Bevacizumab In Patients Research Articles

Combination of Radiotherapy and Atezolizumab plus Bevacizumab in Patients with Advanced Hepatocellular Carcinoma: A Pilot Study

Following the results of the IMbrave150 study, Atezolizumab plus bevacizumab (Atezo/beva) became the first-line treatment in patients with advanced hepatocellular carcinoma (HCC). However, its real-world efficacy has been less satisfied. In this study, we investigated the efficacy of radiotherapy (RT) combined with Atezo/beva in patients with advanced HCC. Twenty patients received combination of RT and Atezo/beva between December 2021 and December 2022 at our institution. RT was administered in 10 fractions of 5 Gy between Atezo/beva cycles. Tumor response were evaluated on both imaging and tumor marker basis. The iRECIST guideline was used to assess treatment response after the combination treatment of RT and Atezo/beva. Primary endpoints were disease control rate (DCR) and overall response rate (ORR), and secondary endpoint was treatment related toxicity. All patients were BCLC C with advanced tumors associated with lymph node metastasis (7, 35%) or distant metastasis (8, 40%). Patients received RT between cycles of Atezo/beva, mostly (14, 70%) between 2nd and 3rd cycles. After a median follow-up of 3.2 months, DCR was 65% and ORR was 20%. Significant decrease in tumor marker of over 2-fold was shown in 10 patients (50%). Regarding treatment related toxicity, only 1 patient (5%) showed grade 3 neutropenic fever, and no grade 4 or 5 toxicity was seen. Combination of radiotherapy and Atezo/beva showed high response rate with tolerable treatment related toxicity in advanced HCC patients. Further prospective studies with larger patient cohort are warranted.

Deep Learning Can Predict Bevacizumab Therapeutic Effect and Microsatellite Instability Directly from Histology in Epithelial Ovarian Cancer

Epithelial ovarian cancer (EOC) remains a significant cause of mortality among gynecologic cancers, with the majority of cases being diagnosed at an advanced stage. Before targeted therapies were available, EOC treatment relied largely on debulking surgery and platinum-based chemotherapy. Vascular endothelial growth factors have been identified as inducing tumor angiogenesis. According to several clinical trials, anti–vascular endothelial growth factor-targeted therapy with bevacizumab was effective in all phases of EOC treatment. However, there are currently no biomarkers accessible for regular therapeutic use despite the importance of patient selection. Microsatellite instability (MSI), caused by a deficiency of the DNA mismatch repair system, is a molecular abnormality observed in EOC associated with Lynch syndrome. Recent evidence suggests that angiogenesis and MSI are interconnected. Developing predictive biomarkers, which enable the selection of patients who might benefit from bevacizumab-targeted therapy or immunotherapy, is critical for realizing personalized precision medicine. In this study, we developed 2 improved deep learning methods that eliminate the need for laborious detailed image-wise annotations by pathologists and compared them with 3 state-of-the-art methods to not only predict the efficacy of bevacizumab in patients with EOC using mismatch repair protein immunostained tissue microarrays but also predict MSI status directly from histopathologic images. In prediction of therapeutic outcomes, the 2 proposed methods achieved excellent performance by obtaining the highest mean sensitivity and specificity score using MSH2 or MSH6 markers and outperformed 3 state-of-the-art deep learning methods. Moreover, both statistical analysis results, using Cox proportional hazards model analysis and Kaplan-Meier progression-free survival analysis, confirm that the 2 proposed methods successfully differentiate patients with positive therapeutic effects and lower cancer recurrence rates from patients experiencing disease progression after treatment (P < .01). In prediction of MSI status directly from histopathology images, our proposed method also achieved a decent performance in terms of mean sensitivity and specificity score even for imbalanced data sets for both internal validation using tissue microarrays from the local hospital and external validation using whole section slides from The Cancer Genome Atlas archive.

Efficacy of paclitaxel-carboplatin with bevacizumab as a late-line therapy for patients with advanced nonsquamous non-small cell lung cancer: A platinum rechallenge.

There is no well-established late-line treatment for advanced nonsquamous non-small cell lung cancer (NSCLC). Therefore, we retrospectively determined the efficacy and safety of platinum rechallenge with paclitaxel-carboplatin and bevacizumab in patients with nonsquamous NSCLC as a late-line therapy in a clinical setting. Thirty patients with nonsquamous NSCLC who received paclitaxel-carboplatin with bevacizumab therapy as a late-line treatment at Sendai Kousei Hospital (Miyagi, Japan) between December 2011 and December 2021 were enrolled into the study. The efficacy and safety of this treatment were evaluated. The patients were further categorized into responders and nonresponders, and predictive factors of treatment response were estimated. The median progression-free survival (PFS) was 6.3 (range, 4.9-6.8) months, and the median overall survival (OS) was 11.8 (range, 7.2-17.2) months. There were no significant differences in PFS and OS between patients with and those without epidermal growth factor receptor mutations. In the univariate analyses of this study, responders were younger than nonresponders (p = 0.012). No fatal adverse events were reported. With the increase in the number of treatment options in recent years, the sequence of treatments and overall therapeutic strategy are becoming increasingly important. Thus, platinum rechallenge with paclitaxel-carboplatin and bevacizumab, a late-line treatment for patients with nonsquamous NSCLC, may be an effective therapeutic option.

Efficacy and safety of atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a systematic review and meta-analysis.

Atezolizumab plus bevacizumab and lenvatinib are the current first-line systematic therapy for unresectable hepatocellular carcinoma (uHCC). However, the selection of initial treatment among the two therapies are controversial. This meta-analysis aims to compare efficacy and safety between atezolizumab plus bevacizumab and lenvatinib. We systematically searched for studies on atezolizumab plus bevacizumab and lenvatinib in the online databases PubMed, Embase, Web of Science and Cochrane Library. The outcome data including overall survival (OS), progression free survival (PFS), tumor response and adverse events (AEs), were independently extracted by two authors in a standardized way. Eight retrospective cohort studies with 3690 patients (atezolizumab plus bevacizumab: 1680, lenvatinib: 2010) were included in the meta-analysis. The atezolizumab plus bevacizumab group had significant longer PFS [hazard ratio (HR) 0.76, 95% confidence intervals (CI) 0.65-0.88; I squared statistic (I2) = 0.0%, p = 0.590], compared with lenvatinib group but no significant difference in OS (HR 0.87, 95% CI 0.75-1.01; I2 = 0.0%, p = 0.597), objective response rate (ORR) [risk ratio (RR) 0.89, 95% CI 0.79-1.02; I2 = 19.3%, p = 0.283] and disease control rate (DCR) (RR 1.03, 95% CI 0.98-1.09; I2 = 0.0%, p = 0.467) among them. Moreover, patients receiving atezolizumab plus bevacizumab exhibited lower incidences of grade 3/4 AEs than those receiving lenvatinib (RR 0.65, 95% CI 0.51-0.83; I2 = 69.3%, p = 0.003). However, in non-viral patients group, lenvatinib delivered favorable outcomes in OS (HR 1.32, 95% CI 1.04-1.67; I2 = 0.0%, p = 0.380) compared with atezolizumab plus bevacizumab. Atezolizumab plus bevacizumab provides potential advantage in efficacy and better safety than lenvatinib in the treatment of uHCC. Lenvatinib is an appropriate effective alternative to atezolizumab plus bevacizumab in patients without viral infecting.

A phase III, multicenter, randomized study of olvimulogene nanivacirepvec followed by platinum-doublet chemotherapy and bevacizumab compared with platinum-doublet chemotherapy and bevacizumab in women with platinum-resistant/refractory ovarian cancer

BackgroundTreatment options for patients with platinum-resistant/refractory ovarian cancers are limited and only marginally effective. The development of novel, more effective therapies addresses a critical unmet medical need. Olvimulogene nanivacirepvec (Olvi-Vec),...

Real‐world experiences of atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma in Hong Kong

AbstractBackground and AimsThe IMbrave150 trial established atezolizumab–bevacizumab as the new standard of care for hepatocellular carcinoma (HCC). However, evidence on its applications in real‐world patients is limited. We report the efficacy and safety of atezolizumab–bevacizumab in a Chinese cohort of HCC patients ineligible for clinical trials.MethodsElectronic medical records of patients diagnosed with HCC and with pharmacy orders of atezolizumab and bevacizumab between 2019 and 2021 were retrospectively reviewed. Patients' demographics, performance status, stage, treatment received, adverse events and death time (if any) were recorded.ResultsThirteen eligible patients were included. mOS of HCC patients was 18.6 months [6.8–30.4], while mPFS was 9.3 months [0–19.4]. No grade 5 adverse events were reported.ConclusionsThis real‐world study provides real‐world experiences of atezolizumab–bevacizumab as first‐line and subsequent therapy in patients with unresectable HCC. Further validation on the efficacy and safety of atezolizumab–bevacizumab as second‐line or later lines of treatment should be conducted.

Circulating and intratumoral immune determinants of response to atezolizumab plus bevacizumab in patients with variant histology or sarcomatoid renal cell carcinoma

Abstract Background Renal cell carcinoma of variant histology (vRCC) encompasses approximately 20% of RCC diagnoses. Due to a poor understanding of the different biologies of vRCCs, there is currently no standard of care for this type of tumor and guidelines are extrapolated from clear-cell RCC trials. A phase II trial of atezolizumab plus bevacizumab in patients with vRCC or sarcomatoid differentiation had an acceptable safety profile and evidence of clinical activity, particularly in tumors with positive PD-L1 expression or sarcomatoid differentiation. To better understand the determinants of immunotherapy response in this population, we characterized blood- and tissue-based immune markers for patients with vRCC, or any RCC histology with sarcomatoid differentiation, enrolled in this phase II trial of atezolizumab and bevacizumab. Methods We used patient data and biospecimens (blood and tumor) from a prospective phase-II clinical trial of the anti-PD-L1 antibody atezolizumab and the anti-VEGF-A antibody bevacizumab in patients with metastatic RCC with variant histology and/or sarcomatoid differentiation (NCT02724878). Blood samples were collected at baseline, prior to therapy (C1D1: cycle one day one), and on-treatment, following two cycles of therapy (C3D1: cycle three day one). Plasma was assayed for the levels of soluble factors (e.g., cytokines and growth factors), and peripheral blood mononuclear cells (PBMCs) were immunophenotyped using flow cytometry. In addition, formalin-fixed, paraffin-embedded (FFPE) archival or pre-treatment study tumor biopsies were analyzed by immunohistochemistry and immunofluorescence for enrolled subjects with available biospecimen. Baseline demographics, clinical characteristics, and treatment outcomes, including progression-free survival (PFS), overall survival (OS), and clinical benefit, were collected, and analyzed from the trial database. This study was approved by each participating institution's institutional review board, and all patients provided written informed consent. We used R (version 4.1.1) to carry out our analyses. We assessed the relationships between biomarker variables were analyzed using Pearson correlations and hierarchical clustering using Euclidean distance. All biomarker variables were Z-score normalized. We calculated an inflammatory module, the systemic inflammation score (SIS), which corresponds to the average score of the five highly correlated inflammatory cytokines: MIP-1b, IL-1, MCP-1, IL-6, and IL-13. We applied pair-wise Wilcoxon tests to evaluate the association of biomarkers with clinical benefit groups and log-rank-tests and univariate Cox regression models to evaluate the relationship of biomarkers with PFS and OS. Results With the exception of two angiogenic cytokines (VEGF-A and Angiopoietin 2) that were more abundant in patients with non-sarcomatoid tumors, baseline circulating cytokines (plasma) had similar distributions between sarcomatoid and non-sarcomatoid subgroups. Baseline circulating inflammatory cytokines were highly correlated with one another, forming an “inflammatory module” that was increased in IMDC-poor risk patients and was associated with worse PFS (p=0.028) and with resistance to therapy (p=0.033). At baseline, an elevated circulating VEGF-A level was associated with a lack of response (p=0.03) and worse PFS (p=0.021). However, a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit (p=0.01) and improved overall survival (p=0.0058). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes, with a reduction in CD4+ PD-L1+ (HR:0.62[0.49-0.91], p=0.016) and CD8+ PD-L1+ T cells (HR:0.59[0.39-0.87], p=0.009) correlated with improved PFS. Within the tumor itself, a higher percentage of terminally exhausted (PD-1+ and either TIM-3+ or LAG-3+) CD8+ T cells was associated with worse PFS (p=0.028). We observed similar trends for all of these results in different subgroups according to sarcomatoid status and histology. Conclusions Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab. Furthermore, they provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations.

The cost-effectiveness analysis of maintenance olaparib plus Bevacizumab in patients with advanced ovarian cancer: based on the final survival results from PAOLA-1 trial

IntroductionIn 2023, the final PAOLA-1 trial (NCT02477644) survival data were published documenting the benefits of therapy consisting of olaparib plus bevacizumab for patients with advanced ovarian cancer (AOC) as a function of molecular status. In light of these new data, the present study was conducted with the goal of evaluating the cost-effectiveness of olaparib plus bevacizumab for the treatment of the overall AOC patient population and for homologous recombination deficiency (HRD)-positive patients, patients with a breast cancer susceptibility gene (BRCA) mutations, homologous recombination proficiency (HRD)-positive, or patients not harboring BRCA mutations AOC from a US payers perspective.MethodsA Markov state-transition model with a 15-year time horizon was used to evaluate outcomes of patients administered Olaparib plus bevacizumab versus bevacizumab. Life-years (LYs), quality-adjusted LYs (QALYs), and the incremental cost-effectiveness ratio (ICER) values were evaluated in this study in light of a $150,000/QALY of willingness-to-pay (WTP) threshold. The stability of the established model was evaluated through sensitivity analyses.ResultsRelative to bevacizumab alone, Olaparib plus bevacizumab was associated with mean incremental costs and QALYs (LYs) of olaparib plus bevacizumab versus bevacizumab were $293,656 and 1.85 (2.16), $265,668 and 3.34 (4.02), $242,746 and 1.71 (2.06), and $193,792 and 0.97 (1.14) for overall, BRCA mutation-positive, HRD-positive, and HRD-positive BRCA mutation-negative AOC patients, respectively. The corresponding ICER values for these patient subgroups were $158,729 ($136,218), $79,434 ($66,120), $141,636 ($117,747), and $200,595 ($169,733) per QALY (LY) gained Utility value and the price of olaparib were identified in sensitivity analyses as the primary factors influencing these results.ConclusionAt current pricing levels, maintenance treatment with olaparib plus bevacizumab treatment may represent a cost-effective therapeutic option for BRCA mutations and HRD-positive AOC patients in the USA.

The prediction of early progressive disease in patients with hepatocellular carcinoma receiving atezolizumab plus bevacizumab.

The IMbrave 150 trial revealed the usefulness of atezolizumab plus bevacizumab therapy in patients with unresectable hepatocellular carcinoma (HCC), making it now considered the first-line systemic chemotherapy agent for HCC. The present study investigated factors associated with early tumor progression of atezolizumab plus bevacizumab in patients with advanced HCC in real-world clinical practice. A total of 184 HCC patients who received atezolizumab plus bevacizumab therapy were studied. We investigated the frequency of early progressive disease (e-PD; PD within 9 weeks) and analyzed the risk factors for e-PD. There were 47 patients (25.5%) diagnosed as e-PD. Patients with e-PD had a worse performance status (PS) and albumin-bilirubin (ALBI) and Child-Pugh (C-P) scores and a significantly higher rate of a systemic therapy than those with non-e-PD. A multivariate analysis showed that PS ≥1 (odds ratio [OR] = 4.5, 95% confidence interval [CI] = 1.9-10, p < 0.001), ALBI score ≥-2.30 (OR = 2.1, 95% CI = 1.0-4.5, p = 0.044) and the history of a systemic therapy (OR = 3.0, 95% CI = 1.4-6.4, p = 0.0038) were significant and independent determinants of e-PD. When examining the liver function trends in e-PD patients, the ALBI scores at 3 and 6 weeks after starting therapy were significantly higher than before the treatment (p < 0.001). The liver function and systemic therapy are useful predictors of e-PD in HCC patients treated with atezolizumab plus bevacizumab in real-world clinical practice.

Efficacy and safety of sintilimab plus bevacizumab in metastatic nasopharyngeal carcinoma after failure of platinum-based chemotherapy: an open-label phase 2 study

There are limited treatment options for patients with metastatic nasopharyngeal carcinoma (mNPC) after failure of platinum-based chemotherapy. In this trial, we assessed the efficacy and safety of sintilimab plus bevacizumab in patients with mNPC where platinum-based chemotherapy has been ineffective. This was a single-centre, open-label, single-arm, phase 2 trial in Guangzhou, China for patients with mNPC progressed after at least one line of systemic therapy. Eligible patients were between 18 and 75 years old, were histologically confirmed differentiated or undifferentiated non-keratinized NPC, were ineffective after platinum-based chemotherapy, and they had at least one measurable metastatic lesion assessed with Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST V.1.1) by investigators and unsuitable for local surgery or radiotherapy. Key exclusion criterion was previous treatment with anti-PD-1/PD-L1 antibodies plus anti-VEGF antibodies and high risk of hemorrhage or nasopharyngeal necrosis. Patients were enrolled and received sintilimab (200mg) plus bevacizumab (7.5mg/kg) intravenously every 3 weeks. Intention-to-treat population was included in primary endpoint analyses and safety analyses. The primary endpoint was objective response rate (ORR) assessed by investigators following the guidelines of RECIST V1.1. Key secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. This trial is registered with ClinicalTrials.gov (NCT04872582). Between July 29, 2021 and August 16, 2022, 33 patients were enrolled. Median age was 46 years (range, 18-64 years), and 63.6% of patients had previously received two or more lines of chemotherapy for metastatic disease. Median follow-up was 7.6 months (range, 4.1-17.5 months). ORR was 54.5% (95% CI, 36.4-71.9%) with 3 complete responses (9.1%) and 15 partial responses (45.5%). Median PFS was 6.8 months (95% CI, 5.2 months to not estimable). Median DOR was 7.2 months (95% CI, 4.4 months to not estimable). Median OS was not reached. The most common potential immune-related adverse event (AE) was Grade 1-2 hypothyroidism (42.4%). Treatment-related grade 3 or 4 AEs occurred in 7 patients (21.2%), including nasal necrosis (3/33), hypertension (1/33), pruritus (1/33), total bilirubin increased (1/33) and anaphylactic shock (1/33). No treatment-related deaths and severe epistaxis occurred. This phase 2 trial showed that sintilimab plus bevacizumab demonstrated promising antitumour activity and manageable toxicities in patients with mNPC after failure of platinum-based chemotherapy. Further trials are warranted, and the detailed mechanisms need to be elucidated. The Guangdong Basic and Applied Basic Research Foundation, the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province, and the Science and Technology Planning Project of International Cooperation of Guangdong Province.

Phase II biomarker identification study of anti-VEGF agents withFOLFIRI for pretreated metastatic colorectal cancer.

Chemotherapy plus antiangiogenic agents, including bevacizumab, ramucirumab and aflibercept, is a standard second-line treatment for patients with metastatic colorectal cancer, but which specific agents should be selected is ambiguous due to a lack of clear evidence from prospective studies. Previous reports have suggested ramucirumab and aflibercept could be more effective than bevacizumab in patients with high VEGF-D and high VEGF-A, respectively. JCOG2004 is a three-arm, randomized, phase II study to identify predictive biomarkers for these agents in patients who have failed first-line treatment. The study will enroll 345 patients from 52 institutions for 2years, with progression-free survival in high VEGF-D (bevacizumab vs ramucirumab) and high VEGF-A (bevacizumab vs aflibercept) serving as the primary end point. Clinical Trial Registration: jRCTs031220058 (www.jrct.niph.go.jp).

Mean Best Corrected Visual Acuity after Intravitreal Bevacizumab in Patients with Diabetic Macular Edema

Purpose: To determine mean best corrected visual acuity after intravitreal bevacizumab in patients with diabetic macular edema. Study Design: Quasi experimental study. Place and Duration of Study: Jinnah Hospital, Lahore and Chaudary Muhammad Akram Hospital Lahore from March 2018 to May 2021. Methods: A total of 200 patients of either gender with diabetic macular edema and age between 40 and 60 years were included in this study. Patients with dense cataract, corneal opacity, uncontrolled diabetes mellitus and those who were treated with pan retinal photocoagulation were excluded. Best corrected Visual Acuity (BCVA) was evaluated with Snellen chart and converted to log MAR. A standard protocol of 0.05 mL of Bevacizumab was prepared from injection Avastin, 100 mg/4 mL vial. Bevacizumab injection was given to all patients, using topical anesthesia, under aseptic measures in the operation theater. A total of 03 injections were given at 1-month interval. After three months, BCVA was recorded. Results were presented in number and percentages. Results: Mean age of the participants was 50.42 ± 6.48 years. Male to female ratio was 1:1.6, with 78 (39.0%) men and 122 (61.0%) women. Mean duration of diabetes mellitus was 5.12 ± 2.23 years. Mean pre-treatment BCVA was 0.51 ± 0.05 and mean post-treatment BCVA at three months was 0.26 ± 0.22. Conclusion: Mean BCVA is increased after intravitreal injection of Bevacizumab in patients with diabetic macular edema.

FOLFOXIRI Plus Cetuximab or Bevacizumab as First-Line Treatment of BRAFV600E-Mutant Metastatic Colorectal Cancer: The Randomized Phase II FIRE-4.5 (AIO KRK0116) Study.

BRAFV600E mutation is associated with a poor outcome in metastatic colorectal cancer (mCRC). This clinical trial investigated the efficacy of triplet chemotherapy (fluorouracil, folinic acid, oxaliplatin, and irinotecan) combined with either cetuximab or bevacizumab in patients with previously untreated BRAFV600E-mutant mCRC. In this controlled, randomized, open-label phase II trial, 109 patients were randomly assigned, 107 of whom were included into the full analysis set (FAS). Patients were randomly assigned in a 2:1 ratio to receive either FOLFOXIRI plus cetuximab in the experimental arm (n = 72) or FOLFOXIRI plus bevacizumab in the control arm (n = 35). The primary end point was objective response rate (ORR) according to RECIST 1.1., evaluated in patients treated according to protocol (ATP population). Progression-free survival (PFS), overall survival (OS), toxicity, and feasibility were analyzed as secondary end points. Eighteen patients discontinued study treatment before the first tumor assessment, thus resulting in the ATP population of 89 patients. In these patients, ORR was 51% (30/59) in the cetuximab-based experimental arm and 67% (20/30) in the bevacizumab-based control arm (odds ratio, 1.93; 80% CI, 1.06 to 3.52; P = .92 [one-sided]). In the full analysis set, median PFS was significantly inferior in the experimental arm (6.7 months v 10.7 months; hazard ratio [HR], 1.89; P = .006). Median OS analyzed at an event rate of 64.5% showed a trend toward shorter survival in cetuximab-treated patients (12.9 months v 17.1 months; HR, 1.4; P = .20). To our knowledge, FIRE-4.5 is the first prospective and randomized study investigating first-line treatment of BRAFV600E-mutant mCRC. FOLFOXIRI plus cetuximab does not induce a higher ORR when compared with FOLFOXIRI plus bevacizumab in first-line treatment of BRAFV600E-mutant mCRC. Bevacizumab-based chemotherapy remains the preferable first-line treatment of patients with BRAFV600E-mutant mCRC.

Successful regression of newly formed corneal neovascularization by subconjunctival injection of bevacizumab in patients with chemical burns.

To investigate the effect and timing of subconjunctival bevacizumab injection on inhibiting corneal neovascularization (CorNV) in patients after chemical burns. Patients with CorNV secondary to chemical burns were involved. Two subconjunctival injections of bevacizumab (2.5 mg/0.1 mL per involved quadrant) with an interval of 4 weeks were administered, and followed up a year. The area occupied by neovascular vessels (NA), accumulative neovascular length (NL), mean neovascular diameter (ND), best-corrected visual acuity (BCVA) and intraocular pressure (IOP) were evaluated. Complication was also recorded. Eleven patients with CorNV were involved. Eight patients had a history of surgery (four had amniotic grafts, one had keratoplasty, and three had amniotic grafts and keratoplasty). Decreasing in NA, NL, and ND were statistically significant at each time point compared to the baseline (p < 0.01). CorNV that developed within 1 month was considerably regressed, and vessels with fibrovascular membranes were found to be narrower and shorter than pretreatment. BCVA improved in five patients (from one to five lines), remained unchanged in five patients, and decreased in one patient compared to pretreatment. Subconjunctival bevacizumab injection has a particular potential for the regression of CorNV, especially newly formed within 1 month in patients after chemical burns.

Effectiveness of treatment with intravitreous Bevacizumab in patients diagnosed with diabetic macular edema at the Hospital Otorrino Oftalmológico of the Caja Nacional de Salud, La Paz – Bolivia

Objetivo: Determinar los cambios en el espesor macular establecido por Tomografía de Coherencia Óptica (OCT) posterior al tratamiento con Bevacizumab intravítreo en pacientes con Edema Macular Diabético, diagnosticados en el Hospital Otorrino Oftalmológico. Material y Métodos: Es un estudio de serie de casos. Se realizo un muestreo por conveniencia de pacientes con edema macular diabético, la muestra obtenida fue de 106 casos de un universo de 146 pacientes con una confiabilidad del 95%, pero según criterios de inclusión y exclusión, la muestra se redujo a 24 pacientes. Resultados: Disminución del espesor macular inicial de 493,8 µm a 287,6 µm. La agudeza visual mejora después del tratamiento con Bevacizumab en 79,2% de los pacientes, de los cuales el 62,5% mejoro hasta la 3era dosis de inyección intravítrea y en relación con la HbA1c (Hemoglobina Glicosilada) valores &lt; a 7% da una frecuencia relativa de 66,7% y &gt; a 7% un 33,3%. Existió mayor representatividad de edad entre un rango de 51 a 60 años en 9 pacientes 37,5%. Conclusiones: El tratamiento del edema macular diabético con Bevacizumab intravítreo produce mejorías significativas tanto anatómicas como funcionales. Los valores de HbA1Ac es influyente tanto para la mejora anatómica como funcional.

The Efficacy, Safety, and Efficiency of the Off-Label Use of Bevacizumab in Patients Diagnosed With Age-Related Macular Degeneration: Protocol for a Systematic Review and Meta-Analysis

Background Age-related macular degeneration (AMD) is recognized as the leading cause of vision loss in older people. Considering the phenomenon of aging societies worldwide, the prevalence of AMD is expected to increase gradually in the future. AMD can be divided into early, intermediate, and late stages, with the early and intermediate stages being mainly asymptomatic, and the late stage being classified as geographic atrophy, neovascular AMD, or both. Current pharmacological treatments for neovascular AMD include anti–vascular endothelial growth factor agents, such as ranibizumab, pegaptanib, and aflibercept. Additionally, it has been reported that the off-label use of intravitreally administered bevacizumab is effective. It is also lower cost than other agents, which makes it an interesting pharmacological approach. Objective This review aims to evaluate the efficacy, safety, and efficiency of bevacizumab for the treatment of neovascular AMD. Methods This review will only consider randomized controlled clinical trials that compare the use of bevacizumab with another pharmacological agent or a placebo in patients aged 50 years and older who are diagnosed with vascular AMD. It will exclude studies that include participants diagnosed with polypoidal choroidal vasculopathy or retinal angiomatous proliferation. To identify and select relevant articles, we will develop a highly sensitive search strategy and apply it in MEDLINE via the PubMed platform. Upon selection of the studies and analysis of the titles, abstracts, and full texts, the results will be presented according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The analysis and extraction of the data will be performed by 2 independent reviewers. Risk of bias will be evaluated with the Critical Appraisal Skills Programme (CASP) checklist. Finally, the same reviewers will also perform a quality assessment of the included studies with the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool. Results The search strategy, after the application of the inclusion and exclusion criteria, identified 15 randomized clinical trials, which are currently being analyzed. This project has no funding and it has been developed by a multidisciplinary research team of pharmacologists and orthoptists. The study was initiated in May 2021 and it is expected to conclude by the end of 2023. Conclusions This review will provide a synthesis of current information and underlying evidence about the off-label use of bevacizumab in neovascular AMD. It will provide a clearer vision of a possible new pharmacological approach, as well as the most suitable treatment designs, for the treatment of neovascular AMD. Trial Registration PROSPERO CRD42021244931; https://tinyurl.com/p6m5ycpk International Registered Report Identifier (IRRID) DERR1-10.2196/38658

Bevacizumab, Irinotecan, and Biweekly Trifluridine/Tipiracil for Metastatic Colorectal Cancer: MODURATE, a Phase Ib Study.

In this phase Ib study MODURATE, we optimized the dosing schedule and tested the efficacy and safety of trifluridine/tipiracil, irinotecan, and bevacizumab in patients with metastatic colorectal cancer with fluoropyrimidine and oxaliplatin treatment failure. We included a dose escalation (3 + 3 design) and an expansion cohort. Patients were administered trifluridine/tipiracil (25-35 mg/m2 twice daily, days 1-5), irinotecan (150-180 mg/m2, day 1), and bevacizumab (5 mg/kg, day 1) every 2 weeks. The recommended phase II dose (RP2D) in the dose escalation cohort was administered to at least 15 patients in both cohorts combined. Twenty-eight patients were enrolled. Five dose-limiting toxicities were observed. RP2D was defined as trifluridine/tipiracil 35 mg/m2, irinotecan 150 mg/m2, and bevacizumab 5 mg/kg. Of 16 patients who received RP2D, 86% (14/16) experienced grade ≥3 neutropenia without febrile neutropenia. Dose reduction, delay, and discontinuation occurred in 94%, 94%, and 6% of patients, respectively. Three patients (19%) showed partial response and 5 had stable disease for >4 months, with a median progression-free and overall survival of 7.1 and 21.7 months, respectively. Biweekly trifluridine/tipiracil, irinotecan, and bevacizumab administration may have moderate antitumor activity with high risk of severe myelotoxicity in previously treated patients with metastatic colorectal cancer [UMIN Clinical Trials Registry (UMIN000019828) and Japan Registry of Clinical Trials (jRCTs041180028)].

EVALUATING EFFICACY AND SAFETY OF SUPRACHOROIDAL TRIAMCINOLONE ACETONIDE FOR PATIENTS WITH RETINAL VEIN OCCLUSION

The prospective study was conducted in the Ophthalmology department, Sir Ganga Ram Hospital, Lahore, from January 2022 to January 2023 to compare the efficacy and safety of intravitreal (IVT) Bevacizumab alone with the suprachoroidal injection of CLS-TA (an injectable form of triamcinolone) along with IVT Bevacizumab in patients with retinal vein occlusion (RVO) induced macular edema in treatment naïve patients. Participants were randomized 1:1 to the IVT Bevacizumab group, and suprachoroidal injection of CLS-TA combined with IVT Bevacizumab group. Participants in both groups were administered drugs and monitored for 30 minutes after the injections. The final evaluation was done after 3 months. Results showed that the Bevacizumab group required 22 re-treatments of the participants for 3 months follow-up, while the combination group required 8 re-treatments (P=0.013). Regarding safety, 1 patient had cataract progression unrelated to the study drug. Combining steroids with vascular endothelial growth factor (VEGF) suppression benefits RVO-induced macular edema. It improves vision, reduces injection frequency, and provides rapid resolution. It is also seen that suprachoroidal delivery of CLS-TA is associated with a reduced risk of increased IOP and cataract progression compared to typical intraocular steroids. Regarding safety, 1 patient had cataract progression unrelated to the study drug. Combining steroids with vascular endothelial growth factor (VEGF) suppression benefits RVO-induced macular edema. It improves vision, reduces injection frequency, and provides rapid resolution. It is also seen that suprachoroidal delivery of CLS-TA is associated with a reduced risk of increased IOP and cataract progression compared to typical intraocular steroids.

Circulating and Intratumoral Immune Determinants of Response to Atezolizumab plus Bevacizumab in Patients with Variant Histology or Sarcomatoid Renal Cell Carcinoma.

Renal cell carcinoma (RCC) of variant histology comprises approximately 20% of kidney cancer diagnoses, yet the optimal therapy for these patients and the factors that impact immunotherapy response remain largely unknown. To better understand the determinants of immunotherapy response in this population, we characterized blood- and tissue-based immune markers for patients with variant histology RCC, or any RCC histology with sarcomatoid differentiation, enrolled in a phase II clinical trial of atezolizumab and bevacizumab. Baseline circulating (plasma) inflammatory cytokines were highly correlated with one another, forming an "inflammatory module" that was increased in International Metastatic RCC Database Consortium poor-risk patients and was associated with worse progression-free survival (PFS; P = 0.028). At baseline, an elevated circulating vascular endothelial growth factor A (VEGF-A) level was associated with a lack of response (P = 0.03) and worse PFS (P = 0.021). However, a larger increase in on-treatment levels of circulating VEGF-A was associated with clinical benefit (P = 0.01) and improved overall survival (P = 0.0058). Among peripheral immune cell populations, an on-treatment decrease in circulating PD-L1+ T cells was associated with improved outcomes, with a reduction in CD4+PD-L1+ [HR, 0.62; 95% confidence interval (CI), 0.49-0.91; P = 0.016] and CD8+PD-L1+ T cells (HR, 0.59; 95% CI, 0.39-0.87; P = 0.009) correlated with improved PFS. Within the tumor itself, a higher percentage of terminally exhausted (PD-1+ and either TIM-3+ or LAG-3+) CD8+ T cells was associated with worse PFS (P = 0.028). Overall, these findings support the value of tumor and blood-based immune assessments in determining therapeutic benefit for patients with RCC receiving atezolizumab plus bevacizumab and provide a foundation for future biomarker studies for patients with variant histology RCC receiving immunotherapy-based combinations.

Response Prediction Model of Atezolizumab plus Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma: Multicenter Retrospective Study

Introduction: Atezolizumab plus bevacizumab (ATZ+BV) treatment has become the first-line regimen for unresectable hepatocellular carcinoma (u-HCC). Prediction of response to it might be clinically beneficial. Using peripheral blood parameters, we aimed to construct a prediction model for ATZ+BV treatment. Methods: Clinical records of 119 patients with u-HCC treated by ATZ+BV were retrospectively analyzed. The primary outcome measurement was defined as any-size reduction at the initial image evaluation. Using baseline values of peripheral blood parameters, a prediction model was constructed by univariate and multivariate logistic regression analysis. Validation was performed internally by bootstrap method. Results: The primary outcome was achieved in 46 patients. Univariate analysis showed that C-reactive protein (CRP), alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were possible predictors. CRP and DCP, and NLR and PLR had correlation (correlation coefficient >0.3), so we used CRP and NLR as representative factors, respectively. Multivariate analysis constructed the following prediction model: Logit = 1.62–0.61×[CRP] −0.38×[Log₁₀AFP] −0.37×[NLR]. Bootstrapped median (95% confidence interval) of coefficients of CRP, Log₁₀AFP, NLR were −0.64 (−1.46 ∼ −0.11), −0.40 (−0.82 ∼ −0.03), and −0.38 (−0.74 ∼ −0.05), respectively. The area under the receiver operating characteristic curve (95% confidence interval) was 0.73 (0.60–0.80). Median overall survival of the favorably and unfavorably predicted groups were 17.0 and 11.0 months (p = 0.03), respectively. Discussion: In patients with u-HCC treated by ATZ+BEV, a prediction model constructed using baseline values of CRP, AFP, and NLR had impact on any-size reduction at the initial image evaluation and on prognosis.