Vascular Endothelial Growth Factor Therapy Research Articles

Beneficial Effects of Micronutrient Supplementation in Restoring the Altered Microbiota and Gut-Retina Axis in Patients with Neovascular Age-Related Macular Degeneration-A Randomized Clinical Trial.

Background/Objectives: Age-related macular degeneration (AMD) is a leading cause of visual impairment in the elderly and is characterized by a multifactorial etiology. Emerging evidence points to the potential involvement of the gut-retina axis in AMD pathogenesis, prompting exploration into novel therapeutic strategies. This study aims to investigate the effects of some micronutrients (such as lutein and zeaxanthin) and saffron (as a supplement)-known for their anti-inflammatory properties-on ophthalmological and microbial parameters in neovascular AMD (nAMD) patients. Methods: Thirty naive nAMD patients were randomized to receive daily micronutrient supplementation alongside anti-VEGF (vascular endothelial growth factor) therapy, or anti-VEGF treatment alone, over a 6-month period, with comparisons made to a healthy control (HC) group (N = 15). Ophthalmological assessments, biochemical measurements, and stool samples were obtained before and after treatment. Gut microbiota (GM) characterization was performed using 16S rRNA sequencing, while short-chain fatty acids (SCFAs), medium-chain fatty acids (MCFAs), and long-chain fatty acids (LCFAs) were analyzed with a gas chromatography-mass spectrometry protocol. Results: Compared to HC, nAMD patients exhibited reduced GM alpha diversity, altered taxonomic composition, and decreased total SCFA levels, in addition to elevated levels of proinflammatory octanoic and nonanoic acids. Micronutrient supplementation was associated with improved visual acuity relative to the group treated with anti-VEGF alone, along with a decrease in the total amount of MCFAs, which are metabolites known to have adverse ocular effects. Conclusions: In conclusion, despite certain limitations-such as the limited sample size and the low taxonomic resolution of 16S rRNA sequencing-this study highlights compositional and functional imbalances in the GM of nAMD patients and demonstrates that micronutrient supplementation may help restore the gut-retina axis. These findings suggest the therapeutic potential of micronutrients in enhancing ocular outcomes for nAMD patients, underscoring the complex interaction between GM and ocular health.

Comparing macular thickness and visual acuity responses retinal vein occlusion versus diabetic macular edema following anti vascular endothelial growth factor therapy: A retrospective analysis

: Vascular growth factor associates Retinal vein occlusion (RVO) and Diabetic Macular Edema (DME). A retrospective analysis using database from a tertiary hospital.: The study aims to evaluate effects of anti-vascular growth factor therapy on patients Diabetic Macular Edema with and retinal vein occlusion,: This study conducted between December 2022 and June 2023 where 30 patients diagnosed with Diabetic macular edema (DME, n=15) or Retinal vein occlusion (RVO, n=15) receiving anti-VEGF were examined. This focused on changes in best corrected visual acuity, central macular thickness and predictors over a period of three months.: Retinal Vein Occlusion (RVO) patients exhibited a more significant improvement in Best Corrected Visual Acuity (BCVA) compared to Diabetic Macular Edema (DME) (25 vs. 10 letters, p = 0.006) after three months. The change in Central Macular Thickness (CMT) also favored RVO (100µm) over DME (40µm, p = 0.012). Final BCVA median was 70 for DME and 65 for RVO (p = 0.461). Considering initial BCVA and CMT, RVO predicted better visual enhancement than DME.: RVO exhibited major BCVA improvement at three months with Anti-Vascular Endothelial Growth Factor. Final vision was indistinguishable for DME and RVO. Anti VEGF stabilizes DME vision. Despite the improvement, early RVO diagnosis and treatment may enhance final vision.

Adaptive resistance of tumor cells to anti-vascular endothelial growth factor therapy: A reversible phenomenon

Vascular endothelial growth factor (VEGF) inhibition is an essential targeted strategy for malignant tumors, but its efficacy is severely constrained by drug resistance. The traditional view holds that the target of VEGF inhibition is endothelial cells, and thus compensatory angiogenesis is considered the main mechanism of drug resistance. In this study, we found that tumor cells themselves could develop acquired resistance to VEGF therapy, indicating an independent resistance mechanism apart from angiogenesis. Notably, this acquired resistance was temporary, disappearing completely four days after discontinuing exposure to the drug in vitro. Our findings suggest that tumor cells may also be targets of VEGF inhibition, and their response to treatment should not be overlooked in contributing to drug resistance.

Supplemental Intravitreal Ranibizumab Injections in Eyes Treated with the Port Delivery System with Ranibizumab in the Archway Trial

PurposeTo determine the proportion and characteristics of eyes with neovascular age-related macular degeneration (nAMD) treated with the Port Delivery System with ranibizumab (PDS) that receive supplemental intravitreal ranibizumab injections due to changes in best-corrected visual acuity (BCVA) and/or central subfield thickness (CST), and to investigate the safety and efficacy of supplemental injections in eyes with the PDS. DesignPost-hoc analyses of data from the phase 3, randomized, multicenter, open-label, active-comparator Archway trial (NCT03677934). ParticipantsAdults with nAMD diagnosed within 9 months of screening previously responsive to anti–vascular endothelial growth factor (anti-VEGF) therapy. Intervention418 patients were randomized to the PDS with ranibizumab 100 mg/mL with fixed refill-exchanges every 24 weeks (Q24W) or monthly intravitreal ranibizumab 0.5 mg for 96 weeks. ResultsOf the 246 eyes treated with the PDS Q24W and assessed for supplemental treatment criteria, the vast majority (94.6%–98.4%) did not receive supplemental treatment during each retreatment interval, with 87.4% not receiving supplemental treatment at any point during the trial. Of the 31 eyes receiving supplemental treatment, 58.1% received 1 injection and 32.3% received 2. At baseline, eyes receiving supplemental treatment were significantly more likely to have thicker retinas (mean CST 370.5μm vs 304.4μm; P = 0.0001), subretinal fluid (54.8% vs 21.2%; P < 0.0001), and larger pigment epithelial detachment height (215.7μm versus 175.9μm; P = 0.003). These features have previously been associated with difficult-to-treat nAMD. Whereas BCVA and CST generally remained constant throughout the trial in eyes without supplemental treatment, the small number of eyes receiving supplemental treatment on average lost 1 line of vision from baseline to week 96 (mean –5.7 Early Treatment Diabetic Retinopathy Study score letters) and CST continued to increase over time. Absolute BCVA at week 96 was similar irrespective of supplemental treatment status (71.1 and 73.7 letters). BCVA and CST generally improved within 28 days of supplemental treatment. ConclusionsAlthough the PDS Q24W effectively maintains vision and retinal stability in most eyes with nAMD, a small proportion of patients with features of difficult-to-treat nAMD may benefit from supplemental intravitreal anti-VEGF injections and initial close monitoring is recommended.

Enhanced Theranostic Efficacy of 89Zr and 177Lu-Labeled Aflibercept in Renal Cancer: A Viable Option for Clinical Practice.

Vascular endothelial growth factor (VEGF) targeted therapy serves as an important therapeutic approach for renal cancer, but its clinical effectiveness is unsatisfactory. Moreover, there is a lack of reliable biomarkers for preoperative assessment of tumor VEGF expression. This study aimed to explore the potential for further applications of 177Lu/89Zr-labeled aflibercept (Abe), a VEGF-binding agent, in imaging visualization of VEGF expression and therapy for renal cancer. To determine specificity uptake in renal cancer, BALB/c mice with VEGF-expressing Renca tumor were intravenously injected with [89Zr]Zr-Abe, [177Lu]Lu-Abe, or Cy5.5-Abe and the blocking group was designed as a control group. PET, SPECT, and fluorescence images were acquired, and the biodistribution of [89Zr]Zr-Abe and [177Lu]Lu-Abe was performed. Additionally, the [177Lu]Lu-Abe, [177Lu]Lu-Abe-block, 177Lu only, Abe only, and PBS groups were compared for evaluation of the therapeutic effect. To assess the safety, we monitored and evaluated the body weight, blood biochemistry analysis, and whole blood analysis and major organs were stained with hematoxylin and eosin after [177Lu]Lu-Abe treatment. DOTA-Abe was successfully labeled with 177Lu and Df-Abe with 89Zr in our study. The uptake in tumor of [89Zr]Zr-Abe was significantly higher than that of [89Zr]Zr-Abe-block (P < 0.05) and provided excellent tumor contrast in PET images. [177Lu]Lu-Abe demonstrated promising tumor-specific targeting capability with a high and persistent tumor uptake. The standardized tumor volume of [177Lu]Lu-Abe was significantly smaller than those of other treatment groups (P < 0.05). [177Lu]Lu-Abe also had smaller tumor volumes and reduced expression of VEGF and CD31 compared to those of the control groups. Fluorescence images demonstrate higher tumor uptake in the Cy5.5-Abe group compared to the Cy5.5-Abe-block group (P < 0.05). In conclusion, [89Zr]Zr-Abe enables noninvasive analysis of VEGF expression, serving as a valuable tool for assessing the VEGF-targeted therapy effect. Additionally, all of the findings support the enhanced therapeutic efficacy and safety of [177Lu]Lu-Abe, making it a viable option for clinical practice in renal cancer.

Cabozantinib and Axitinib After Vascular Endothelial Growth Factor Therapy in Patients with Advanced Renal Cell Carcinoma: A Retrospective Cohort Study from England.

The tyrosine kinase inhibitors cabozantinib and axitinib have been widely used in England to treat advanced renal cell carcinoma following prior vascular endothelial growth factor-targeted therapy, but data on real-world usage remain limited. Our objective was to describe the real-world treatment patterns and outcomes of patients with advanced renal cell carcinoma who received second-line or later-line (≥2L) cabozantinib or axitinib after vascular endothelial growth factor-targeted therapy in clinical practice in England. This retrospective cohort study used clinical practice data (collected 2011-20) from the English Cancer Analysis System database. Patient characteristics, treatment sequence and duration, and overall survival (time from initiation of cabozantinib/axitinib treatment to death) were evaluated. Data from 1485 eligible adults with advanced renal cell carcinoma were analyzed: 440 received ≥ 2L cabozantinib (2L for 88.6% of them); 1045 received ≥ 2L axitinib (2L for 89.5%). The most common first-line treatments were sunitinib (2L cabozantinib subcohort, 48%; 2L axitinib subcohort, 46%) and pazopanib (46% and 54%, respectively); nivolumab was the most common third-line treatment (18% and 19%, respectively). Median (interquartile range) 2L therapy duration was 5.52 (2.73-11.74) months for cabozantinib and 4.60 (1.45-12.36) months for axitinib. Following adjustment for potential confounders using inverse probability weighting, overall survival (median [interquartile range]) was longer for ≥ 2L cabozantinib (11.2 [5.7-28.0] months) than for ≥ 2L axitinib (10.4 [4.7-22.0] months; log-rank p = 0.0034). The Cancer Analysis System database is a valuable research resource providing extensive real-world clinical data. Real-world overall survival was longer with ≥ 2L cabozantinib than with axitinib. ClinicalTrials.gov, NCT04637204; registered November 2020.

Analiza zmian parametrów angiografii optycznej koherentnej tomografii wykonanej u pacjentów z zakrzepem naczyń żylnych siatkówki przed leczeniem iniekcjami inhibitora czynnika wzrostu śródbłonka naczyniowego i po leczeniu

Optical coherence tomography angiography is a modern, non-invasive method for assessing hemodynamics in retinal and choroidal vessels. The study presents changes occurring in optical coherence tomography angiography examination in patients with retinal vein occlusion, before and after therapy with intravitreal anti vascular endothelial growth factor injections. Anti vascular endothelial growth factor therapy in patients with retinal vein occlusion reduces the non-perfusion area, improves retinal blood flow, reduces retinal ischemia, reduces cystoid macularedema, and improves visual acuity.

Sarcomatoid carcinoma of the kidney. A case report

Sarcomatoid renal cell carcinoma is a rare and very aggressive variant of kidney cancer. These tumors are undifferentiated and arise from all renal cell carcinomas. Diagnosis is exclusively histological and therapeutic modalities are based on extended nephrectomy, targeted anti-VEGF (vascular endothelial growth factor) therapies and more recently immune checkpoint inhibitors. We report the case of a patient affected by this very rare type of cancer with a very poor prognosis and we will discuss the diagnostic, therapeutic and prognostic characteristics of this rare and very aggressive entity.

Cost-Utility Analysis of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration

To quantify the cost-utility ratio of the ranibizumab Port Delivery System (PDS; SUSVIMO) versus intravitreal ranibizumab injections for treating neovascular age-related macular degeneration (nAMD) based upon Archway Phase 3 Trial data. Cost-utility analysis. Archway Phase 3 Clinical Trial nAMD participants previously responsive to anti-VEGF therapy were randomized 3:2. Two hundred forty received PDS refills q 24 weeks and 162 received ranibizumab injections. Ophthalmic patient, time tradeoff utilities, direct medical and societal cost perspectives, 12-year, 1-year, and 5-year timelines, United States 2022 real dollars, and a 3% annual discount rate were employed. Utilities were adjusted for nAMD conversion in fellow eyes during the 12-year, mean participant life expectancy. Premature death associated with severe vision loss was integrated as per the population-based Salisbury Eye Evaluation Study. Quality-adjusted life-year (QALY) accruals, costs, and incremental and average cost-utility ratios in $/QALY (dollars expended per QALY gained). Versus no therapy, the 1-year PDS QALY gain was 0.0156 (6.8%) versus 0.0063 (0.82%) for intravitreal injections (P < 0.001), whereas the respective 12-year QALY gains were 1.714 (28%) and 1.639 (26.8%) (P= 0.99). One-year direct PDS ophthalmic costs totaled $21 825 with 2 ranibizumab fills, whereas ranibizumab injection therapy totaled $18 405 with 11.8 injections. The 1-year incremental PDS $/QALY versus injections was cost effective at $75 497/QALY. Five-year PDS therapy was not incrementally cost effective at $304 108/QALY, nor was the 12-year therapy at $761 646/QALY. Average 12-year cost-utility ratios were $78773/QALY for the PDS and $47 917/QALY for injection therapy. Adding-$476 442 12-year offsetting societal costs netted $314 521 to society per PDS participant versus $370 958 per participant for injection therapy. Ranibizumab PDS therapy was not incrementally cost effective versus ranibizumab injection therapy at 12 or 5 years but was at 1 year. Injection therapy had a more favorable 12-year average cost-utility ratio. Vision gain was the major determinant of participant value gain and was the same for both interventions. Both interventions were highly cost effective utilizing average cost-utility analysis with the societal cost perspective. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Novel mediators regulating angiogenesis in diabetic foot ulcer healing.

A non-healing diabetic foot ulcer (DFU) is a debilitating clinical problem amounting to socioeconomic and psychosocial burdens. DFUs increase morbidity due to prolonged treatment and mortality in the case of non-treatable ulcers resulting in gangrene and septicemia. The overall amputation rate of the lower extremity with DFU ranges from 3.34% to 42.83%. Wound debridement, antibiotics, applying growth factors, negative pressure wound therapy, hyperbaric oxygen therapy, topical oxygen, and skin grafts are common therapies for DFU. However, recurrence and nonhealing ulcers are still major issues. Chronicity of inflammation, hypoxic environment, poor angiogenesis, and decreased formation of the extracellular matrix (ECM) are common impediments leading to nonhealing patterns of DFUs. Angiogenesis is crucial for wound healing since proper vessel formation facilitates nutrients, oxygen, and immune cells to the ulcer tissue to help in clearing out debris and facilitate healing. However, poor angiogenesis due to decreased expression of angiogenic mediators and matrix formation results in nonhealing and ultimately amputation. Multiple proangiogenic mediators and vascular endothelial growth factor (VEGF) therapy exist to enhance angiogenesis, but the results are not satisfactory. Thus, there is a need to investigate novel pro-angiogenic mediators that can either alone or in combination enhance the angiogenesis and healing of DFUs. In this article, we critically reviewed the existing pro-angiogenic mediators followed by potentially novel factors that might play a regulatory role in promoting angiogenesis and wound healing in DFUs.

Difficulty in Assessing the Systemic Adverse Effects of Intravitreal Anti–Vascular Endothelial Growth Factor Therapy

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Anti–Vascular Endothelial Growth Factor Therapy for Complications of Diabetic Retinopathy—From Treatment to Prevention?

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Dexamethasone Intravitreal Implant (Ozurdex)

&#x0D; CADTH recommends that Ozurdex not be reimbursed by public drug plans for the treatment of adult patients with diabetic macular edema (DME) who are pseudophakic and have had an inadequate response to prior anti–vascular endothelial growth factor (VEGF) therapy.&#x0D; Evidence from 1 clinical trial and 2 observational studies was insufficient to demonstrate a benefit with Ozurdex treatment over other available treatment options in the relevant patient population. It was highly uncertain how Ozurdex compared with anti-VEGF therapy in terms of improving clearness or sharpness of vision due to many limitations in the 3 studies, and there was no evidence comparing Ozurdex with triamcinolone acetonide.&#x0D; Patients identified a need for new treatments that are less invasive and/or require fewer injections, but Ozurdex is administered the same way as other drugs for DME and there was not enough strong clinical evidence to show that patients would experience a tangible benefit from reduced treatment frequency with Ozurdex.&#x0D;

PCR275 Patient Experience With Anti–Vascular Endothelial Growth Factor (VEGF) Therapy in Neovascular Age-Related Macular Degeneration (nAMD) and Diabetic Macular Edema (DME): A Multinational Survey

Intravitreal anti–vascular endothelial growth factor (VEGF) therapy is efficacious for neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). However, the frequent treatment and monitoring required for optimal real-world outcomes can be burdensome to patients and can impact adherence to treatment. This study aimed to understand patient treatment experience with anti-VEGF standard of care.

Pulmonary Hypertension in Preterm Infants Treated With Laser vs Anti–Vascular Endothelial Growth Factor Therapy for Retinopathy of Prematurity

Anti-vascular endothelial growth factor (VEGF) therapy for retinopathy of prematurity (ROP) has potential ocular and systemic advantages compared with laser, but we believe the systemic risks of anti-VEGF therapy in preterm infants are poorly quantified. To determine whether there was an association with increased risk of pulmonary hypertension (PH) in preterm infants with ROP following treatment with anti-VEGF therapy as compared with laser treatment. This multicenter retrospective cohort study took place at neonatal intensive care units of 48 children's hospitals in the US in the Pediatric Health Information System database from 2010 to 2020. Participants included preterm infants with gestational age at birth 22 0/7 to 31 6/7 weeks who had ROP treated with anti-VEGF therapy or laser photocoagulation. Anti-VEGF therapy vs laser photocoagulation. New receipt of pulmonary vasodilators at least 7 days after ROP therapy was compared between exposure groups, matched using propensity scores generated from preexposure variables, and adjusted for birth year and hospital. The odds of receiving an echocardiogram after 30 days of age was also included to adjust for secular trends and interhospital variation in PH screening. Among 1577 patients (55.9% male) meeting inclusion criteria, 689 received laser photocoagulation and 888 received anti-VEGF treatment (95% bevacizumab, 5% ranibizumab). Patients were first treated for ROP at median 36.4 weeks' postmenstrual age (IQR, 34.6-38.7). A total of 982 patients (491 in each group) were propensity score matched. Good covariate balance was achieved, as indicated by a model variance ratio of 1.15. More infants who received anti-VEGF therapy were treated for PH, but when adjusted for hospital and year, this was no longer statistically significant (6.7%; 95% CI, 2.6-6.9 vs 4.3% 95% CI, 4.4-10.2; adjusted odds ratio, 1.62; 95% CI, 0.90-2.89; P = .10). Anti-VEGF therapy was not associated with greater use of pulmonary vasodilators after adjustment for hospital and year. Our findings suggest exposure to anti-VEGF may be associated with PH, although we cannot exclude the possibility of residual confounding based on systemic comorbidities or hospital variation in practice. Future studies investigating this possible adverse effect seem warranted.

Pulmonary Hypertension and Anti–Vascular Endothelial Growth Factor Therapy for Retinopathy of Prematurity—Is There a Link?

Pulmonary Hypertension and Anti–Vascular Endothelial Growth Factor Therapy for Retinopathy of Prematurity—Is There a Link?

Non-neovascular fluid in age-related macular degeneration: observe-and-extend regimen in a case-series study

ObjectifDécrire l’évolution du liquide non néovasculaire dans la dégénérescence maculaire liée à l’âge (DMLA) après l'administration d'anti-VEGF (facteur de croissance endothélial vasculaire) ou après une période d'observation sans injection. NatureÉtude rétrospective portant sur une série de cas. MéthodesOnt été inclus des yeux qui présentaient une DMLA s'accompagnant de drusens maculaires et/ou d'un décollement drusénoïde de l’épithélium pigmentaire associée à l'apparition d'un liquide non néovasculaire. On a réalisé une angiographie-tomographie par cohérence optique (OCTA) dans tous les yeux afin d'exclure la présence d'une néovascularisation maculaire. Le liquide sous-rétinien (LSR) a été mesuré afin de déterminer la réponse à la suite de l'administration d'anti-VEGF et après une période d'observation sans injection. RésultatsAinsi, 10 yeux de 9 patients qui présentaient une DMLA intermédiaire s'accompagnant de LSR ont été étudiés pendant une médiane de 59,5 mois (fourchette : 7–128 mois). De ce nombre, 6 patients (6 yeux) avaient déjà reçu un anti-VEGF. La durée médiane du suivi sans injection était de 13,5 mois (fourchette : 4–44 mois). L’épaisseur du LSR est demeurée stable et n'a pas changé pendant le suivi sans injection dans tous les yeux (n = 6) qui avaient reçu des injections et dans tous les yeux (n = 4) qui n'avaient jamais reçu d'injection. Par ailleurs, on a observé une atrophie complète de l’épithélium pigmentaire rétinien (EPR) et des couches externes de la rétine dans 6 yeux, tandis qu'on a noté une atrophie incomplète de l'EPR et des couches externes de la rétine dans 1 seul œil. Tous les yeux présentaient au moins 2 biomarqueurs visibles à l'OCT et associés à un risque élevé de progression vers l'atrophie. ConclusionNotre étude fournit des données préliminaires sur la progression du liquide non néovasculaire dans la DMLA, avec ou sans injection d'anti-VEGF. L'apparition de liquide pourrait tenir à une dysfonction de la pompe de l'EPR. Il est essentiel de faire la distinction entre le liquide néovasculaire et le liquide non néovasculaire par l'intermédiaire de techniques d'imagerie multimodale, notamment l'OCTA, pour éviter d'administrer inutilement un anti-VEGF. On peut envisager un regime « d'observation-et-extension » (observe-and-extend) en présence de DMLA qui s'accompagne d'un liquide non néovasculaire.

The Association of Fluid Volatility With Subretinal Hyperreflective Material and Ellipsoid Zone Integrity in Neovascular AMD.

PurposeTo evaluate the association of fluid volatility with ellipsoid zone (EZ) integrity and subretinal hyperreflective material (SHRM) volume during anti–vascular endothelial growth factor (VEGF) therapy in neovascular age-related macular degeneration (nAMD).MethodsThis study was a post hoc analysis of the OSPREY study. Retinal volatility was quantified as the standard deviation across weeks 12 to 56 for six optical coherence tomography (OCT) metrics: central subfield thickness (CST), total fluid (TF) volume, subretinal fluid (SRF) volume, intraretinal fluid (IRF) volume, macular total retinal fluid index (TRFI), and central macular TRFI. Eyes with volatility ≤ 25th or ≥ 75th percentile values were compared.ResultsEyes with low volatility in several exudative metrics showed greater change from baseline in SHRM volume at week 12 than eyes with high volatility. During the maintenance phase (weeks 12–56), eyes exhibiting high SRF volatility demonstrated increased SHRM volume compared to eyes with low SRF volatility (P = 0.027). Eyes exhibiting high volatility in CST, TF, and SRF demonstrated less improvement in EZ total attenuation (P < 0.001, P = 0.033, and P = 0.043, respectively) than eyes with low volatility. Early exudative instability (i.e., between weeks 4–8 or weeks 8–12) in multiple parameters (i.e., CST, TF, IRF, macular TRFI, or central macular TRFI) was associated with greater volatility during the maintenance phase (P < 0.05).ConclusionsGreater volatility in exudative OCT metrics, particularly SRF volatility, was associated with a greater increase in SHRM and less improvement in EZ integrity, suggesting that volatility is detrimental to multiple anatomic features in nAMD. Early exudative instability during the loading phase of treatment was associated with longer-term volatility in exudation.

A phase II/III trial of chemotherapy plus cetuximab versus chemotherapy plus bevacizumab versus atezolizumab plus bevacizumab following progression on immune checkpoint inhibition in recurrent/metastatic head and neck cancers: ECOG-ACRIN EA3202.

TPS6098 Background: There is no standard treatment beyond progression on first-line pembrolizumab (P) in patients with R/M HNSCC. Vascular endothelial growth factor (VEGF) modulates anti-tumor immunity via proliferation of inhibitory T regulatory and myeloid-derived suppressor cells, inhibition of dendritic cell maturation and suppression of effector T cell responses. Efficacy data from other disease sites and from early-phase trials done in HNSCC suggests promising clinical activity of VEGF and PD-1 inhibitor combination therapy. We have thus designed a Phase II/III, randomized, multi-arm trial to evaluate the efficacy of atezolizumab (A) and bevacizumab (B) beyond progression on P in patients with R/M HNSCC. Methods: EA3202 is enrolling patients with CPS ≥1% R/M HNSCC previously treated with P either alone or in combination with other checkpoint inhibitors without progression for at least 12 weeks. In phase II, patients will be randomized to one of three treatment arms: platinum doublet chemotherapy (C) plus cetuximab (E) for six cycles followed by E maintenance (control arm), C + B for six cycles followed by B maintenance, or A + B. Therapy in each arm will continue until progression, toxicity, or for a total period of two years. Patients will be stratified by p16 status, CPS score (≥ 20 vs. &lt; 20), distant metastases (M0 vs M1), and disease progression pattern with first-line P (while on P vs. after discontinuation). 216 patients will be enrolled. The primary endpoint for phase II is progression-free survival (PFS). Each experimental arm will be compared to the control arm at a one-sided alpha level of 0.10. Pre-specified rules will be used to pick a winner among the two experimental arms, which will then advance to phase III against the control arm. 214 patients will be enrolled in phase III for a total sample size of 430 patients. The primary endpoint for phase III is overall survival (OS) which will be compared using a stratified log-rank test. Secondary endpoints include OS in the two phase III arms among the CPS ≥ 20 cohort and comparison of grade 3 or higher treatment-related adverse events between the two arms. A total of 277 OS events will be required for full information for phase III evaluation to give a nominal ̃90% power at one-sided alpha level 0.0125. 144 patients enrolled in phase II (from the control and selected experimental arms) will be included in the phase III analysis. With this design the overall study power is at least 80% under a true 40% hazard reduction for PFS and 35% hazard reduction for OS. Blood and tumor tissue will be banked. EA3202 was activated in December 2021. It is the first randomized study to compare systemic treatments for R/M HNSCC in the immunotherapy era and will define the best second-line treatment approach beyond P. Clinical trial information: NCT05063552.

Month 60 Outcomes After Treatment Initiation With Anti–Vascular Endothelial Growth Factor Therapy for Macular Edema Due to Central Retinal or Hemiretinal Vein Occlusion

To investigate 5-year outcomes in eyes initially treated with aflibercept or bevacizumab for macular edema due to central retinal or hemiretinal vein occlusion. Long-term follow-up (LTF) after a randomized clinical trial from 64 centers in the United States. Participants were followed up to 60 months and treated at investigator discretion after completing the 12-month treatment protocol. Main outcomes were visual acuity letter score (VALS) and central subfield thickness (CST) on optical coherence tomography. Seventy-five percent (248/330) of eligible participants completed at least 1 visit between months 24 and 60, and 45% completed the month 60 visit. Among participants completing month 60, overall mean VALS improvement over baseline was 13.5 (95% CI: 9.6, 17.5), less than the mean improvement of 20.6 (95% CI: 18.7, 22.4) observed at month 12, with no significant differences between originally assigned study groups. Further, 66% (99/150) had at least 1 treatment between months 48 and 60 with a mean (SD) of 3.41 (3.69) treatments over this period. Mean CST was 671 μm at baseline and 261 μm (95% CI: 241.2, 280.9) at month 60. Although VALS improved substantially when patients were treated per protocol through month 12, improvement lessened when treatment was at investigator discretion and fewer treatments were received although VALS remained markedly improved over baseline through year 5. Most patients continued to receive treatment in year 5. This suggests that continued monitoring and, if warranted, treatment with anti-VEGF therapy benefits patients with macular edema associated with central retinal or hemiretinal vein occlusion. Publication of this article is sponsored by the American Ophthalmological Society.