Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Research Articles

Risk of Dyslipidemia Associated with VEGF/VEGFR Inhibitors: A Meta-Analysis

OBJECTIVE: This meta-analysis was performed to investigate hyperlipidemia in patients with carcinoma treated with vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) inhibitors. METHODS: We searched for eligible phase II and III studies using PubMed and Embase databases. We then summarized reported occurrences of hyperlipidemia in patients with different cancers. Relative risk ratios (RRs) and 95% confidence intervals (CIs) were calculated by Revman 5 software in meta-analysis. RESULTS: Eleven trials (4760 subjects) were included in this meta-analysis. Overall, VEGF/VEGFR inhibitors had similar incidence of hypertriglyceridemia (RR = 0.56, 95% CI = 0.24%-1.32%, P = .19), hypercholesterolemia (RR = 1.15, 95% CI = 0.42%-3.16%, P = .78), and LDL elevation (RR = 4.58, 95% CI = 0.80%-26.25%, P = .09) than control drugs, under high heterogeneity. Moreover, subgroup analyses found VEGF/VEGFR inhibitors had higher incidence of hypertriglyceridemia (RR = 1.86, 95% CI = 1.37%-2.52%, P < .001) and hypercholesterolemia (RR = 2.95, 95% CI = 2.02%-4.30%, P = .006) than blank control or placebo control drugs (placebo-controlled-group), although with lower incidence of hypertriglyceridemia (RR = 0.29, 95% CI = 0.12%-0.69%, P < .001) and hypercholesterolemia (RR = 0.39, 95% CI = 0.28%-0.56%, P < .001) than positive control drugs (positive-controlled-groups). CONCLUSION: The use of VEGF/VEGFR inhibitors, especially the multitargeted VEGFR tyrosine kinase inhibitors (VEGFR-TKIs), was associated with higher risk of hyperlipidemia than the use of placebo, but this risk was less than that associated with mTOR or FGFR inhibitors. It indicated that clinicians need to pay close attention to the occurrence of hyperlipidemia in VEGFR-TKIs therapies.

Apatinib, a novel VEGFR-2 tyrosine kinase inhibitor, for relapsed and refractory nasopharyngeal carcinoma: data from an open-label, single-arm, exploratory study

SummaryPurpose Apatinib, a new tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, has shown promising efficacy against several solid cancers, but evidence of its efficacy against relapsed and refractory nasopharyngeal carcinoma is limited. We investigated the efficacy and safety of apatinib for relapsed and refractory nasopharyngeal carcinoma in an open-label, single-arm, phase II clinical trial. Fifty-one patients with relapsed and refractory nasopharyngeal carcinoma in the First Affiliated Hospital, Zhengzhou University, who met the inclusion criteria were enrolled in the study. All patients received apatinib at an initial dose of 500 mg daily (1 cycle = 28 days). The primary and secondary endpoints were overall response rate, progression-free survival, and overall survival. We evaluated treatment effects and recorded apatinib-related adverse events by performing regular follow-ups and workup. The overall response rate (complete and partial responses) was 31.37% (16/51). The median overall survival and progression-free survival were 16 (95% CI, 9.32–22.68) and 9 months (95% CI, 5.24–12.76), respectively. Most patients tolerated treatment-related adverse events of grades 1 and 2; hypertension (29, 56.86%), proteinuria (25, 49.02%), and hand–foot syndrome (27, 52.94%) were the most common adverse events. There were no treatment-related deaths. Apatinib showed good efficacy and safety in patients with relapsed and refractory NPC.

Abnormal Vascular Phenotypes Associated with the Timing of Interruption of Retinal Vascular Development in Rats.

Pathological angiogenesis is a leading cause of blindness in several retinal diseases. The key driving factor inducing pathological angiogenesis is the pronounced hypoxia leading to a marked, increased production of vascular endothelial growth factor (VEGF). The aim of this study was to determine whether the abnormal vascular growth occurs in a manner dependent on the degree of the vascular defects. Vascular defects of two different degrees were created in the retina by subcutaneously treating neonatal rats with the VEGF receptor (VEGFR) tyrosine kinase inhibitor KRN633 on postnatal day (P) 4 and P5 (P4/5) or P7 and P8 (P7/8). The structure of the retinal vasculature changes was examined immunohistochemically. Prevention of vascular growth and regression of some preformed capillaries were observed on the next day, after completion of each treatment (i.e., P6 and P9). The vascular regrowth occurred as a result of eliminating the inhibitory effect on the VEGFR signaling pathway. KRN633 (P4/5)-treated rats exhibited a retinal vasculature with aggressive intravitreal neovascularization on P21. On the other hand, the appearance of tortuous arteries is a representative vascular pathological feature in retinas of KRN633 (P7/8)-treated groups. These results suggest that an interruption of the retinal vascular development at different time points induces different vascular pathological features in the retina. Pharmacological agents targeting the VEGF signaling pathway are useful for creating an abnormal retinal vasculature with various pathological features in order to evaluate the efficacy of anti-angiogenic compounds.

FGFR1 is associated with c-MYC and proangiogenic molecules in metastatic renal cell carcinoma under anti-angiogenic therapy.

This study aimed to investigate the clinicopathological significance of FGFR1 and c-MYC expression, particularly in relation to angiogenesis in clear cell renal cell carcinoma (CCRCC). Immunohistochemistry and fluorescence in-situ hybridisation were conducted with tissue microarrays from 91 metastatic CCRCC patients who received VEGF receptor tyrosine kinase inhibitors (VEGFR-TKIs). The expression of angiogenic molecules, FGFR1 and c-MYC, and tumoral vascular density (TVD) and mRNA expression and TVD of 533 CCRCCs in The Cancer Genome Atlas (TCGA) were analysed. FGFR1, pFGFR1 and c-MYC expression was observed in 29.1, 74.4 and 30.8% of tumours, respectively. FGFR1high was an independent worse prognostic factor for overall (HR=1.871, P=0.032) and progression-free (HR=1.976, P=0.016) survival. FGFR1high was significantly related to VEGFR-TKI responsiveness (P=0.011). The presence of FGFR1high /c-MYChigh showed a positive correlation with proangiogenic markers, including VEGF (P=0.018) and HIF-1α (P<0.0001). FGFR1high /c-MYChigh tumours showed higher TVDs together with higher VEGFR2 and PDGFR-β expression (both P<0.0001). FGFR1 and c-MYC expression was also positively correlated with the expression of hypoxia-related and proangiogenic-related genes in the TCGA data. FGFR1 and c-MYC may be involved in tumour angiogenesis and FGFR1 may represent a promising therapeutic target in metastatic CCRCC.

Scientific Rationale for Combined Immunotherapy with PD-1/PD-L1 Antibodies and VEGF Inhibitors in Advanced Hepatocellular Carcinoma.

A successful phase III trial for the combination of atezolizumab and bevacizumab (the IMbrave150 trial) in advanced hepatocellular carcinoma has recently been reported. This is groundbreaking because nivolumab and pembrolizumab, both programmed cell death-1 (PD-1) antibodies, have failed to show efficacy as first- and second-line therapeutics, respectively, in phase III clinical trials. Immunotherapy with a combination of atezolizumab and bevacizumab resulted in better survival than treatment with sorafenib for the first time since sorafenib was approved in 2007. The high efficacy of the combination of PD-1/programmed death ligand 1 (PD-L1) and vascular endothelial growth factor (VEGF) antibodies is not only due to their additive effects on tumor growth, but also to their reprogramming of the immunosuppressive microenvironment into an immunostimulatory microenvironment. These results were confirmed in a phase Ib trial that showed significantly longer progression-free survival in the atezolizumab plus bevacizumab group than in patients that received atezolizumab alone. These results demonstrate that immunotherapy with a combination of PD-1/PD-L1 and VEGF inhibitors is effective and may result in a reprogramming of the tumor microenvironment. The results of an ongoing phase III trial of a PD-1 antibody in combination with the VEGF receptor tyrosine kinase inhibitor (TKI) are highly anticipated.

Whole-body diffusion-weighted magnetic resonance imaging for the detection of bone metastases and their prognostic impact in metastatic renal cell carcinoma patients treated with angiogenesis inhibitors

Background: Metastatic renal cell carcinoma (mRCC) patients with bone metastases (BM) are at high risk for skeletal related events and have a poorer outcome when treated with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). Computed tomography (CT) lacks sensitivity to detect BM in mRCC. We aimed to determine the added value of whole body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) to CT for the detection of BM in mRCC and to estimate the prognostic impact of the number of BM in mRCC patients treated with VEGFR-TKIs.Material and methods: We conducted a prospective study including consecutive mRCC patients treated with a first-line VEGFR-TKI in the metastatic setting. All patients underwent a pretreatment thoracic-abdominal-pelvic CT and WB-DWI/MRI. CT and WB-DWI/MRI were compared for the detection of BM. The number of detected BM was correlated with response rate (RR), progression-free survival (PFS) and overall survival (OS) after start of the VEGFR-TKI.Results: Ninety-two patients were included. BM were found in 55% of the patients by WB-DWI/MRI and in 43% of the patients by CT (p = .003). Mean number of BM discovered per patient was 6.8 by WB-DWI/MRI versus 1.9 by CT (p = .006). The cutoff of ≤5 versus >5 BM on WB-DWI/MRI had the highest discriminative power for all outcome measures. Patients with >5 BM had a lower RR (10% versus 42%), more frequently early progressive disease (43% versus 13%, p = .003), shorter PFS (4 versus 10 months, p = .006) and shorter OS (10 versus 35 months, p < .0001) compared to patients with ≤5 BM.Conclusion: WB-DWI/MRI detects significantly more BM in mRCC patients than CT, allowing better estimation of the prognostic impact of BM in mRCC patients treated with VEGFR-TKIs. The prognostic impact should now be validated in patients treated with immune checkpoint inhibitors.

A comparison of transcatheter arterial chemoembolization used with and without apatinib for intermediate- to advanced-stage hepatocellular carcinoma: a systematic review and meta-analysis.

BackgroundHepatocellular carcinoma (HCC) is a common cancer worldwide and prognosis for patients with the disease remains poor. Most patients are diagnosed at an advanced stage and are only eligible for palliative therapy. As a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor (VEGFR2-TKI), apatinib has a certain antitumor effect for a variety of solid tumors. In clinical practice, clinicians have attempted to treat intermediate- to advanced-stage HCC patients with a combination of transcatheter arterial chemoembolization (TACE) and apatinib. However, a consensus on the therapeutic effects of this treatment is yet to be reached. This meta-analysis was conducted to compare the therapeutic efficacy and clinical safety of the combination therapy of TACE plus apatinib with that of TACE alone in patients with intermediate- to advanced-stage HCC.MethodsRelevant studies were identified by searching PubMed, Embase, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Biomedical Literature Database (CBM), Chinese Science and Technology Periodical Database (VIP) and the reference lists of retrieved articles up to July 31, 2019. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to express the therapeutic effects of TACE plus apatinib versus TACE on survival, objective response rate, disease control rate, progressive disease rate and adverse events using a mixed-effect model. Subgroup analyses of study type, dosage of apatinib, TACE regimen, study sample size between treatment groups and control groups were performed. Publication bias was assessed using fail-safe N, Begg-Mazumdar test and Egger’s test.ResultsFrom 23 eligible studies, a total of 1,342 patients were included in this review and meta-analysis. Among these studies, 18 were randomized clinical trials and 5 were case-control studies. Compared with those being treated with TACE alone, patients receiving TACE plus apatinib showed significantly better half-year survival (OR, 2.741, 95% CI, 1.745–4.306) and 1-year survival (OR, 2.284, 95% CI, 1.442–3.620). The superiority of TACE and apatinib over TACE monotherapy was evident in the disease control rate (OR, 2.919, 95% CI, 2.184–3.903), objective response rate (OR, 2.683, 95% CI, 2.099–3.429) and progressive disease rate (OR, 0.341, 95% CI, 0.255–0.456), respectively.ConclusionsThe combination treatment of apatinib and TACE provides better survival benefits for intermediate- to advanced-stage HCC patients when compared to TACE monotherapy and should be recommended for suitable patients with unresectable HCC. However, further investigation into future prospective clinical studies is warranted.

Clinical Outcomes by Nephrectomy Status In METEOR, A Randomized Phase 3 Trial of Cabozantinib Versus Everolimus in Patients with Advanced Renal Cell Carcinoma

Background: We investigated outcomes with cabozantinib versus everolimus in patients with advanced renal cell carcinoma (RCC) with or without prior nephrectomy in the phase 3 METEOR trial (NCT01865747). Methods: Patients (N = 658) with advanced clear cell RCC and prior treatment with≥1 VEGFR tyrosine kinase inhibitor (TKI) were randomized to cabozantinib 60 mg/day or everolimus 10 mg/day. Pre-specified subgroup analyses of progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were conducted by prior nephrectomy status. Response was assessed by independent radiology committee. Results: Most enrolled patients (85%) had prior nephrectomy. Baseline prognostic factors (e.g. MSKCC risk group) were less favorable for patients without prior nephrectomy. Cabozantinib improved outcomes versus everolimus in the subgroups with and without nephrectomy—hazard ratios (95% CIs) of 0.51 (0.41–0.64) and 0.51 (0.30–0.86), respectively, for PFS, and 0.66 (0.52–0.84) and 0.75 (0.44–1.27), respectively, for OS. Median OS was numerically longer in patients with versus those without prior nephrectomy in both treatment arms. ORR for cabozantinib versus everolimus was 17% versus 4% for the prior nephrectomy subgroup and 21% versus 2% for the subgroup without prior nephrectomy. Among evaluable patients without prior nephrectomy, reductions of renal target lesions occurred in 94% (16/17) of patients in the cabozantinib arm versus 44% (8/18) in the everolimus arm. The safety profiles of both subgroups were generally consistent with that of the overall study population. Conclusion: Cabozantinib improved PFS, ORR, and OS compared with everolimus in patients with advanced RCC irrespective of nephrectomy status.

Angiogenesis and Immunity in Renal Carcinoma: Can We Turn an Unhappy Relationship into a Happy Marriage?

The frontline treatment options for patients with metastatic renal cell carcinoma (mRCC) are evolving rapidly since the approval of combination immunotherapies by the U.S. Food and Drug Administration (USFDA) and the European Medicines Agency (EMA). In particular, in combination with vascular endothelial growth factor receptor (VEGFR) tyrosine-kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs) have significantly improved the outcome of patients with mRCC compared to TKI monotherapy. Here, we review the preclinical data supporting the combination of ICIs with VEGFR TKIs. The VEGF-signaling inhibition could ideally sustain immunotherapy through a positive modulation of the tumor microenvironment (TME). Antiangiogenetics, in fact, with their inhibitory activity on myelopoiesis that indirectly reduces myeloid-derived suppressor cells (MDSCs) and regulatory T cells’ (Tregs) frequency and function, could have a role in determining an effective anti-tumor immune response. These findings are relevant for the challenges posed to clinicians concerning the clinical impact on treatment strategies for mRCC.

First-line Treatment of Metastatic Renal Cell Carcinoma in the Immuno-oncology Era: Systematic Review and Network Meta-analysis.

Combination treatments with immuno-oncology (IO) agents and IO agents plus a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) have been approved for first-line treatment of patients with metastatic renal cell carcinoma (mRCC). No direct comparisons have been performed among these treatment options. We performed a systematic review and network meta-analysis to compare and rank the available regimens for first-line treatment in terms of survival benefit and efficacy. In accordance with the Preferred Reporting Items for Systematic Review statement, a systematic search of reported studies was performed in MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE up to May 31, 2019. Network meta-analysis models were adjusted using the Bayesian method. Four randomized clinical trials, with a total of 3758 patients, met the inclusion criteria. Considering systemic therapy, 1880 patients had received sunitinib and 550, 432, 442, and 454 patients had received ipilimumab plus nivolumab (ipi+ nivo), pembrolizumab plus axitinib (pembro+ axi), avelumab plus axitinib (avelu+ axi), and atezolizumab plus bevacizumab (atezo+ bev). No difference was found in overall survival between ipi+ nivo and pembro+ axi for the intention to treat population (hazard ratio [HR], 1.34; 95% credible interval [CrI], 0.92-1.97). No difference was found in progression-free survival among the treatments. The overall response rate (ORR) was superior with pembro+ axi and avelu+ axi compared with the ORR with the other treatments (atezo+ bev vs. pembro+ axi: HR, 0.66; 95% CrI, 0.52-0.84; ipi+ nivo vs. pembro+ axi: HR, 0.73; 95% CrI, 0.59-0.90; atezo+ bev vs. avelu+ axi: HR, 0.55; 95% CrI, 0.43-0.71; avelu+ axi vs. ipi+ nivo: HR, 1.66; 95% CrI, 1.31-2.12), with no differences across them (HR, 1.21; 95% CrI, 0.95-1.53). In the present indirect comparison, for an intention to treat population, we found no survival differences between pembro+ axi and ipi+ nivo. All treatments showed better progression-free survival compared with sunitinib that was similar among them. The combination of an IO agent (pembrolizumab or avelumab) and axitinib seemed to be the most effective therapy for the ORR.

Efficacy of adjuvant vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (VEGFRi) in renal cell carcinoma (RCC): A systematic review and meta-analysis.

680 Background: To perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) comparing the efficacy of adjuvant VEGFRi in locally advanced, non-metastatic clear renal-cell carcinoma (RCC). Methods:Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. We included studies that compared the addition of VEGFRi versus placebo, after nephrectomy. Analyzed endpoints were overall survival (OS) and disease-free survival (DFS). The data extracted from the studies were combined by using Hazard Ratio (HR) or Risk Ratio (RR) with their corresponding Confidence Intervals of 95% (CI95%). Results: Overall, 121 references were identified and screened. The final analysis included 5 trials (S-TRAC, ATLAS, ASSURE, PROTECT and SORCE) comprising 6,128 patients that underwent previous nephrectomy for RCC. The DFS was similar in patients who received VEGFRi (fixed effect: HR=0.94, CI95%=0.87 to 1.03; p=0.19), with no heterogeneity (Chi2 = 4.33, df = 5 (P=0.50); I2 = 0%). Overall survival also was not statistically better in patients who received VEGFR inhibitors (HR=1.01, CI95%=0.90 to 1.15; p=0.84), with no heterogeneity (Chi2= 3.57, df = 5 (P=0.61); I2 = 0%). In the final combined analysis of the higher-risk disease group (pT3, pT4, or N+ disease), patients who received VEGFRi had a longer DFS (fixed effect: HR=0.85, CI95%=0.74 to 0.97; p=0.02), with no heterogeneity (Chi2 = 2.46, df = 3 (P=0.48); I2 = 0%). Overall survival was not statistically different for these higher-risk disease patients (fixed effect: HR=0.93, CI95%=0.74 to 1.16; p=0.5). Conclusions: This is the first meta-analysis including the five available RCTs in the literature (the previous meta-analysis reviewed only four), comparing adjuvant VEGFRi versus placebo in patients submitted to nephrectomy with a locally advanced, non-metastatic RCC. Adjuvant VEGFRi did not increase the OS in this group of patients. Amodest benefit of DFS with the use of adjuvant VEGFR inhibitors was restricted to patients with the highest risk of relapse.

Real-world data of cabozantinib in patients with VEGF-refractory metastatic renal cell carcinoma (mRCC): Results from the French Early Access Program (CABOREAL).

683 Background: Cabozantinib (Cabo) is approved in Europe for the treatment of mRCC in first line and after failure of tyrosine kinase inhibitors (TKI). We report the results from real-world use of Cabo in the French Early Access Program (EAP) (CABOREAL [NCT03744585]). Methods: Data were retrospectively collected from 26 centers. Patients (pts) were treated with Cabo during the Temporary Authorization for Use (ATU) period from Sep 12, 2016 to licensing in Feb 19, 2018. Pts were eligible after 2 prior VEGFR TKI unless clinical decision for 2nd line (L). The aim was to evaluate the use and activity of Cabo in real-life conditions. Overall survival (OS) was calculated from initiation of Cabo. Results: Overall, 410 pts were included. Median age was 63 years, 85% had clear-cell histology, 41% and 32% were intermediate/poor IMDC risk, respectively. Pts were mostly ECOG 1 (42%) or 2 (30%); 229 (56%) pts had bone metastasis (mets). Median follow-up was 14.4 months (m). Cabo was used as 2L, 3L and 4L or beyond for 101 (25%), 137 (33%) and 172 (41%) pts respectively; 204 pts (50%) were pretreated with nivolumab (Nivo). Activity results and dose reduction are summarized in the table. Starting dose was 60 mg (290 pts, 71%), 40 mg (109 pts, 27%) and 20 mg (8 pts, 2%). Treatment interruption occurred for 267 pts (65%), dose modification for 240 pts (59%) and schedule change for 64 pts (16%). Median daily dose was 40 mg/day. Treatment discontinuation occurred for 348 (85%) pts, with 86 (25%) due to adverse events. Notably, 184 (54%) pts received a subsequent systemic therapy. Conclusions: We report the largest real-world study of Cabo in mRCC to date. CABOREAL demonstrates that using dose modification, median Cabo duration was 7.6 m in a heavily pretreated population, with the longest treatment duration in patients with prior Nivo exposure. Clinical trial information: NCT03744585. [Table: see text]

Deferred Cytoreductive Nephrectomy Following Presurgical Vascular Endothelial Growth Factor Receptor–targeted Therapy in Patients with Primary Metastatic Clear Cell Renal Cell Carcinoma: A Pooled Analysis of Prospective Trial Data

BackgroundCancer du Rein Métastatique Nephrectomie et Antiangiogéniques (CARMENA) concluded that sunitinib alone is not inferior to cytoreductive nephrectomy (CN) followed by vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma. It remains uncertain whether deferred CN is beneficial in this setting. ObjectiveThe aim of this study was to compare outcome in patients treated with presurgical VEGFR-TKI followed by CN (deferred CN) with that in patients receiving CN followed by VEGFR-TKI (upfront CN). Design, setting, and participantsPooled data from prospective trials in which a strategy of deferred CN in the absence of disease progression was investigated were compared with a retrospective dataset of upfront CN. Outcome measurements and statistical analysisOverall survival (OS) in the Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate-risk group. Results and limitationsPatients were treated between 2006 and 2016. In the MSKCC intermediate-risk group, 144 patients with a strategy of deferred CN after systemic therapy were compared with 131 patients treated with upfront CN. OS in the deferred cohort was 33.0 mo (95% confidence interval [CI] 25.0–51.0) compared with 22.8 mo (95% CI 17.9–30.6) after upfront CN (hazard ratio 0.72 [95% CI 0.52–0.996], p = 0.047). This study is limited by retrospective comparison of data, subgroup analysis, and a lack of intention-to-treat data for the upfront CN cohort. ConclusionsIn MSKCC intermediate-risk patients, a strategy of deferred CN in the absence of progression yields OS, which compares favourably with upfront CN and published trial data from CARMENA. This warrants a formal individual patient data analysis of CARMENA, SURTIME, and single-arm prospective studies to define the role and timing of deferred CN in intermediate-risk patients. Patient summaryIn this study, we report outcomes in patients with metastatic renal cell cancer treated with targeted therapy followed by nephrectomy, which compared favourably with nephrectomy followed by targeted therapy and results from published studies.

Synthesis of Piperidine Conjugated Dihydroquinazolin-4(1H)-ones and their Antiproliferative Activity, Molecular Docking Studies and DFT Calculations

Background: Xanthatin, fluoropyrimidine and thienopyrimidine, pyrazolopyrimidine, pyrimidine carboxamides, and SKLB1002 are reported as VEGFR2 tyrosine kinase inhibitors. Recently, many studies related to different heterocycles conjugated with dihydroquinazolinones are known to have very good biological activities. In this study, we are intended to explore the cytotoxic studies of piperidine conjugated dihydroquinazolinones against colorectal/colon cancer cell lines and along with molecular docking studies and DFT calculations. Methods: The colorectal/colon cell lines HCT116 and A549 cell lines were treated with these compounds and cytotoxic activities were evaluated by MTT dye uptake method. We performed molecular modelling for compound 3d using the Auto Dock software. The binding of compound 3d with target proteins was studied with the collection of experimentally determined PDB database. Optimized geometry by DFT calculations was performed with B3LYP/6-31G (d) basis set. Results: Piperidine-conjugated dihydroquinazolinone analogues displayed anticancer activity. Particularly, the compound 3d with electron-withdrawing substituents on a phenyl ring showed significant cytotoxicity against HCT116 and A549 cell lines. Molecular docking studies proved that the compound 3d has good fitting by forming hydrogen bonds with amino acid residues at the active sites of VEGFR2. The HOMO, LUMO, their energies and UV visible spectrum were predicted using DFT calculations. Conclusion: Four piperidine-conjugated dihydroquinazolinones were synthesized and evaluated against colorectal and colon cancer cell lines. Compound 3d significantly inhibited the growth of HCT116 and A549. Molecular docking studies displayed good fitting of compound 3d by forming different H-bonds with the amino acid at the active sites of the VEGFR2 target. Using a theoretical approach, we optimized HOMO and LUMO plots for the compound 3d.

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC)

The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.

Outcomes of Patients with Metastatic Renal Cell Carcinoma Treated with Targeted Therapy After Immuno-oncology Checkpoint Inhibitors

BackgroundImmuno-oncology (IO) therapies have changed the treatment standards of metastatic renal cell carcinoma (mRCC). However, the effectiveness of targeted therapy following discontinuation of IO therapy in real-world settings has not been well studied. ObjectiveTo describe treatment sequence and assess clinical effectiveness of targeted therapy for mRCC patients who received prior IO therapy. Design, setting, and participantsA retrospective, longitudinal cohort study using data from eight international cancer centers was conducted. Patients with mRCC were ≥18yr old, received IO therapy in any line, and initiated targeted therapy following IO therapy discontinuation. InterventionPatients were treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) or mammalian target of rapamycin inhibitors (mTORIs). Outcome measurements and statistical analysisOutcomes were time to treatment discontinuation (TTD), overall survival (OS), and objective response rate (ORR). Crude and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazard models. Models were adjusted for age, sex, therapy line, and International Metastatic RCC Database Consortium risk group. Results and limitationsAmong 314 patients, 276 (87.9%) and 38 (12.1%) were treated with VEGFR-TKI and mTORI therapy, respectively. The most common tyrosine kinase inhibitor treatments were axitinib, cabozantinib, and sunitinib following IO therapy. In adjusted models, patients treated with VEGFR-TKI versus mTORI therapy had lower hazard of TTD after IO treatment (aHR=0.46; 95% CI: 0.30–0.71; p < 0.01). One-year OS probability (65% vs 47%, p < 0.01) and proportion of ORR (29.8% vs 3.6%, p < 0.01) were significantly greater for patients treated with VEGFR-TKIs versus those treated with mTORIs. ConclusionsTargeted therapy has clinical activity following IO treatment. Patients who received VEGFR-TKIs versus mTORIs following IO therapy had improved clinical outcomes. These findings may help inform treatment guidelines and clinical practice for patients post-IO therapy. Patient summaryPatients may continue to experience clinical benefits from targeted therapies after progression on immuno-oncology treatment.

BMI, irAE, and gene expression signatures associate with resistance to immune-checkpoint inhibition and outcomes in renal cell carcinoma

BackgroundClinical variables may correlate with lack of response to treatment (primary resistance) or clinical benefit in patients with clear cell renal cell carcinoma (ccRCC) treated with anti-programmed death 1/ligand one antibodies.MethodsIn this multi-institutional collaboration, clinical characteristics of patients with primary resistance (defined as progression on initial computed tomography scan) were compared to patients with clinical benefit using Two sample t-test and Chi-square test (or Fisher’s Exact test). The Kaplan–Meier method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS) in all patients and the subsets of patients with clinical benefit or primary resistance. Cox’s regression model was used to evaluate the correlation between survival endpoints and variables of interest. To explore clinical factors in a larger, independent patient sample, The Cancer Genome Atlas (TCGA) was analyzed. RNAseq gene expression data as well as demographic and clinical information were downloaded for primary tumors of 517 patients included within TCGA-ccRCC.ResultsOf 90 patients, 38 (42.2%) had primary resistance and 52 (57.8%) had clinical benefit. Compared with the cohort of patients with initial benefit, primary resistance was more likely to occur in patients with worse ECOG performance status (p = 0.03), earlier stage at diagnosis (p = 0.04), had no prior nephrectomy (p = 0.04) and no immune-related adverse events (irAE) (p = 0.02). In patients with primary resistance, improved OS was significantly correlated with lower International Metastatic RCC Database Consortium risk score (p = 0.02) and lower neutrophil:lymphocyte ratio (p = 0.04). In patients with clinical benefit, improved PFS was significantly associated with increased BMI (p = 0.007) and irAE occurrence (p = 0.02) while improved OS was significantly correlated with overweight BMI (BMI 25–30; p = 0.03) and no brain metastasis (p = 0.005). The cohort TCGA-ccRCC was examined for the correlations between gene expression patterns, clinical factors, and survival outcomes observing associations of T-cell inflammation and angiogenesis signatures with histologic grade, pathologic stage and OS.ConclusionsClinical characteristics including performance status, BMI and occurrence of an irAE associate with outcomes in patients with ccRCC treated with immunotherapy. The inverse association of angiogenesis gene signature with ccRCC histologic grade highlight opportunities for adjuvant combination VEGFR2 tyrosine kinase inhibitor and immune-checkpoint inhibition.

Concurrent Treatment of VEGFR Tyrosine Kinase Inhibitors (TKIs) and Factor Xa Inhibitors Is Associated with Increased Bleeding Risks

ABSTRACT Background: Some cancer patients with thromboembolism require dual treatment of VEGFR TKIs and factor Xa inhibitors (direct or indirect), which may contribute to increased bleeding risks. However, the safety of such combination treatment has not been well characterized in the literature or national guidelines. Methods: This is a single center retrospective study, where we identified metastatic cancer patients (renal cancer, colorectal cancer, sarcoma, etc) who received concurrent VEGFR TKIs (pazopanib, sunitinib, sorafenib, axitinib, regorafenib, vandetanib, lenvatinib or cabozantinib) and Xa inhibitors (low-molecular weight heparin [LMWH] or direct oral anticoagulants [DOACs] including rivaroxaban or apixaban) at the Ohio State University Medical Center. We assessed bleeding risks of dual therapies vs. factor Xa inhibitors alone, using the same patients as self controls. We reviewed medical charts of all identified patients for clinically significant bleeding events (defined as combined major bleeding and clinically relevant non-major bleeding by the International Society of Thrombosis and Haemostasis criteria). The Cox proportional hazard model was used to compare the differences of time to first clinically significant bleeding event between the groups of concurrent use and anticoagulant use only. Results: A total of 86 patients (26 females and 60 males) were included: 78 Caucasians, 6 African Americans, and 2 others. 81 patients had concurrent TKI and LMWH treatment; 20 patients had concurrent TKI and DOACs; and 85 patients have had been on factor Xa inhibitor alone (LMWH or DOACs) at some point. Some patients had been on both LMWH and DOACs at different time periods. Overall, there were 29 clinically significant bleeding events (including 8 major bleeding) during concurrent treatment and 17 events (4 major bleeding) during factor Xa inhibitor alone over a median follow up of 63 days (52 days for concurrent treatment and 99 days for Xa inhibitor alone). In this self-control study, concurrent treatment was associated with a statistically higher risk of clinically significant bleeding events (HR, 2.84; 95% CI, 1.43-5.64, P &amp;lt; 0.01), which reached 37% patient population in the first 3 months, while the bleeding associated with factor Xa inhibitor alone seemed spaced out at the entire length of anticoagulation (8% by 6 months). Similar trend was found in the analysis of patient group of concurrent TKI and LMWH vs. LMWH alone (HR, 1.96; 95% CI, 0.95-4.02, P = 0.067), although significance was not reached likely due to insufficient power. Sample size was inadequate for meaningful comparison between concurrent VEGFR TKI and DOAC vs. DOAC alone. Conclusions: Concurrent treatment of VEGFR TKI and factor Xa inhibitors is associated with a significantly increased bleeding risks when compared with factor Xa inhibitors alone in patients with metastatic cancer. Disclosures No relevant conflicts of interest to declare.

478O - Phase II study of fruquintinib plus gefitinib in stage IIIb/IV NSCLC patients harboring EGFR activating mutations

BackgroundFruquintinib is a potent and highly selective oral small molecule tyrosine kinase inhibitor of VEGFR. Preclinical data showed that a combined blockade of VEGFR and EGFR had synergistic antitumor effects. In the JO25567 trial, bevacizumab plus erlotinib had significantly prolonged median progression-free survival (PFS) in EGFR mutant NSCLC patients. Approaching this combined blockade with two oral drugs may improve ease of use for patients and greater therapeutic flexibility for physicians, while the high selectivity and shorter half-life of fruquintinib vs. a VEGF antibody may provide a better safety profile. MethodsThis is a single arm, open-label, multi-center, 2-cohort study in first line EGFR mutant NSCLC patients (NCT02976116). All patients receive 250 mg QD gefitinib (Gefi) continuously. Fruquintinib (Fruq) is given at 4 mg QD for 3 weeks followed by 1 week off in the first 4-week cycle. In cohort 1 the fruquintinib dose is escalated to 5 mg under the same 4-week cycle if no ≥grade 3 adverse event (AE) or ≥grades 2 liver dysfunction occurs in the first cycle. In cohort 2 fruquintinib remains at 4 mg. The primary objective is to assess the efficacy (objective response rate, ORR) and tolerability of this combination. The secondary objective is to assess PFS. ResultsAs of July 5, 2019, 26 and 24 patients have been enrolled in cohort 1 and cohort 2, respectively, and received at least one dose of each drug. Among them 26 had L858R mutation, and 24 had exon 19 deletions. The efficacy and safety data are summarized in the table below.Table478OTableCohort 1 N = 26Cohort 2 N = 24All N = 50EFFICACYORR73.1%70.8%72.0%Median PFS (months)14.714.714.7SAFETYAny TEAE26 (100%)24 (100%)50 (100%)≥ grade 3 TEAE17 (65.4%)11 (45.8%)28 (56.0%)SAE6 (23.1%)3 (12.5%)9 (18.0%)TEAE leading to Fruq / Gefi discontinuation6 (23.1%) / 6 (23.1%)4 (16.7%) / 4 (16.7%)10 (20.0%) / 10 (20.0%)TEAE leading to Fruq / Gefi interruption9 (34.6%) / 14 (53.8%)8 (33.3%) / 15 (62.5%)17 (34.0%) / 29 (58.0%)TEAE leading to Fruq / Gefi reduction18 (69.2%) / 0 (0%)15 (62.5%) / 0 (0%)33 (66.0%) / 0 (0%) ConclusionsFruquintinib plus gefitinib showed an overall acceptable safety profile and promising efficacy. 4 mg of fruquintinib (in combination with 250 mg of gefitinib) was better tolerated than 5 mg, without compromising efficacy. Confirmatory studies at this recommended dose are required to further verify the full potential of this treatment. Clinical trial identificationNCT02976116. Legal entity responsible for the studyHutchison MediPharma. FundingHutchison MediPharma. DisclosureS. Lu: Advisory / Consultancy: Hutchison MediPharma. Y. Chen: Full / Part-time employment: Hutchison MediPharma. W. Su: Full / Part-time employment: Hutchison MediPharma. All other authors have declared no conflicts of interest.

1186PD - Safety and efficacy of the oral CXCR4 inhibitor X4P-001 + axitinib in advanced renal cell carcinoma patients: An analysis of subgroup responses by prior treatment

1186PD - Safety and efficacy of the oral CXCR4 inhibitor X4P-001 + axitinib in advanced renal cell carcinoma patients: An analysis of subgroup responses by prior treatment