabetic subjects, are poorly known, and no specific recommendations on their prevention and management are available. In this review, we summarised the current data on this topic, focusing on the different cancer class drugs involved in retinal damage: anti-oestrogen, classical cytolytic chemotherapy (alkylating agents, taxanes, topoisomerase inhibitors, and antimetabolites), mitogen-activated protein kinase, tyrosine-kinase, and vascular endothelial growth factor inhibitors are the cancer drugs associated with retinal damage and visual disturbance. However, further studies are necessary to improve knowledge on the molecular and clinical relation between cancer therapies and retinopathy, in order to provide clinicians with evidence-based protocols to optimise the management of these conditions and minimise vision loss occurrence, impaired quality of life, and public health expense.

A phase Ib/II study of atezolizumab plus tivozanib in pancreatic, gallbladder, and bile duct malignancies.

TPS715 Background: Checkpoint inhibitor therapy represents a significant advance in cancer care however it is not an effective intervention in the treatment of several immunologically cold tumors including pancreatic, gallbladder, and bile duct malignancies where checkpoint inhibitors have produced objective response rates ranging from 0-6%. VEGF is thought to play a key role in modulating the anti-tumor immune response as it is secreted by tumors and leads to endothelial cell proliferation, vascular permeability, and vasodilation. This in turn leads to the development of an abnormal vasculature with excessive permeability and poor blood flow, thus limiting immune surveillance. In addition, VEGF inhibits dendritic cell differentiation, limiting the presentation of tumor antigens to CD4 and CD8 T cells. Through the inhibition of VEGF, it may be possible to potentiate the effect of immune checkpoint blockade. Combined use of a VEGF receptor tyrosine kinase inhibitor (TKI) and checkpoint inhibitor is already standard of care in advanced kidney and cervical cancers. Methods: This is a single institution, single arm, open-label phase Ib/II study with the co-primary endpoints of safety and efficacy of the combination of the VEGF receptor TKI tivozanib and checkpoint inhibitor atezolizumab. Eligible patients will include those with pancreatic, gallbladder, and bile duct cancers, as well as well-differentiated grade 2 and 3 neuroendocrine tumors, ovarian and vulvar cancer, soft tissue sarcoma, castrate resistant prostate cancer, and HER2 positive hormone receptor negative breast cancer, that is metastatic and progressed on at least one line of therapy. Key exclusion criteria will include patients with known mismatch repair deficiency, microsatellite instability, or high tumor mutational burden. The phase Ib portion will assess the safety profile of the combination of tivozanib and atezolizumab with a potential dose de-escalation of tivozanib using a 3+3 study design. Three patients will be treated at the dose of tivozanib 1.34 mg per day (dose level 0) for 21 days of each 28-day cycle and atezolizumab 1680 mg on day 1 of every 28-day cycle. If one dose limiting toxicity (DLT) is found then 3 more patients will be enrolled at dose level 0. If &gt;1 DLT occurs in the first 3 patients or &gt;1 DLT in the first 6, another 3+3 study will begin at dose level -1 (0.89 mg of tivozantib). If 1 DLT occurs in these 3 patients at dose level -1 then another 3 will be enrolled at this dose. The study will be stopped for toxicity if there is &gt;1 DLT in the first 3 patients at dose level -1 or if there are &gt;1 DLT in the 6 patients at dose level -1. The phase II portion will enroll up to 26 patients using the dose of tivozanib found to be safe in the Ib portion. Disease response assessment every 12 weeks with CT Chest, Abdomen, and Pelvis via RECIST 1.1. Treatment will continue until progression or intolerance. Clinical trial information: NCT05000294 .

EMERALD-1: A phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization.

LBA432 Background: For &gt;20 years, TACE has been a standard of care for embolization-eligible uHCC; however, most people with uHCC treated with TACE progress within 1 year. Embolization creates a proinflammatory tumor microenvironment and increases VEGF signals; clinical studies have established the role of immune checkpoint inhibitors (ICIs; e.g. D) and VEGF inhibitors (e.g. B) in advanced HCC. Methods: In EMERALD-1 (NCT03778957; double-blind, global, Phase 3 study), participants (pts) with embolization-eligible uHCC, Child-Pugh A to B7 liver function, Eastern Cooperative Oncology Group performance status 0–1, and no evidence of extrahepatic disease were randomized 1:1:1 to the D+B+TACE, D+TACE, or TACE arms. TACE was cTACE or DEB-TACE (investigator choice). Pts received D (1500 mg) or placebo for D (Q4W) plus TACE. After completion of last TACE, pts received D (1120 mg) or placebo for D plus B (15 mg/kg) or placebo for B (Q3W). Primary endpoint was progression-free survival (PFS) for D+B+TACE vs TACE. Secondary endpoints included PFS for D+TACE vs TACE, overall survival (OS), objective response rate (ORR), time to progression (TTP), and safety for D+B+TACE or D+TACE vs TACE. PFS, ORR, and TTP were assessed by blinded independent central review (RECIST v1.1). Results: In total, 616 pts with BCLC Stage A (25.8%), Stage B (57.3%), and Stage C (16.1%) were randomized to D+B+TACE (n=204), D+TACE (n=207), or TACE (n=205). Demographic and baseline characteristics were generally balanced across arms. At final PFS analysis, the primary objective was met: PFS significantly improved for D+B+TACE vs TACE (median [m]PFS 15.0 vs 8.2 months [mo]; hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.61–0.98; p=0.032 [threshold 0.0434]). Results were consistent across most prespecified subgroups. The secondary endpoint of PFS for D+TACE vs TACE was not statistically significant (mPFS 10.0 vs 8.2 mo; HR, 0.94; 95% CI, 0.75–1.19; p=0.638). ORR was 43.6%, 41.0%, and 29.6%, and mTTP was 22.0, 11.5, and 10.0 mo for D+B+TACE, D+TACE, and TACE, respectively. No new safety signals were identified. In the D+B+TACE (n=154), D+TACE (n=232), and TACE (n=200) safety analysis sets, respectively, 32.5%, 15.1%, and 13.5% of pts had maximum Grade 3/4 treatment-related adverse events (TRAEs); 8.4%, 4.3%, and 3.5% discontinued due to TRAEs; and 0%, 1.3%, and 2.0% died due to TRAEs. Pts continue to be followed for OS. Conclusions: D+B+TACE is the first ICI-based regimen in a global Phase 3 trial to show statistically significant and clinically meaningful improvement in PFS, vs TACE, in pts with embolization-eligible uHCC. Safety was manageable and consistent with the safety profiles of D, B, and TACE in uHCC. D+B+TACE has the potential to set a new standard of care in uHCC. Clinical trial information: NCT03778957 .

Coformulated quavonlimab and pembrolizumab (pembro) in combination with lenvatinib (lenva) as first-line (1L) therapy for patients (pts) with advanced hepatocellular carcinoma (HCC): Phase 2 KEYSTEP-004 study.

484 Background: Combinations of a PD-1/L1 inhibitor with a CTLA-4 or VEGF inhibitor have been approved as 1L treatment options for pts with advanced HCC. The multicenter, phase 2 KEYSTEP-004 study (NCT04740307) was conducted to evaluate the coformulation of quavonlimab (CTLA-4 inhibitor) and pembro (PD-1 inhibitor) in combination with lenva (multi–tyrosine kinase inhibitor) as 1L treatment for pts with advanced HCC. Methods: Pts were ≥18 y of age, had histologically or radiographically confirmed HCC with no prior systemic therapy, and were not amenable to curative therapy; had Child-Pugh class A; and ECOG PS 0 or 1. The study consisted of a safety lead-in phase (approximately 6-20 pts) to evaluate the tolerability of the recommended phase 2 dose of lenva with a possibility of dose modification based on dose-limiting toxicities (DLTs) and an efficacy expansion phase (approximately 110 pts). In the safety lead-in phase, pts received a fixed-dose coformulation of quavonlimab 25 mg and pembro 400 mg IV Q6W in combination with lenva 8 mg (body weight [BW] &lt;60 kg) or 12 mg (BW ≥60 kg) PO QD. Allocation to the efficacy expansion phase was allowed if the doses of lenva were determined to be tolerable. Primary end points were ORR per RECIST v1.1 by BICR and safety. Secondary end points included DOR, DCR, and PFS per RECIST v1.1 by BICR and OS. Results: No DLTs were observed in the 6 pts enrolled in the safety lead-in phase. 115 pts in the safety lead-in phase or the efficacy expansion phase were treated with the fixed-dose coformulation of quavonlimab and pembro plus lenva 8 or 12 mg. 94 pts (81.7%) were male, median age was 64 y (range, 32-83), and 80 pts (69.6%) had AFP ≤400 ng/mL. As of the June 22, 2023, data cutoff date, median follow-up (time from first dose to database cutoff date or death) was 7.7 mo (range, 0.9-22.1), and 89 pts (77.4%) discontinued treatment, most commonly due to progressive disease (39.1%). Confirmed ORR was 37.4% (95% CI, 28.5-46.9), with 5 CRs (4.3%) and 38 PRs (33.0%). DCR was 79.1% (95% CI, 70.6-86.1). Median DOR was 10.6 mo (range, 1.2+ to 23.1+). Median PFS and OS were 8.2 mo (95% CI, 6.2-10.2) and 22.1 mo (95% CI, 15.5-not reached), respectively; 12-mo PFS and OS rates were 32.2% and 65.2%, respectively. Treatment-related adverse events (TRAEs) occurred in 109 pts (94.8%); most common (≥25%) were hypertension (35.7%) and diarrhea (27.8%). Grade 3-5 TRAEs occurred in 66 pts (57.4%); most common (≥5%) were hypertension (8.7%) and immune-mediated enterocolitis (7.0%). 8 pts (7.0%) died due to AEs; 2 were considered treatment related (acute respiratory failure and subarachnoid hemorrhage). Conclusions: The coformulation of quavonlimab and pembrolizumab in combination with lenvatinib demonstrated manageable safety; further investigation is warranted to understand the efficacy of this triplet as 1L treatment for advanced HCC. Clinical trial information: NCT04740307 .

Combining low-dose regorafenib with pembrolizumab for patients with MSI-H colorectal cancer: REGPEM-CRC-01.

TPS238 Background: Treatment for microsatellite instability-high (MSI-H)/mismatch repair deficient (MMR-D) colorectal cancer (CRC) has rapidly evolved in the last decade. The KEYNOTE 177 trial recently established pembrolizumab as a frontline therapy for patients with MSI-H CRC. However, in this study, approximately 40% of patients were noted to have disease progression within 6 months of treatment. Furthermore, an additional 10% of patients experienced acquired resistance to therapy. Therefore, there is an unmet need to improve outcomes for patients with MSI-H CRC. Preclinical studies have shown vascular endothelial growth factor (VEGF) signaling to be overactive in MSI-H compared to MSS CRC (Hansen et al. Colorectal Dis. 2011). Moreover, exploratory analysis of CALBG-80405 and PARADIGM trials showed that patients with MSI-H CRC were more likely to benefit from anti-VEGF therapy than those with MSS disease. Regorafenib, an FDA-approved agent for patients with mCRC, is a potent VEGF inhibitor with immune modulatory effects on the tumor microenvironment. We hypothesize that adding low-dose regorafenib to pembrolizumab as frontline therapy may create synergistic activity in addition to the known clinical activity of each agent in MSI-H CRC. Methods: In the lead-in arm of this prospective study, 22 patients will be enrolled. Patients will receive regorafenib 60 mg daily on days 1–14 (2 weeks on) followed by 7 days off (1 week off) in combination with pembrolizumab 200 mg in the cycle 1. In the following cycles, patients will receive regorafenib 90 mg daily for 2 weeks on 1 week off in combination with pembrolizumab 200 mg every 3 weeks. The primary outcome for the lead-in arm is overall response rate (ORR) within 12 months of treatment by RECIST 1.1. criteria. A formal one-sided hypothesis test will be conducted for futility, assuming that we will reject the null hypothesis of a target ORR only if we have strong evidence. In this study, we assume a null hypothesis that ORR is 0.60, which would reflect significant clinical improvement over the current standard of ORR = 0.43 from KEYNOTE 177. The alternative hypothesis is that ORR is less than 0.60. For the lead-in phase of the study, the emphasis is on controlling Type I error to be small, approximately 0.05. In the randomized phase of the study, patients will receive pembrolizumab monotherapy or pembrolizumab in combination with regorafenib 90 mg. The sample size for the randomized phase of trial was determined based on an assumed median of PFS of 28 months with pembrolizumab and regorafenib combination (investigational arm). The standard of care pembrolizumab monotherapy results in a median PFS of 16 months when given as a first-line therapy. We hypothesize the proposed treatment will increase median PFS to 28 months from 16 months (N=132; H0: 16 months vs., H1: 28 months; Type I error: 0.05, power 80%). Clinical trial information: NCT06006923 .

Recent Progress in Systemic Therapy for Advanced Hepatocellular Carcinoma.

Patients with advanced hepatocellular carcinoma (HCC) have several systemic treatment options. There are many known risk factors for HCC, and although some, such as hepatitis C, are now treatable, others are not. For example, metabolic dysfunction-related chronic liver disease is increasing in incidence and has no specific treatment. Underlying liver disease, drug resistance, and an increasing number of treatment options without specific biomarkers are all challenges in selecting the best treatment for each patient. Conventional chemotherapy is almost never used for advanced-stage disease, which instead is treated with immunotherapy, tyrosine kinase inhibitors, and VEGF inhibitors. Immune checkpoint inhibitors targeting various receptors have been or are currently undergoing clinical evaluation. Ongoing trials with three-drug regimens may be the future of advanced-stage HCC treatment. Other immune-modulatory approaches of chimeric antigen receptor-modified T cells, bispecific antibodies, cytokine-induced killer cells, natural killer cells, and vaccines are in early-stage clinical trials. Targeted therapies remain limited for HCC but represent an area of potential growth. As we shift away from first-line sorafenib for advanced HCC, clinical trial control arms should comprise a standard treatment other than sorafenib, one that is a better comparator for advancing therapies.

Bispecific VEGF-A and Angiopoietin-2 Antagonist RO-101 Preclinical Efficacy in Model of Neovascular Eye Disease

ObjectiveTo investigate preclinical data regarding efficacy and biocompatibility of a bispecific protein, RO-101, with effects on Vascular Endothelial Growth Factor-A (VEGF-A) and Angiopoietin-2 (Ang-2) for use in retinal diseases. Study DesignExperimental study. SubjectsBrown Norway rats, New Zealand White Cross rabbits. MethodsPreclinical study data of RO-101 in terms of target-specific ELISA binding affinity to VEGF-A and Ang-2, vitreous half-life, inhibition of target-receptor interaction, laser Choroidal Neovascular Membrane (CNVM) animal model, Human Umbilical Vein Endothelial Cell (HUVEC) migration, and biocompatibility was obtained. Where applicable, study data was compared to other anti-VEGF agents. Main Outcome MeasuresBinding affinity, half-life, biocompatibility, and efficacy of RO-101. Neovascularization prevention by RO-101. ResultsRO-101 demonstrated a strong binding affinity for VEGF-A and Ang-2 and in vitro was able to inhibit binding to the receptor with higher affinity than faricimab. The half-life of RO-101 is comparable or longer than current VEGF inhibitors used in retinal disease. RO-101 was found to be biocompatible with retinal tissue in Brown Norway rats. RO-101 was as effective or more effective than current anti-VEGF therapeutics in causing regression of neovascular growth in vivo. ConclusionRO-101 is a promising candidate for use in retinal diseases. In preclinical models, RO-101 demonstrated similar or higher regression of neovascular growth to current anti-VEGF therapeutics with comparable or longer half-life. It also demonstrates strong binding affinity for VEGF-A and Ang-2. It also was shown to be biocompatible with retinal tissue in animal studies, indicating potential compatibility for use in humans.

Exploring the Spectrum of VEGF Inhibitors' Toxicities from Systemic to Intra-Vitreal Usage in Medical Practice.

The use of Vascular Endothelial Growth Factor inhibitors (VEGFi) has become prevalent in the field of medicine, given the high incidence of various pathological conditions necessitating VEGF inhibition within the general population. These conditions encompass a range of advanced neoplasms, such as colorectal cancer, non-small cell lung cancer, renal cancer, ovarian cancer, and others, along with ocular diseases. The utilization of VEGFi is not without potential risks and adverse effects, requiring healthcare providers to be well-prepared for identification and management. VEGFi can be broadly categorized into two groups: antibodies or chimeric proteins that specifically target VEGF (bevacizumab, ramucirumab, aflibercept, ranibizumab, and brolucizumab) and non-selective and selective small molecules (sunitinib, sorafenib, cabozantinib, lenvatinib, regorafenib, etc.) designed to impede intracellular signaling of the VEGF receptor (RTKi, receptor tyrosine kinase inhibitors). The presentation and mechanisms of adverse effects resulting from VEGFi depend primarily on this distinction and the route of drug administration (systemic or intra-vitreal). This review provides a thorough examination of the causes, recognition, management, and preventive strategies for VEGFi toxicities with the goal of offering support to oncologists in both clinical practice and the design of clinical trials.

Profiling of VEGF Receptors and Immune Checkpoints in Recurrent Respiratory Papillomatosis.

Recurrent respiratory papillomatosis (RRP) is caused by human papilloma virus (HPV) infection of the aerodigestive tract that significantly impacts quality-of-life including the ability to communicate and breathe. Treatment was traditionally limited to serial ablative procedures in the O.R. with possible local adjuvant therapy, but new systemic therapies, such as Vascular endothelial growth factor (VEGF) inhibitors, are showing significant promise. This study aims to determine whether rationale exists for combination therapeutic approaches using VEGF inhibitors and/or immune checkpoint blockade. Using fresh specimens from the O.R., we performed flow cytometry on papilloma, normal adjacent tissue, and blood. Papilloma and surrounding tissue were examined for expression of PD-L1, PD-L2, Galectin-9, VEGFR2, and VEGFR3. CD8+ and CD4+ T cells were assayed for expression of PD-1, TIGIT, LAG3, and TIM3. Our data shows that papilloma tissue exhibits significantly higher levels of PD-L1 and PD-L2 compared to adjacent tissue. Elevated levels of the VEGF receptor VEGFR3 were also observed in papilloma tissue. When examining T cells within the papilloma, elevated PD-1 and TIGIT expression was observed on CD8+ T cells, while levels of PD-1, TIGIT, and TIM3 were elevated on CD4+ T cells compared to PBMCs. Heterogenous marker expression was observed between individuals. Our analysis shows that RRP tissue shows elevated levels of multiple immune check point targets and VEGFR3, with varied patterns unique to each papilloma patient. Some of these immune checkpoint markers already have novel immunotherapies available or in development, providing molecular rationale to offer these systemic treatments to selected patients affected by RRP alongside VEGF inhibitors. Laryngoscope, 134:2819-2825, 2024.

European Unmet Needs in the Management of Neovascular Age-Related Macular Degeneration in Daily Practice: Data from the Fight Retinal Blindness! Registry

PurposeTo evaluate the proportion, predictors and outcomes of neovascular age-related macular degeneration (nAMD) patients treated with a high burden of vascular endothelial growth factor (VEGF) inhibitor injections (IVT) after two years in routine clinical practice. DesignRetrospective analysis of data from a prospectively designed observational outcomes registry, Fight Retinal Blindness! project, of patients treated in European centers. ParticipantsTreatment-naïve eyes (one eye per patient) starting VEGF inhibitors for nAMD from January 2017 to March 2020 with 24 months of follow-up. We analyzed three treatment burden groups defined by the mean interval of the three closest injections to the 24-month visit: (1) those with a high treatment burden had injection intervals ≤ 42 days, (2) those with a low treatment burden had injection intervals between 43 and 83 days and those with tolerable treatment burden had injection intervals between 84 and 365 days. MethodsMultinomial regression was used to evaluate baseline risk predictors of patients requiring a high treatment burden. Main Outcome MeasuresThe proportion of patients that experienced a high treatment burden at 2 years and its predictors. ResultsWe identified 2,038 eligible patients completing 2 years of treatment (2038/3943 patients [60%]) with a median (Q1, Q3) of 13 (10, 17) injections. The proportion of patients with a high treatment burden was 25% (516 patients) at 2 years. Younger patients (Odds ratio (OR), 0.97; 95%CI, 0.96-0.99; P<0.01) were more likely to have high treatment burden, while eyes with type 3 CNV at baseline were significantly less likely (OR, 0.26; 95%CI, 0.13-0.52; P<0.01). Regarding type of fluid, patients with subretinal fluid only at baseline (OR, 3.85; 95%CI, 1.34-11.01; P=0.01) and persistent active intraretinal (OR, 1.56; 95%CI, 1.18-2.06; P<0.01) or subretinal fluid only (OR, 2.21; 95%CI, 1.52-3.21; P<0.01) after the loading phase had a higher risk of high treatment burden at 2 years. ConclusionsHigh treatment burden is common issue in routine clinical practice in Europe, with a quarter of patients requiring injections of conventional VEGF inhibitors every 6 weeks at 2 years and 40 percent discontinuing treatment within 2 years.

Adverse events of immune checkpoint therapy alone versus when combined with vascular endothelial growth factor inhibitors: a pooled meta-analysis of 1735 patients.

Combining immune checkpoint therapy (ICT) and vascular endothelial growth factor inhibitors (VEGFi) may result in increased treatment-related and immune-related adverse events (TRAEs and irAEs) compared to ICT alone. This metanalysis was conducted to identify prospective phase II or III clinical studies that evaluated the toxicity profile of ICT + VEGFi compared to ICT alone. A systematic search was performed across all cancer types and major databases until August 10, 2022, and screening was done by two independent investigators. Inclusion criteria included phase 2 or 3 studies with at least one arm of patients treated with combination therapy and one arm treated with monotherapy. Adverse event data were pooled using a restricted maximum likelihood fixed effects model, and heterogeneity using Cochran's Q (chi-square) test. 7 out of 9366 studies met the inclusion criteria, and 808 and 927 patients were treated with ICT monotherapy and a combination of ICT with VEGFi, respectively. Only one study reported irAEs, so the analysis was restricted to TRAEs. The total number of TRAEs was significantly higher in the ICT + VEGFi group (RR:1.49; 95% CI 1.37 -1.62; p=1.5×10-21), and more frequent treatment withdrawals were attributed to TRAEs (RR:3.10; 95% CI 1.12-8.59; p=0.029). The highest TRAE effect size increases noted for rash (RR 6.50; 95% CI 3.76 - 11.25; p=2.1×10-11), hypertension (RR:6.07; 95% CI 3.69-10.00; p=1.3×10-12), hypothyroidism (RR:5.02; 95% CI 3.08 - 8.19; p=8.9×10-11), and diarrhea (RR:4.94; 95% CI 3.21-7.62; p=3.8×10-13). Other significantly more frequent TRAEs included nausea, anemia, anorexia, and proteinuria. Combination therapy with ICT and VEGFi carries a higher risk of certain TRAEs, such as rash, hypertension, hypothyroidism, diarrhea, nausea, anorexia, and proteinuria, compared to ICT monotherapy. More granular details on the cause of AEs, particularly irAEs, should be provided in future trials of such regimens.

Simulating neuronal development: exploring potential mechanisms for central nervous system metastasis in acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is prone to metastasize to the central nervous system (CNS), which is an important cause of poor treatment outcomes and unfavorable prognosis. However, the pathogenesis of CNS metastasis of ALL cells has not been fully illuminated. Recent reports have shed some light on the correlation between neural mechanisms and ALL CNS metastasis. These progressions prompt us to study the relationship between ALL central nervous system metastasis and neuronal development, exploring potential biomarkers and therapeutic targets of CNS metastasis. ALL central nervous system metastasis- and neuronal development-related differentially expressed genes (DEGs) were identified by analyzing gene expression datasets GSE60926 and GSE13715. Target prediction and network analysis methods were applied to assess protein-protein interaction networks. Gene Ontology (GO) terms and pathway enrichment for DEGs were assessed. Co-expressed differentially expressed genes (co-DEGs) coupled with corresponding predicted microRNAs (miRNAs) were studied as well. Reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry were employed for the validation of key co-DEGs in primary ALL cells. Furthermore, ALL cells were treated with a vascular endothelial growth factor (VEGF) inhibitor to block neuronal development and assess changes in the co-DEGs. We identified 216, 208, and 204 DEGs in ALL CNS metastasis specimens and neuronal development samples (GSE60926 and GSE13715). CD2, CD3G, CD3D, and LCK may be implicated in ALL CNS metastasis. LAMB1, MATN3, IGFBP3, LGALS1, and NEUROD1 may be associated with neuronal development. Specifically, four co-DEGs (LGALS1, TMEM71, SHISA2, and S100A11) may link ALL central nervous system metastasis and neuronal development process. The miRNAs for each co-DEG could be potential biomarkers or therapeutic targets for ALL central nervous system metastasis, especially hsa-miR-22-3p, hsa-miR-548t-5p, and hsa-miR-6134. Additionally, four co-DEGs (LGALS1, TMEM71, SHISA2, and S100A11) were validated in CNS-infiltrated ALL cells. The VEGF inhibitor demonstrated a suppressive effect on mRNA and protein expression of key co-DEGs. The bioinformatic survey and key gene validation suggest a possible correlation between ALL CNS metastasis and the neuronal development process. Simulating the neuronal development process might be a possible strategy for CNS metastasis in ALL. LGALS1, TMEM71, SHISA2, and S100A11 genes are promising and novel biomarkers and targets in ALL CNS metastasis.