Vascular Endothelial Growth Factor Tyrosine Kinase Research Articles

Small molecule inhibitors of the VEGF and tyrosine kinase for the treatment of cervical cancer.

Cervical cancer accounts for most deaths due to cancer in women, majorly in developing nations. The culprit behind this disease is the human papillomavirus(HPV) which accounts for more than 90% of cervical cancer cases. The viral strains produce proteins that favor the knocking down of the apoptosis process and continuous growth of cells in the cervix leading to tumor growth. Proangiogenic growth factors, such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), angiopoietins, and other endothelial growth factors (EGF), are secreted by tumor cells and the surrounding microenvironment, which further advances the development of cancer. The extracellular domain of receptor tyrosine kinases is employed by ligands (like VEGF and EGF) to engage and activate them by inducing receptor dimerization, which facilitates the cascade impact of these factors. The tyrosine kinase domains of each receptor autophosphorylate each other, activating the receptor and initiating signaling cascades that promote angiogenesis, migration, proliferation, and survival of endothelial cells. Cancer cells benefit from its modified signaling pathways, which cause oncogenic activation. Upon early cervical cancer detection, the second-line therapy strategy involves blocking the signaling pathways with VEGF and small molecule tyrosine kinase inhibitors (TKIs). This review paper highlights the genesis of cervical cancer and combating it using VEGF and tyrosine kinase inhibitors by delving into the details of the currently available inhibitors. Further, we have discussed the inhibitor molecules that are currently in various phases of clinical trials. This paper will surely enhance the understanding of cervical cancer and its treatment approaches and what further interventions can be done to alleviate the disease currently serving as a major health burden in the developing world.

Beneficial effects of dietary omega 3 polyunsaturated fatty acids on offspring brain development in gestational diabetes mellitus

Various mechanisms through which maternal diet influences offspring brain development in gestational diabetes mellitus (GDM) remains unclear. We speculate that prenatal omega 3 fatty acids will improve the levels of brain neurotrophins and vascular endothelial growth factor (VEGF), an angiogenic factor leading to improved cognitive performance in the offspring. GDM was induced in Wistar rats using streptozotocin. They were assigned to either control, GDM or GDM+O (GDM + omega-3 fatty acid supplementation). The offspring were followed till 3 mo of age and cognitive assessment was undertaken. Data analysis was carried out using one-way ANOVA followed by LSD test. GDM induction increased (p < 0.01) dam glucose levels and lowered brain derived neurotrophic factor (BDNF) levels (p = 0.056) in the offspring at birth. At 3 months, GDM group showed significantly lower levels of neurotrophic tyrosine kinase receptor-2 (NTRK-2) and VEGF, lower mRNA levels of NTRK-2 and cAMP response element-binding protein (CREB) (P < 0.05 for all) as compared to control. The GDM offspring had a higher escape latency (p < 0.01), made lesser % correct choices and more errors (p < 0.05 for both). Prenatal supplementation with omega 3 polyunsaturated fatty acids was beneficial since it ameliorated some of the adverse effects of GDM.

Effects of neoadjuvant VEGF‑TKI treatment on surgery for renal cell carcinoma: A systematic review and meta‑analysis.

To evaluate the effects of neoadjuvant vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) treatment on surgery in patients with renal cell carcinoma (RCC), sources from Embase, PubMed and the Cochrane Library databases collected from inception to December, 2022 were used for analysis in the present study, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data regarding surgical outcomes were collected. The pooled effect sizes were calculated in terms of the risk ratio (RR)/standard mean difference (SMD) with 95% confidence intervals (CIs) using the random-effects model. Subgroup and sensitivity analyses were used to explore the source of heterogeneity within the data. In total, 9 identified articles involving 829 patients (336 in the neoadjuvant + surgery group; 493 in the surgery group) were included in the present study, according to the criteria. The results demonstrated that there were no significant differences in blood loss (SMD=-0.11; 95% CI, -0.63-0.41; P=0.68), postoperative length of hospital stay or total length of hospital stay (SMD=0.23; 95% CI, -0.55-1.01; P=0.57) or complications (RR=1.16; 95% CI, 0.80-1.67; P=0.44) between the two groups. However, neoadjuvant therapy reduced the operation time (SMD=-0.67; 95% CI, -1.25- -0.09; P=0.02) and resulted in a greater proportion of patients choosing partial nephrectomy (RR=1.84; 95% CI, 1.47-2.31; P<0.00001). In the subgroup analysis, the blood loss was significantly lower in patients with RCC with inferior vena cava tumor thrombus in the neoadjuvant group (SMD=-1.10; 95% CI, -1.82- -0.38; P=0.003). In conclusion, the results of the present study indicated that neoadjuvant VEGF-TKI treatment in patients with RCC shortened operation time, decreased blood loss and did not cause an increase in perioperative complications. In addition, this treatment modality may encourage patients to opt for partial nephrectomy to preserve renal function.

Critical review of the current and future prospects of VEGF-TKIs in the management of squamous cell carcinoma of head and neck.

As the prognosis for squamous cell carcinoma of the head and neck remains unsatisfactory when compared to other malignancies, novel therapies targeting specific biomarkers are a critical emerging area of great promise. One particular class of drugs that has been developed to impede tumor angiogenesis is vascular endothelial growth factor-tyrosine kinase inhibitors. As current data is primarily limited to preclinical and phase I/II trials, this review summarizes the current and future prospects of these agents in squamous cell carcinoma of the head and neck. In particular, the combination of these agents with immunotherapy is an exciting area that may be a promising option for patients with recurrent or metastatic disease, evidenced in recent trials such as the combination immune checkpoint inhibitors with lenvatinib and cabozantinib. In addition, the use of such combination therapy preoperatively in locally advanced disease is another area of interest.

Trends of Utilization of Systemic Therapies for Metastatic Renal Cell Carcinoma in the Canadian Health Care System.

Standard-of-care therapies for metastatic renal cell carcinoma (mRCC) have greatly evolved. However, the availability of emerging options in global health care systems can vary. We sought to describe the integration and usage of systemic therapies for mRCC in Canada since 2011. We included patients with mRCC enrolled in the Canadian Kidney Cancer Information System, a prospective cohort of patients from 14 Canadian academic centers, who received systemic therapy from January 1, 2011, to December 31, 2021. Patients were stratified by treatment era (cohort 1: 2011-2015, cohort 2: 2016-2021). Stacked bar charts were used to present treatment proportions; Sankey diagrams were used to show the evolution of treatment sequencing between the two cohorts. Four thousand one hundred seven patients were diagnosed with mRCC, of whom 2,752 (67%) received systemic therapy. Among these patients, mean age was 64 years, 74% were male, 75% had clear cell histology, and International Metastatic RCC Database Consortium risk classification was favorable, intermediate, and poor in 16%, 56%, and 28%, respectively. Utilization of immune checkpoint inhibition (ICI)-based treatments has increased in Canada and reflects global and local patterns of approval and adoption. The use of therapies after doublet ICI has mostly shifted toward vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs) that were previously used in first line with subsequent treatments reflecting approved and available agents after previous VEGF-TKI. Clinical trial participation among patients who received systemic therapy was 18% in first, 21% in second, and 24% in third line. In Canada's publicly funded health care system, availability of standard mRCC therapies broadly reflects access from government-funded clinical trials and compassionate access program sources. In an evolving therapeutic landscape, ongoing advocacy is required to continue to facilitate patient access to efficacious therapies.

Efficacy and Toxicity of Combined Inhibition of EGFR and VEGF in Patients With Advanced Non-small Cell Lung Cancer Harboring Activating EGFR Mutations: A Systematic Review and Meta-analysis.

Dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways have demonstrated promising results for treatment of advanced non-small cell lung cancer. We conducted a systematic review and meta-analysis to assess the efficacy and toxicity of the combined treatment with EGFR tyrosine kinase inhibitors (TKIs) and VEGF blockade for patients with advanced non-small cell lung cancer harboring activating EGFR mutations, in comparison to EGFR TKIs alone. The electronic databases were searched for relevant randomized trials between 2000 and 2022. The primary endpoints were overall survival (OS) and progression-free survival. Secondary endpoints included objective response rate (ORR), disease control rate, and grade ≥3 adverse events (AEs). The pooled hazard ratios (HR) and odds ratios were meta-analyzed using the generic inverse variance and the Mantel-Haenszel methods. A total of 1528 patients from 8 trials were evaluated for analyses. The combination treatment decreased the risk of disease progression by 37% (HR=0.63; 95% CI, 0.56 to 0.72) but had no added benefit on OS compared with EGFR inhibition alone (HR=0.90; 95% CI, 0.76 to 1.05). There was no significant difference in objective response rate or disease control rate between treatments. There was a significantly increased number of AEs reported in the dual treatment arm (odds ratio=3.02; 95% CI, 1.71 to 5.31), with proteinuria and hypertension being the most significantly increased AEs. This meta-analysis suggests combined inhibition of EGFR and VEGF pathways significantly improves progression-free survival, with no OS benefit, and increases AEs. Mature OS data are needed along with results from more trials exploring this strategy with third-generation EGFR TKIs to strengthen these results.

Toxicities of anti-VEGF therapies used in metastatic renal cell carcinoma: A real-world experience.

e16533 Background: Tumor endothelial proliferation inhibition using vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs) have revolutionized metastatic renal cell carcinoma (mRCC) therapy. We retrospectively analyzed data on various anti-VEGF adverse events (AEs) utilizing the FDA Adverse Events Reports System (FAERS). Methods: We examined the FAERS public dashboard data on VEGF inhibitors’ reported AEs for the years 2019-2021. Data analyzed using descriptive statistics. Results: A total of 34,651 AEs were identified for anti-VEGF therapies, of which 29,328 (84.6%) were serious and 5,830 (16.82%) reported deaths (Table). Lenvatinib has most reported serious hemorrhagic events and thyroid impairment in 5.5% and 1.2%, respectively, and least (3.4%) reported dermatologic toxicity (including Hand-foot skin reaction, depigmentation, and rash. Cabozantinib has most (2.8%) reported gastrointestinal (GI) perforation and fistula. Pazopanib has most bone marrow suppression (BMS)—neutropenia, leukopenia, thrombocytopenia, and anemia (43.3%), dermatologic toxicity (25.8%), hepatotoxicity—jaundice, elevated transaminases, hyperbilirubinemia, hepatic encephalopathy, coagulopathy, ascites, and/or hepatorenal syndrome (23.9%), arterial thromboembolic events (ATE)—comprising cerebral infarction, ischemic stroke, transient ischemic attack, myocardial infarction, angina (19.8%), proteinuria and nephrotic syndrome (NS; 10.4%), pulmonary toxicity—interstitial lung disease, and pneumonitis (7.2%), posterior reversible encephalopathy syndrome (PRES; 4.9%), cardiotoxicity—cardiac failure (3.1%), and tumor lysis syndrome (TLS; 0.9%). Sunitinib has most reported osteonecrosis of the jaw AEs (ONJ; 37.3%), QT Prolongation and various arrhythmias (11.9%), severe hypertension (SHTN—including accelerated, urgency, and emergency; 10.0%), and aortic complications—including aortic aneurysm, dissection, and rupture (3.1%). Conclusions: Pazopanib has most while axitinib has least reported BMS, ATE, and pulmonary AEs. Cabozantinib has most reported GI AEs and sunitinib has most reported ONJ, SHTN, QT prolongation, arrhythmias, and aortic complications. With expanding treatment landscape for mRCC, this study helps shed light on the different anti-VEGF toxicity profiles and would therefore support treatment decision making.

Vascular endothelial growth factor-tyrosine kinase inhibitors: Novel mechanisms, predictors of hypertension and management strategies

Vascular endothelial growth factor inhibition has become a cornerstone of cancer therapy. Significant adverse effect is associated with these therapies, with hypertension among the most prevalent. We aim to provide a current review of the mechanisms by which these therapies induce hypertension, the risk factors and predictors of the development of hypertension, and management strategies to minimize the risk of cardiovascular complications in patients receiving vascular endothelial growth factor inhibition as part of cancer treatment.

Phase 1b/2 umbrella study of investigational immune and targeted combination therapies for patients with advanced clear cell renal cell carcinoma (ccRCC).

TPS404 Background: New treatments for first and subsequent lines of therapy for ccRCC are needed. An adaptive, open-label, rolling-arm, multicenter, phase 1b/2 umbrella platform trial in advanced ccRCC is being conducted to evaluate the safety and efficacy of multiple combinations of investigational agents targeting CTLA-4 (quavonlimab [MK-1308]), hypoxia-inducible factor 2α (belzutifan [MK-6482]), lymphocyte-activation gene 3 (favezelimab [MK-4280]), immunoglobulinlike transcript 4 (MK-4830), PD-1 (pembrolizumab), and vascular endothelial growth factor–tyrosine kinase inhibitor (VEGF-TKI; lenvatinib) for advanced ccRCC. Substudy 03A (NCT04626479) will evaluate first-line therapy combinations, and substudy 03B (NCT04626518) will evaluate therapies in patients experiencing progression on PD-1/PD-L1 inhibitors and VEGF-TKIs in combination or in sequence. Methods: Adults with histologically confirmed ccRCC and KPS score ≥70% are eligible. Patients in substudy 03A cannot have previously received systemic therapy for advanced ccRCC. Patients in substudy 03B must have progression (per RECIST v1.1) on or after treatment with a PD-1/PD-L1 inhibitor and a VEGF-TKI for advanced ccRCC. Both substudies will have a safety lead-in phase for experimental combinations with investigational agents to establish a recommended phase 2 dose, followed by an efficacy phase. Experimental arms will enroll approximately 80 (03A) and 50 (03B) patients. Patients will be randomly assigned 2:1 (03A) or 1:1 (03B) to an experimental arm or a reference arm (pembrolizumab 400 mg IV every 6 weeks [Q6W] + lenvatinib 20 mg orally once daily [QD]). Experimental arms in 03A are MK-1308A (coformulation of quavonlimab 25 mg and pembrolizumab 400 mg IV Q6W) + lenvatinib (20 mg orally QD), MK-4280A (coformulation of favezelimab 800 mg and pembrolizumab 200 mg IV every 3 weeks [Q3W]) + lenvatinib (20 mg orally QD), and belzutifan (120 mg orally QD) + lenvatinib (20 mg orally QD) + pembrolizumab (400 mg Q6W IV). Experimental arms in 03B are MK-1308A, MK-4280A, pembrolizumab (400 mg Q6W IV) + belzutifan (120 mg orally QD), lenvatinib (20 mg orally QD) + belzutifan (120 mg orally QD), and pembrolizumab (200 mg IV Q3W) + MK-4830 (800 mg IV Q3W). Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Primary end points for the safety lead-in phase are safety and tolerability; coprimary end points for the efficacy phase are safety and objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points during the efficacy phase are duration of response, progression-free survival (RECIST v1.1 by BICR), clinical benefit rate, and overall survival. Both substudies are recruiting patients in Australia, Canada, France, Israel, South Korea, Spain, New Zealand, the United Kingdom, and the United States. Clinical trial information: NCT04626479; NCT04626518.

A Novel Eye Drop Formulation for Potential Treatment of Neovascular Age-Related Macular Degeneration.

PurposeDrug delivery to posterior ocular tissues via topical eye drop administration is arduous due to the unique anatomy and physiology of the eye. Therefore, treatments for posterior eye disease have to be administered via intravitreal injection or systemic route, both of which have their drawbacks. Herein, the objective of this work was to demonstrate that a specially designed eye drop formulation could effectively deliver small-molecule vascular endothelial growth factor (VEGF) inhibitor to posterior ocular tissues for antiangiogenic therapy.MethodsThe unique eye drop formulation, termed ITRI AXN eye drops, was obtained from self-assembly of (2-hydroxypropyl)-β-cyclodextrin with a VEGF tyrosine kinase inhibitor, a hydrophilic polymer, hypromellose, and a complex stabilizer, caffeine. In vivo ocular pharmacokinetics studies were performed with New Zealand White (NZW) rabbits and Non Human Primates (NHP). The antiangiogenesis effect was evaluated on the Long-Evans rat with laser-induced choroidal neovascularization and pigmented Dutch-Belted rabbits with VEGF-induced retinal neovascularization.ResultsThe successful drug transport from ocular surface to posterior ocular cavity was indicated by a drug biodistribution pattern in pharmacokinetic studies. Excellent drug exposure in the choroid and retina with the concentrations of 900- and 750-fold greater than drug IC50 0.5 hours post the eye drop administration (drug level: 0.8%) was observed on the NHP study. The obtained formulation also demonstrated a comparable antiangiogenic outcome with the intravitreal injection of anti-VEGF antibody on rat and rabbit disease models.ConclusionsOur eye drop formulation has demonstrated great promise in antiangiogenic therapy against retinal and choroidal neovascularization in animal models. The results suggest that the aim of this work can be successfully achieved by the novel eye drop formulation.Translational RelevanceThe preclinical results provide evidence that ITRI AXN eye drops could effectively deliver therapeutics to the choroid and retina for antiangiogenic therapy.

Balancing efficacy and quality of life measurements among metastatic renal cell carcinoma (RCC) studies.

Metastatic renal cell carcinoma (mRCC) treatments have rapidly evolved in the last few years. While vascular endothelial growth factor (VEGF) inhibition had previously been the mainstay of treatment for first-line advanced RCC therapy in the past decade, it has now rapidly changed into combination checkpoint inhibitors with or without VEGF TKIs, although there remains a role for VEGF tyrosine kinase inhibitor monotherapy for patients with favorable-risk disease and for those with intermediate and poor-risk disease with the use of cabozantinib. Perspectives on the Quality-adjusted survival Time without Symptoms of disease or Toxicity (Q-TWiST) analysis for the CABOSUN trial, as well as different aspects of efficacy regarding different first-line therapy for advanced or metastatic RCC are discussed herein.

Circulating cytokines associated with clinical response to systemic therapy in metastatic renal cell carcinoma

BackgroundCirculating cytokines and angiogenic factors have been associated with clinical outcomes in patients with metastatic renal cell carcinoma (RCC) receiving systemic therapy. However, none have yet examined cytokine concentrations in...

Associations between plasma cytokine levels and gut microbiota composition in metastatic renal cell carcinoma (mRCC).

351 Background: Plasma cytokines and the gut microbiome have been shown separately to influence the response to systemic therapy in mRCC. We sought associations between serum cytokines and gut microbial composition in patients (pts) with mRCC. Methods: Eligibility requirements included histologically proven mRCC and an intent to receive either vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or immune checkpoint inhibitor (ICI). Blood samples were collected prior to treatment initiation and immunologic profiles were evaluated using a Human Cytokine 30-plex protein assay (Invitrogen). Stool was collected at baseline and shotgun metagenomic sequencing was performed to quantify gut microbial populations using previously published methods (Salgia et al Eur Urol 2020). Results: A total of 50 pts were studied (36:14 M:F) with a median age of 67 (range, 32-85). Twenty pts and 30 pts had subsequent initiation of VEGF-TKI and ICI therapy, respectively. Levels of Akkermansia spp were significantly higher in pts who were IL-6 low (P = 0.023). In contrast, pts who were IL-6 high had higher levels of enteric pathogens, including Salmonella spp and Enterococcus spp. Both Akkermansia spp and Bacteroides spp levels were higher in pts who were IL-8 low. Associations between cytokine levels, microbiome composition, and treatment response will be presented. Conclusions: Given studies suggesting the role of Akkermansia spp in enhancing ICI response (Routy et al Science 2018), our data provide a critical link between the gut microbiome and systemic immunomodulation.

Osteonecrosis of the jaw in metastatic renal cell carcinoma (mRCC) patients treated with zolendronic acid and denosumab: An observational retrospective multicenter trial.

299 Background: Bone is one of the most common site of metastasis occurring in 30% of metastatic renal cell carcinoma (mRCC) patients (pts)3,4. Skeletal metastases from mRCC are usually osteolytic and associated to high rate of morbidity and complication through skeletal related events (SRE). Bone-targeted therapies (BTT) such as zolendronic acid (ZOL AC) and denosumab (Dmab), shown to decrease the time-to-first and subsequent SREs12. Osteonecrosis of the jaw (ONJ) is a rare but potentially serious adverse event associated with BTT. It occurs in 1-2% of pts treated with BTT and in 10-17% of mRCC pts treated with ZOL AC or Dmab. Vascular endothelial growth factor-Tyrosine kinase inhibitors (VEGF-TKI) represent the backbone treatment for mRCC. Nevertheless, it is unclear whether the association of DMAB and ZOL AC to VEGF-TKITTagents could be associated to higher incidence of ONJ. Methods: We retrospectively collected data, from 2 Italian referring centers for mRCC, about 74 pts with bone metastases from mRCC who received, concurrently or sequentially to VEGF-TKI or immune-oncology (IO), AC ZOL and DMAB from January 2013 to January 2020. All pts provided informed consent for inclusion in the study. Results: All pts received VEGF-TKI as first line treatment. 17 pts received AC ZOL whereas 57 received DMAB. All pts received odontological consultation and orthopantomography before start BTT. The median time of Dmab and AC ZOL exposure was 11.6 months. ONJ occurred in 10/74 pts (7.4%): 6/10 pts were on first line treatment and 4/10 on second line. Treatments administered at the time of ONJ diagnosis were nivolumab (1/10), cabozantinib (2/10), sorafenib (1/10), sorafenib (1/10), sunitinib (4/10) and one pts was off therapy. Conclusions: In this real-life Italian population, treatment with BTT in mRCC pts treated with VEGF-TKI inhibitors and IO is associated to higher incidence of ONJ compared to previous report of pts treated with BTT for bone metastasis and lower compared to previous reports in mRCC. Despite the retrospective collection, we provided one of the largest sample of pts treated concurrently with VEGF-TKI or IO and BTT. Physicians should be careful in the use of BTT combined with other treatments in mRCC pts.

Distinct cytokines predict response to immunotherapy and targeted therapy in metastatic renal cell carcinoma (mRCC).

352 Background: Previous studies have suggested a link between plasma cytokines and mRCC outcomes with systemic therapy. In a prospective study, we assessed whether plasma cytokines could separately predict outcome with immunotherapy or targeted therapy. Methods: Eligible patients (pts) had histologically proven mRCC with intent to receive a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) or an immune checkpoint inhibitor (ICI). Immunologic profiles were evaluated at several time points using a Human Cytokine 30-plex protein assay (Invitrogen). Clinical benefit (CB) was defined as complete response, partial response, or stable disease ≥ 6 months. Results: A total of 56 pts (40:16 M:F) were enrolled; 23 pts and 33 pts received VEGF-TKI and ICI, respectively. The most common VEGF-TKI was cabozantinib; the most common ICI was nivolumab. CB was similar between VEGF-TKI and ICI arms (65% vs 54%). Pts with CB from VEGF-TKIs had lower pretreatment levels of IL-6 (p = 0.02), IL-1RA (p = 0.03), and G-CSF (p = 0.02). Major shifts in plasma cytokines were seen as early as one month; these data will be presented. Conclusions: Distinct plasma cytokines predict benefit with VEGF-TKIs and ICIs. Ongoing work will incorporate analysis of pts receiving VEGF-TKI and ICI combination therapy.

Randomized trial assessing impact of probiotic supplementation on gut microbiome and clinical outcome from targeted therapy in metastatic renal cell carcinoma.

Studies suggest a link between the gut microbiome and metastatic renal cell carcinoma (mRCC) outcomes, including evidence that mRCC patients possess a lower abundance of Bifidobacterium spp. compared to healthy adults. We sought to assess if a Bifidobacterium‐containing yogurt product could modulate the gut microbiome and clinical outcome from vascular endothelial growth factor‐tyrosine kinase inhibitors (VEGF‐TKIs). mRCC patients initiating VEGF‐TKIs, regardless of the line of therapy, were randomized to probiotic‐supplemented (two 4 oz. servings of the probiotic yogurt product daily) or probiotic‐restricted arms. Stool samples were collected prior to therapy and at weeks 2, 3, 4, and 12. Microbiome composition was assessed using whole‐metagenome sequencing. A total of 20 patients were randomized. Bifidobacterium animalis, the active ingredient of the probiotic supplement, reached detectable levels in all patients in the probiotic‐supplemented arm versus two patients in the probiotic‐restricted arm. Clinical benefit rate was similar in probiotic‐supplemented versus probiotic‐restricted arms (70% vs. 80%, p = 0.606). Linear discriminant analysis (LDA) effect size analysis of MetaPhIAn2 abundance data predicted 25 enriched species demonstrating an LDA score >3 in either clinical benefit or no clinical benefit. In patients with clinical benefit (vs. no clinical benefit), Barnesiella intestinihominis and Akkermansia muciniphila were significantly more abundant (p = 7.4 × 10−6 and p = 5.6 × 10−3, respectively). This is the first prospective randomized study demonstrating modulation of the gut microbiome with a probiotic in mRCC. Probiotic supplementation successfully increased the Bifidobacterium spp. levels. Analysis of longitudinal stool specimens identified an association between B. intestinihominis, A. muciniphila, and clinical benefit with therapy. Trial Registration: NCT02944617

1358P Efficacy and toxicity of combined inhibition of EGFR and VEGFR in advanced non-small cell lung cancer patients harboring activating EGFR mutations: A systematic review and meta-analysis

Dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways have demonstrated promising results for treatment of advanced non-small cell lung cancer (NSCLC). We conducted a systematic review and meta-analysis to assess the efficacy and toxicity of combined treatment with EGFR tyrosine kinase inhibitors (TKIs) and VEGF monoclonal antibodies for patients harboring activating EGFR mutations.

Abstract 1312: Identifying the genomic correlates of clinical benefit (CB) from immunotherapies (IO) and vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKI) in metastatic renal cell carcinoma (mRCC)

Abstract Background: Along with the expanding treatment landscape of mRCC, a substantial need for ways to predict individual patients' (pts) benefit from different therapies has emerged. Recent studies highlight the clinical significance of tumor-specific genomic alterations, revealing a prognostic and/or predictive role of PBRM1 mutations with IO in mRCC (Miao et al Nature 2018). Employing a large institutional database, we aimed to identify genomic correlates of CB from IO and VEGF-TKIs in mRCC. Methods: Consecutive pts who underwent genomic profiling (GP) as part of routine clinical care at the City of Hope Comprehensive Cancer Center were retrospectively identified. GP included the GEM ExTra assay, a clinical tumor-normal whole exome sequencing and tumor whole transcriptome sequencing test performed at Ashion Analytics (Phoenix, AZ), a CAP-accredited, CLIA-certified laboratory. The clinical database included detailed information regarding demographics, treatment, response and survival outcomes. Pts who had complete response (CR), partial response (PR) or stable disease (SD) for &amp;gt;6 months were considered as having CB. Progressive disease (PD) as best response was considered no clinical benefit (NCB). Genomic findings were compared between pts with CB and NCB in the IO and VEGF-TKI cohorts. Results: Among the 58 (45:13 M:F) pts, 17 received sequencing treatment involving both a VEGF-TKI and IO, resulting in 32 pts in the IO cohort and 43 pts in the VEGF-TKI cohort. The most commonly used IO and VEGF-TKIs were nivolumab (59%) and sunitinib (40%). CB rate and median progression free survival were 59.4% (CR: 3.1%, PR: 18.8%, SD: 37.5%) and 15.6 months (95%CI NR-NR) in the IO cohort, and 86% and 14.2 months (95%CI 9.0 - 18.5) in the VEGF-TKI cohort. The most frequently detected alterations in the overall cohort were in VHL (64%), PBRM1 (38%), SETD2 (24%), KDM5C (17%) and TERT (12%). Interestingly, TERT promoter mutations and PBRM1 mutations were found to be mutually exclusive. In both IO and VEGF-TKI cohorts, tumor mutational burden did not differ between CB and NCB pts. No single genes were significantly associated with CB from VEGF-TKIs. While PBRM1 loss of function (LOF) was more common in IO pts with CB, and SETD2, KDM5C, TP53 alteration were more common in IO pts with NCB, there was no statistical significance observed (p values &amp;gt; 0.05). TERT promoter mutations were associated with NCB in the IO cohort (p=0.038). TERT promoter mutant tumors did not have CB with IO. Conclusion: Our analysis found that TERT promoter mutations are enriched in pts with NCB from IO and were mutually exclusive with PBRM1 LOF which had previously been shown to be an indicator of IO sensitivity. These results suggest that TERT promoter mutations may be a negative predictor of IO outcomes, which warrants future investigations with a larger sample size. Citation Format: Nazli Dizman, Sara Byron, Yung Lyou, Paulo Gustavo Bergerot, JoAnn Hsu, Andre-Philippe Sam, Denise Phan Trieu, Jeffrey Trent, Sumanta Kumar Pal. Identifying the genomic correlates of clinical benefit (CB) from immunotherapies (IO) and vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKI) in metastatic renal cell carcinoma (mRCC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1312.

Significance of tumor microenvironment in acquiring resistance to vascular endothelial growth factor-tyrosine kinase inhibitor and recent advance of systemic treatment of clear cell renal cell carcinoma.

The development of systemic therapies, including vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKI) and mammalian target of rapamycin (mTOR) inhibitors, represents a major breakthrough in the treatment of patients with renal cell carcinoma (RCC). However, inherent resistance is observed in some patients and acquired resistance commonly develops in many patients within several months of the initiation of systemic therapies. Since these treatments rarely cure patients, their aim is to suppress tumor progression and prolong survival. Therefore, the establishment of dependable criteria that predict responses and resistance to systemic therapies is clinically important, and the underlying molecular mechanisms also need to be elucidated for the future development of more effective therapies. We herein review recent advances in research on the molecular mechanisms underlying resistance, with a focus on morphological characteristics, tumor angiogenesis, and the tumor immune microenvironment in RCC and their relationships with VEGF-TKI treatments. Recent therapies using immune checkpoint inhibitors (ICI) and newly developed VEGF-TKI also appear to be effective for advanced RCC, with stable and durable responses to ICI being observed in some RCC patients. These new drugs and their outcomes have been briefly described.

Correlates of clinical benefit from immunotherapy and targeted therapy in metastatic renal cell carcinoma: comprehensive genomic and transcriptomic analysis

BackgroundThe clinical significance of tumor-specific genomic alterations in metastatic renal cell carcinoma (mRCC) is emerging, with several studies suggesting an association between PBRM1 mutations and response with immunotherapy (IO). We...