Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor Research Articles

FDA Approval Summary: Belzutifan for Patients with Advanced Renal Cell Carcinoma.

On December 14, 2023, the United States Food and Drug Administration (FDA) approved belzutifan (Welireg, Merck & Co., Inc.) for patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 or programmed death-ligand 1 (PD-1/PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). FDA granted traditional approval based on LITESPARK-005 (NCT04195750), an open-label, randomized, head-to-head trial of 746 patients with advanced RCC that progressed following both a PD-1/PD-L1 inhibitor and a VEGF-TKI. Patients were randomized (1:1) to receive belzutifan or everolimus. The primary endpoints were progression-free survival (PFS) assessed by blinded independent central review (BICR) and overall survival (OS). A statistically significant improvement in PFS was demonstrated for belzutifan compared with everolimus [hazard ratio (HR)=0.75 (95% CI: 0.63, 0.90); 1-sided p-value=0.0008]. Kaplan-Meier curves reflected non-proportional hazards with similar median PFS estimates of 5.6 months (95% CI: 3.9, 7.0) in the belzutifan arm and 5.6 months (95% CI: 4.8, 5.8) in the everolimus arm. While not reaching full maturity, OS results appeared to show a favorable trend in the belzutifan arm compared to everolimus [HR=0.88 (95% CI: 0.73, 1.07)]. The confirmed objective response rate by BICR was 22% and 3.6% in belzutifan and everolimus arms, respectively. Observed toxicities differed between treatment arms, but drug discontinuations and interruptions due to treatment-emergent adverse events were lower on the belzutifan arm compared to the everolimus arm, and a descriptive analysis of patient-reported symptom and functional outcomes was suggestive of favorable tolerability for belzutifan compared to everolimus.

42 Belzutifan versus everolimus for previously treated advanced clear cell renal cell carcinoma: Subgroup analysis of the phase 3 LITESPARK-005 study

Abstract Background Belzutifan monotherapy is approved for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a PD-(L)1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) based on the results of the phase 3 LITESPARK-005 study (NCT04195750). In LITESPARK-005, belzutifan improved progression-free survival (PFS; HR 0.75; 95% CI, 0.63-0.90; P < 0.001) and objective response rate (ORR; 21.9% vs 3.5%; P < 0.00001) versus everolimus at first interim analysis (IA1); overall survival (OS) did not reach statistical significance at IA2 (HR 0.88; 95% CI, 0.73-1.07; P = 0.1). We present efficacy outcomes by prespecified subgroups from IA2. Methods Patients with clear cell RCC whose disease progressed after anti–PD-(L)1 and VEGF-targeted therapies and who had 1-3 prior systemic regimens were randomly assigned 1:1 to belzutifan 120 mg by mouth once daily or everolimus 10 mg by mouth once daily until progression or intolerable toxicity. The dual primary end points of PFS by central review per RECIST v1.1 and OS and the key secondary end point of ORR were evaluated by prespecified baseline characteristic subgroups: IMDC risk (favorable vs intermediate/poor), prior VEGF-TKIs (1 vs 2-3), and number of prior lines of therapy (1 vs 2 vs 3). These analyses were not controlled for multiplicity and no formal statistical testing occurred. The database cutoff date was June 13, 2023. Results Overall, 746 patients were assigned to belzutifan (n = 374) or everolimus (n = 372). Baseline characteristics were balanced between groups. Median follow-up was 25.7 months (range, 16.8-39.1). Across analyzed subgroups, PFS and OS results were consistent with the primary analysis (Table). ORR favored belzutifan over everolimus for all subgroups: IMDC favorable risk (22.8% vs 6.0%), IMDC intermediate/poor risk (22.7% vs 2.8%), 1 prior VEGF-TKI (19.7% vs 3.7%), 2 prior VEGF-TKIs (25.7% vs 3.3%), 1 prior line of therapy (28.3% vs 5.8%), 2 prior lines (19.1% vs 2.4%), and 3 prior lines (24.6% vs 3.9%). Conclusions Consistent with the intention-to-treat population of LITESPARK-005, PFS and ORR favored belzutifan over everolimus across prespecified subgroups. These results support belzutifan as a new treatment option for patients with advanced clear cell RCC after prior anti–PD-(L)1 and VEGF-targeted therapies.

Belzutifan (Welireg) for advanced renal cell carcinoma.

Belzutifan (Welireg – Merck), a first-in-class hypoxia-inducible factor inhibitor, has been approved by the FDA for treatment of advanced renal cell carcinoma (RCC) in adults who received prior treatment with a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). Belzutifan was previously approved for use in patients with von Hippel-Lindau disease.

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.

Nephrotoxicity Associated with Contemporary Renal Cell Carcinoma Regimens: A Systematic Review and Meta-Analysis

Background: The nephrotoxicity profile of contemporary first-line regimens for treatment of metastatic renal cell carcinoma (mRCC) has not been systematically studied in published clinical trials. Objective: To assess the rates of nephrotoxic events of contemporary first-line regimens for treatment of mRCC in comparison to vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) mono-therapy. Methods: We performed a systematic search of the literature looking for randomized clinical trials that contemplated National Comprehensive Cancer Network (NCCN) recommended first-line regimens for treating mRCC in which the control arm was a VEGF-TKI. Selected trials could either include an experimental arm of immune checkpoint inhibitor (ICI) plus VEGF-TKI combination or ICI-ICI combination. Nephrotoxic events were defined as proteinuria, hypertension, blood creatinine increase, acute kidney failure or nephritis, which were all described separately. Results: Five studies satisfied our inclusion criteria. Combination of ICI with VEGF-TKI showed a statistically significant higher degree of proteinuria compared to VEGF-TKI alone. There was no statistically significant difference in rates of hypertension between ICI-TKI and VEGF-TKI alone, but VEGF-TKI alone was statistically significantly more associated with hypertension than immunotherapy alone. Other renal toxicities, such as an increase in creatinine, acute kidney injury (AKI) and nephritis, were uncommon and not consistently reported in each trial. Conclusions: Contemporary regimens for first-line treatment of mRCC are associated with a higher grade of proteinuria than VEGF-TKI alone, while VEGF-TKI is more associated with hypertension than an ICI-ICI combination. Description of many renal toxicities across the studies reported have been diverse and a standardized definition across clinical trials would be helpful to reliably interpret the data regarding nephrotoxicity in the setting of treatment of renal cell carcinoma.

Immunoglobulin as a predictive biomarker for the efficacy of immune checkpoint inhibitor combined with VEGF-TKI in metastatic renal cell carcinoma.

4543 Background: The combination of immune checkpoint inhibitor (ICI) and vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) is recommended as the first-line treatment in patients with metastatic clear cell renal cell carcinoma (ccRCC). However, no effective serum biomarker has been used to predict the therapy response and potential benefits. Abnormal content and changes of immunoglobulin (IG) in serum or cancer tissue may indicate cancer progression and impact the prognosis. We examined the content of serum IG and analyzed the alteration after treatment to assess the efficacy of ICI and VEGF-TKI. Methods: Eighty-four patients with metastatic ccRCC were enrolled in this study. The total serum IG level was determined as the sum of IgA, IgG, and IgM. The data of baseline level and alteration of IG after 3-mo treatment was complete in 72 ccRCC patients. These patients were then divided into two groups based on alteration in their IG levels: the IG-increased group and the IG-decreased group. This study aimed to investigate the correlation between the baseline level of immunoglobulin (IG), changes in its content after 3-mo of treatment, and clinical outcomes. Results: Eighty-four patients were retrospectively enrolled with a median follow-up of 17.3 months (2.5-45.1). The objective response rate (ORR) was 41.67%, and the median overall survival (OS) was 31 months in our cohort. The baseline level of IG was not associated with ORR or OS. However, dynamic alteration in IG level after 3-mo treatment had a significant impact on ORR and OS in ccRCC patients. The ORR was 2.7% in the IG-increased group and 80.0% in the IG-decreased group. The OS was 21.0 months (95% CI 14.0–NA) in the IG-increased group and 48.0 months (28·0–NA) in the IG decreased-group (Hazard ratio [HR] 4.59, p=0·003). Conclusions: The change of serum IG level after 3-mo treatment served as an effective predictor of drug response and the prognosis for metastatic ccRCC patients. Value of serum IG needs to be validated in multi-centers and the mechanism of it should be further investigated.

Evolving Treatment Options for Metastatic Renal Cell Carcinoma (mRCC)

Approximately a third of patients diagnosed with kidney cancer in the United States present with advanced disease and those who present with distant metastases historically had dismal 5-year relative survival. However, over the last several years, advancements have led to improved life expectancy and patient outcomes in those who develop advanced renal cell carcinoma. Metastatic clear cell renal cell carcinoma (mccRCC) treatment has rapidly evolved with multiple drug approvals since 2006. Moreover, multiple combination regimens including a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) plus immune checkpoint inhibitor (ICI) and the combination of ipilimumab plus nivolumab have supplanted first-line VEGF-TKI monotherapy. Thus, the insights we gained from prospective randomized controlled trials focusing on systemic therapy beyond first-line therapy in mRCC patients treated in the TKI monotherapy era quickly became less relevant with the adoption of contemporary first-line combination regimens. Herein, we will review contemporary first- and second-line therapies for mccRCC, as well as highly anticipated clinical trials looking into novel regimens beyond first-line therapy in patients who have received combination therapy.

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.

MP14-05 ADJUVANT VEGF-TKI INHIBITORS AFTER SURGERY IMPROVES PROGRESSION FREE SURVIVAL (BUT NOT SURVIVAL) IN HIGH-RISK RCC PATIENTS

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) I (MP14)1 Sep 2021MP14-05 ADJUVANT VEGF-TKI INHIBITORS AFTER SURGERY IMPROVES PROGRESSION FREE SURVIVAL (BUT NOT SURVIVAL) IN HIGH-RISK RCC PATIENTS Giuseppe Fallara, Marco Bandini, Alessandro Larcher, Giuseppe Rosiello, Alberto Martini, Giuseppe Basile, Gianmarco Colandrea, Daniele Cignoli, Pierre Karakiewicz, Zhe Tian, Federico Pederzoli, Andrea Necchi, Andrea Salonia, Alberto Briganti, Roberto Bertini, Francesco Montorsi, Axel Bex, and Umberto Capitanio Giuseppe FallaraGiuseppe Fallara More articles by this author , Marco BandiniMarco Bandini More articles by this author , Alessandro LarcherAlessandro Larcher More articles by this author , Giuseppe RosielloGiuseppe Rosiello More articles by this author , Alberto MartiniAlberto Martini More articles by this author , Giuseppe BasileGiuseppe Basile More articles by this author , Gianmarco ColandreaGianmarco Colandrea More articles by this author , Daniele CignoliDaniele Cignoli More articles by this author , Pierre KarakiewiczPierre Karakiewicz More articles by this author , Zhe TianZhe Tian More articles by this author , Federico PederzoliFederico Pederzoli More articles by this author , Andrea NecchiAndrea Necchi More articles by this author , Andrea SaloniaAndrea Salonia More articles by this author , Alberto BrigantiAlberto Briganti More articles by this author , Roberto BertiniRoberto Bertini More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Axel BexAxel Bex More articles by this author , and Umberto CapitanioUmberto Capitanio More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001995.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The use of adjuvant vascular endothelial growth factor–tyrosine kinase inhibitor (VEGF-TKI) agents after curative intent nephrectomy for renal cell carcinoma (RCC) are still matter of debate. The ASSURE, PROTECT and ATLAS trial failed to meet their primary end-points. Conversely, S-TRAC showed a disease-free survival (DFS) benefit. Recently, the SORCE trial was published. We aimed to re-assess the role of VEGF-TKIs after the publication of this last trial. METHODS: A systematic meta-analysis including 5 published RCTs was performed based on the PRISMA guidelines. DFS, overall survival (OS) and risk of adverse events of grade >3 as for Common Terminology Criteria for Adverse Events (CTCAE) classification were assessed in both arms. Sub analysis were conducted for high-risk patients and for clear cell RCC. Different definitions of high-risk subgroups were used: for the ATLAS, ASSURE and S-TRAC trials high- risk patients were defined as those with at least pT3 and/or pN1 diseases, for the SORCE trial high-risk patients were defined as those with Leibovich score 6-11, whereas for the PROTECT trial no sub analysis for high-risk patients was available. Hazard ratios (HR) and relative risk (RR) were pooled and tested using Z scores, with the significance level set at p<0.05. I2 statistic and Tau2 were used to assess heterogeneity across the studies. RESULTS: We found a marginal positive HR of 0.92 (95% confidence interval [CI] 0.85-1.00; p-value=0.049) for DFS in favor of adjuvant VEGF-TKI agents. This benefit was more pronounced for DFS in the sub-groups of only high-risk patients (HR: 0.89, 95% CI 0.80-0.99; p-value=0.026), but less pronounced in ccRCC only subgroup (HR 0.92, 95% CI: 0.85-1.00; p-value=0.044). Overall survival benefit was instead not reached. However, pooled relative risk for high-grade (grade ≥3 according to CTCAE classification) adverse events was irremediably high, 2.56 (95% CI: 2.15-3.04; p- value<0.001). CONCLUSIONS: After SORCE trial, we provided level 1a evidence of beneficial effect of adjuvant therapy on DFS. However, given the marginal benefit in terms of DFS and the drawback of high-grade adverse events, adjuvant VEGF-TKIs therapy should not be recommended in non-metastatic high-risk RCC after surgery, even after the SORCE trial publication. Source of Funding: © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e253-e254 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Giuseppe Fallara More articles by this author Marco Bandini More articles by this author Alessandro Larcher More articles by this author Giuseppe Rosiello More articles by this author Alberto Martini More articles by this author Giuseppe Basile More articles by this author Gianmarco Colandrea More articles by this author Daniele Cignoli More articles by this author Pierre Karakiewicz More articles by this author Zhe Tian More articles by this author Federico Pederzoli More articles by this author Andrea Necchi More articles by this author Andrea Salonia More articles by this author Alberto Briganti More articles by this author Roberto Bertini More articles by this author Francesco Montorsi More articles by this author Axel Bex More articles by this author Umberto Capitanio More articles by this author Expand All Advertisement Loading ...

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...

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.

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.

ASSET: Alternative schedule sunitinib in metastatic renal cell carcinoma (RCC)—Cardiopulmonary exercise testing (CPET).

300 Background: Sunitinib (SUN) is a vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) approved for treatment of advanced RCC and high risk RCC after nephrectomy. Evidence suggests that a 2 week (wk) on, 1 wk off schedule (2/1) of SUN administration may be more tolerable than the standard 4 wk on, 2 wk off schedule (4/2). We investigated changes in cardiopulmonary function and related parameters over time in RCC patients treated with both schedules of SUN. Methods: Patients starting SUN for RCC, with KPS ≥80 and normal organ and marrow function, were enrolled and randomized 1:1 to schedule 4/2 or 2/1. Subjects were required to be able to walk and jog on a treadmill and to complete an acceptable CPET at baseline (BL). Primary endpoint was change in peak oxygen uptake (VO2peak) on both schedules at 12 wk from BL. Key secondary endpoints were change from BL to 12 wk in: left ventricular ejection fraction (LVEF), upper and lower body strength (1-RM), functional measures (chair stand, timed up-and-go [TUG], 6-minute walk test [6MWT], quality of life (QOL; FACT-Fatigue, FKSI-19), anxiety and depression (HADS) and exercise behavior (Godin Leisure Score). ANCOVA models controlling for baseline values were used to analyze the primary and secondary endpoints. Results: Between 11/20/2017 and 6/24/2019, 9 out of a planned 30 patients consented to participate at Duke. Two patients declined to participate and 7 patients were enrolled on study: 4 on Arm A and 3 on Arm B. All 7 patients completed the 12 wk study. Median age, BMI, and VO2peak were 65 yrs, 30.5 kg/m2, and 19.2 ml kg−1 min−1. We observed no difference in the primary endpoint of VO2peak between arms (p=0.84). We report BL to 12 wk change scores for all patients starting SUN (Table). In addition, mean change scores (SE) for QOL by FACIT-Fatigue and FKSI-19 were -2.88 (1.5) and 1.2 [9.8]; anxiety and depression by HADS 1.14 (1.3); and physical activity 1.14 (1.7). Conclusions: We observed non-significant declines in most measures of physical fitness and function during the first 12 wk of treatment with SUN. To our knowledge, this is the first reported study of these parameters in patients with RCC. Given that a VEGF TKI, alone and with an immune checkpoint inhibitor, remains a standard of care for metastatic ccRCC, studies should be undertaken to examine whether exercise training can prevent declines in physical fitness and function. Clinical trial information: NCT03109015 . [Table: see text]

FRESCO-2: A global phase III study of the efficacy and safety of fruquintinib in patients (pts) with metastatic colorectal cancer (mCRC).

TPS154 Background: Pts with mCRC have limited treatment options following progression on standard therapies. Current standard of care (SOC) after pts progress on trifluridine/tipiracil (TAS-102) or regorafenib is re-challenge with previous systemic treatments, enrollment in a clinical trial, or best supportive care (BSC). Fruquintinib (Elunate) is a novel, highly selective, vascular endothelial growth factor (VEGF) receptor (VEGFR)-1, -2, and -3 tyrosine kinase inhibitor (TKI) ( Cancer Biol Ther 2014;15:1635-1645). Fruquintinib is approved in China to treat pts with mCRC who received or are intolerant to fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, and, if RAS wild type, anti-epidermal growth factor receptor (EGFR) therapy. Approval was based on results of the phase 3 FRESCO study (2013-013-00CH1; NCT02314819; JAMA 2018;319:2486-2496), in which fruquintinib 5 mg daily (QD), 3 weeks on, 1 week off (3 on/1 off), significantly improved overall survival (OS) in pts with mCRC in the 3rd-line+ setting when compared to placebo (median OS 9.3 months [mo] versus 6.6 mo; hazard ratio [HR] 0.65; p &lt; .001). Progression-free survival (PFS) was also superior (median PFS 3.7 mo versus 1.8 mo; HR 0.26; p &lt; .001). The toxicities of fruquintinib were consistent with those of other VEGF TKIs and were manageable. At the time FRESCO was conducted in China, SOC for pts with mCRC differed from that in the US, EU, and Japan. We describe here a global phase 3 study (FRESCO-2; 2019-013-GLOB1; NCT04322539) being conducted to investigate fruquintinib’s efficacy and safety in pts with refractory mCRC and a treatment profile representative of the global SOC. Methods: FRESCO-2 is a randomized, double-blind, placebo-controlled study to compare fruquintinib + BSC to placebo + BSC. Key inclusion criteria are progression on or intolerance to treatment with TAS-102 and/or regorafenib; previous treatment with standard approved therapies including chemotherapy, anti-VEGF therapy, and, if RAS wild type, anti-EGFR therapy. Prior therapy with immune checkpoint or BRAF inhibitors is required for pts with corresponding tumor alterations. Pts (~522) will be randomized 2:1 to receive either fruquintinib 5 mg orally (PO) QD + BSC or placebo 5 mg PO QD + BSC, with a 3 on/1 off schedule. Randomization will be stratified by prior therapy, RAS status, and duration of metastatic disease. The primary endpoint is OS; secondary endpoints include PFS, disease control rate, objective response rate, duration of response, and safety. Final OS analyses will be performed when 364 OS events are observed; futility analysis will be conducted with 1/3 (121) OS events. If enrichment of post-regorafenib pts occurs, enrollment to that strata will be capped at approximately 262. FRESCO-2 will be activated in the US, EU, and Japan; global enrollment is anticipated over 13 mo. Clinical trial information: NCT04322539.

Abstract 5426: Genomic and immunohistochemical characterization of patients with advanced papillary renal cell carcinoma: Focus on exceptional responders

Abstract Background: Approximately 10-15% of patients with renal cell carcinoma (RCC) demonstrate papillary histology. Unfortunately for patients with advanced disease, there is no standard therapy for papillary RCC (pRCC). Herein, we provide detailed biologic characterization of patients with pRCC who have achieved exceptional responses to either targeted therapy or checkpoint inhibition. Methods: Patients with pRCC were identified from an institutional database. Demographic and treatment-related data were compiled. Genomic characterization using CLIA-certified next-generation sequencing (NGS) platforms (FoundationOne; Foundation Medicine, Cambridge, MA or GEM ExTra: Ashion/TGen, Phoenix, AZ) was performed when deemed clinically relevant; this data was used to characterize the frequency of relevant genomic alterations (GAs) in this subset. Archived tissue was obtained when available and immunohistochemical staining was performed for CD4, CD8, CD11b and other markers to characterize T-cell subtype. Staining for MET, ALK and other protooncogenes was also performed and the spatial relationship between these proteins and immune cells was characterized. Results: 64 pts with pRCC were identified (50:14 M:F). By International Metastatic RCC Database Consortium (IMDC) criteria, 3 were good risk, 42 were intermediate/poor risk, and 19 were considered unevaluable. Patients received a median of two lines of therapy (range, 1-7). The most common genomic alterations encountered among fifteen patients with available NGS profiling were BAP1 (20%) and TERT (20%). Three patients with ALK mutations were identified – each was treated with FDA approved ALK-inhibitors and all had a response to therapy, with a median progression-free survival (PFS) of 9.65 months (range, 1.25–23.47). Two patients with MET mutations were identified. Fifteen patients received an immune-checkpoint inhibitor as part of their care – eight (53%) experienced a PFS of greater than three months (median PFS, 3.1 months; range, 0.25–43.4). 30 patients received a MET-directed therapy (median PFS, 2.8 months; range, 0.4–29.9), including both patients with recorded MET GAs (PFS of 5.3 and 7.87 months, respectively), and 41 patients received a Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitor (VEGF-TKI) (median PFS, 4.2 months; range, 0.33–134.47). In total, fifteen patients achieved an exceptional response (&amp;gt;10 months) to therapy. Six such patients also had NGS data and tissue available for immunohistochemical characterization. Immunohistochemical characterization will be reported at the meeting. Conclusions: Our results indicate that genomic profiling can yield actionable targets in pRCC. Matching these targets to relevant targeted therapies produces clinically meaningful responses. Citation Format: Nicholas J. Salgia, Nazli Dizman, Isa Mambetsariev, Tamara Mirzapoiazova, Dan Zhao, Prakash Kulkarni, Ravi Salgia, Sumanta K. Pal. Genomic and immunohistochemical characterization of patients with advanced papillary renal cell carcinoma: Focus on exceptional responders [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 5426.

Epigallocatechin-3-gallate inhibits tumor angiogenesis: involvement of endoglin/Smad1 signaling in human umbilical vein endothelium cells

Strategies targeting endoglin are currently being investigated in clinical trials as an anti-angiogenic therapy. The redundancy between endoglin and vascular endothelial growth factor (VEGF) signaling in angiogenesis was verified. Increased endoglin signaling after an anti-VEGF treatment was observed in patients. Treatment with an endoglin-neutralizing antibody increased VEGF signaling in endothelial cells. Therefore, strategies targeting both the endoglin and VEGF pathways were applied to determine whether the anti-angiogenic effects were increased in vitro. Five possible hits for endoglin were identified from 2000 compounds in the Traditional Chinese Medicine Database using Discovery Studio 4.5 Epigallocatechin-3-gallate (EGCG) attenuates angiogenesis by downregulating VEGF; however, researchers have not determined whether its anti-angiogenic effects are mediated by endoglin/Smad1 signaling. A major contribution of this study is that EGCG significantly inhibited the upregulation of endoglin in semaxanib-treated human umbilical vein endothelial cell. Thus, a combination treatment with EGCG and a VEGF tyrosine kinase inhibitor would be appropriate to reverse drug resistance. EGCG alone significantly decreased endoglin/pSmad1 levels in HUVECs. In the angiogenesis assay, the migration, invasion, and tube formation of HUVECs were markedly suppressed by higher concentrations of EGCG. A combination treatment with EGCG and semaxanib further produced increased anti-angiogenic effects. The main contribution of the study indicated that EGCG significantly decreased the semaxanib-induced overexpression of endoglin. Therefore, a combination treatment including EGCG will probably solve the drug resistance to anti-VEGF treatments.

Overview of Current and Future First-Line Systemic Therapy for Metastatic Clear Cell Renal Cell Carcinoma

Treatment of metastatic clear cell renal cancer (mccRCC) has seen substantial progress over the last 20years, with many regulatory approvals since 2006 culminating in a substantial increase to overall survival (OS). Six therapies are currently available for first-line use, with additional treatments currently being tested in this setting, some of which are expected to be approved soon based on new data from the CABOSUN and CheckMate-214 trials. Based on the available evidence, we strongly believe that vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) therapy over mechanistic target or rapamycin (mTOR; formerly known as mammalian target of rapamycin) inhibitor therapy is the most effective first-line option regardless of risk category assignment. High-dose interleukin-2 (HDIL-2) therapy remains a reasonable treatment option in patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-1 and have minimal comorbid conditions. In the near future, these agents are likely to be surpassed by cabozantinib and by combination immune checkpoint inhibitor therapy with nivolumab and ipilimumab. Independent review has recently confirmed superiority of first-line cabozantinib over sunitinib in a phase 2 trial of 157 patients with intermediate or poor risk mccRCC (progression-free survival [PFS] 8.6 vs 5.3months, hazard ratio [HR] 0.48, p = 0.0008). In a separate study of 1096 patients treated with either upfront sunitinib or the combination of nivolumab and ipilimumab, those with intermediate and poor risk had significant improvement in both PFS (11.6 vs 8.4months, HR 0.82, p = 0.0331) and OS (not reached vs 26months, p < 0.0001). Responses were greater in patients with positive programmed death receptor ligand-1 (PD-L1) tumor staining, and pending regulatory approval may become standard of care in untreated patients with intermediate to poor risk disease with positive PD-L1 status. This likely represents the beginning of additional novel immunotherapy combinations for the first-line treatment of mccRCC.

Roles of VEGF-Flt-1 signaling in malignant behaviors of oral squamous cell carcinoma.

BackgroundVascular endothelial growth factor (VEGF) is a highly specific signaling protein for vascular endothelial cells that plays a critical role in tumor growth and invasion through angiogenesis, and may contribute to cell migration and activation of pre-osteoclasts, osteoclasts and some tumor cells.ObjectivesWe aimed to clarify the detailed roles of VEGF-Flt-1 signaling in bone invasion of oral squamous cell carcinoma (OSCC) cells.ResultsForty-two (42) of 54 cases with gingival SCC (77.8%) strongly expressed VEGF, and had a significantly increased number of Flt-1+ osteoclasts (p<0.01) and more aggressive bone invasion (p<0.05). PlGF, a ligand of Flt-1, induced osteoclastogenesis in single culture of bone marrow cells (BMCs), and inhibition of Flt-1-signaling by VEGF tyrosine kinase inhibitor and It’s down stream (Akt and ERK1/2) inhibitos reduced osteoclastogenesis in PlGF-stimulated BMCs (p<0.01). In molecular level, PlGF stimulation significantly upregulated RANKL expression in Flt-1-expressing HSC2 cells via phosphorylation of Akt and ERK1/2. In the co-culture of VEGF-producing HSC2 cells and BMCs, number of TRAP-positive osteoclasts markedly increased (p<0.01). The osteoclastogenesis was significantly inhibited by RANKL-neutralizing antibody (p<0.01) as well as by VEGF tyrosine kinase inhibitor (p<0.01) and it’s downstream (Akt and ERK1/2) inhibitors (p<0.01, p<0.05, respectively).ConclusionVEGF-Flt-1 signaling induces osteoclastogenesis in OSCC through two possible ways: 1) VEGF produced from OSCC cells can directly stimulate the Flt-1 pathway in preosteoclasts to induce migration to future bone resorbing area and differentiation into osteoclasts, and 2) VEGF-Flt-1 signaling upregulates RANKL expression in OSCC cells, which indirectly leads to osteoclast differentiation. Therefore, blocking of the VEGF-Flt-1 signaling may help inhibit bone invasion of OSCC.

The role of Cediranib in ovarian cancer

ABSTRACTIntroduction: Treatment options for relapsed ovarian cancer have increased over the decade with the addition of targeted agents, such as PARP inhibitors and antiangiogenic agents. Bevacizumab, a monoclonal antibody binding vascular endothelial growth factor (VEGF), was the first anti-angiogenic agent to be incorporated in the ovarian cancer treatment landscape. Other molecules utilising different mechanisms of action to target angiogenesis have been developed, including cediranib, an oral potent inhibitor of VEGF Tyrosine Kinase Inhibitor that has demonstrated activity in both phase II and phase III studies.Areas covered: Herein we will review cediranib as well as the evidence for its use in ovarian cancer, both as monotherapy and in combination with chemotherapy, PARP inhibitors and immunotherapy. A literature search was made in PubMed and on ClinicalTrials.gov for clinical trials with cediranib.Expert opinion: The addition of cediranib for the treatment of ovarian cancer is promising, and has demonstrated a significant improvement in progression free survival in a phase III trial in combination with chemotherapy and maintenance treatment. Cediranib is currently being explored in ovarian cancer and other gynaecological malignancies aiming to improve patient care; further research will help define its role in standard clinical practice for patients with ovarian cancer.