Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Research Articles

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

LBA43 - Randomized phase III ANGEL study of rivoceranib (apatinib) + best supportive care (BSC) vs placebo + BSC in patients with advanced/metastatic gastric cancer who failed ≥2 prior chemotherapy regimens

BackgroundRivoceranib is an oral, selective tyrosine kinase inhibitor of VEGFR-2 with demonstrated efficacy for gastric cancer in China. ANGEL was a global phase III study to evaluate the efficacy and safety of rivoceranib in gastric cancer. MethodsMain eligibility criteria included advanced/metastatic adenocarcinoma of the stomach or gastroesophageal junction after failure of≥2 prior lines of chemotherapy; ECOG PS≤1. Patients were stratified by geographic region (Asia vs North America/Europe), disease measurability, prior ramucirumab use, and treatment therapy line (3rd or≥4th), and randomized (2:1 ratio) to rivoceranib 700mg qd po or matched placebo with BSC until disease progression, intolerable toxicity or withdrawal of consent. Primary endpoint: overall survival (OS, ITT population). Secondary endpoints: progression-free survival (PFS); objective response rate (ORR); disease control rate (DCR); quality of life (QoL); safety. Clinical trial registration: NCT03042611. ResultsOverall, 460 patients (rivoceranib n=308, placebo n=152) were enrolled from Feb 2017 – Oct 2018. Baseline demographics were balanced. While mOS in≥3rd-line patients did not show statistical difference for rivoceranib vs placebo (5.78 vs 5.13mo; HR=0.93; 95% CI 0.74–1.15; p=0.4850), mPFS was significantly improved with rivoceranib (2.83 vs 1.77mo; HR=0.57; 95% CI 0.46–0.79; p<0.0001), as was ORR (6.87% vs 0%; p=0.0020) and DCR (42.37% vs 13.08%; p<0.0001) in patients with measurable lesions. Furthermore, in≥4th-line patients (rivoceranib n=122, placebo n=63) mOS (6.43 vs 4.73mo; HR=0.65; 95% CI 0.46–0.92; p=0.0195) and mPFS (3.52 vs 1.71mo; HR=0.38; 95% CI 0.27–0.53; p<0.0001) were significantly improved with rivoceranib vs placebo. Treatment was generally well tolerated; the most common treatment-related AEs were hypertension (34%) and hand-foot syndrome (26%). ConclusionsWhile OS was not significantly improved in the overall population, most other efficacy endpoints including OS in≥4th-line suggest that rivoceranib has a benefit and is well tolerated in patients with gastric cancer. Clinical trial identificationNCT03042611. Editorial acknowledgementLee Miller, Miller Medical Communications Ltd. Legal entity responsible for the studyLSK BioPharma. FundingLSK BioPharma. DisclosureY. Kang: Advisory / Consultancy: ONO; Advisory / Consultancy: BMS; Advisory / Consultancy: Daehwa; Advisory / Consultancy: LSK Biopharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Macrogenics; Advisory / Consultancy: Zymeworks; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Merck Serono; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Astellas; Research grant / Funding (institution): Roche. M. Di Bartolomeo: Honoraria (self), Speaker Bureau / Expert testimony: Lilly spa; Honoraria (self), Speaker Bureau / Expert testimony: Servier; Honoraria (self), Speaker Bureau / Expert testimony: Merck-Serono; Honoraria (self), Speaker Bureau / Expert testimony: MSD; Travel / Accommodation / Expenses: Roche spa; Travel / Accommodation / Expenses: Sanofi. I. Chau: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli-Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): Janssen-Cilag; Research grant / Funding (institution): Sanofi Oncology. H.H. Yoon: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): LSK; Honoraria (institution), Advisory / Consultancy: BeiGene; Advisory / Consultancy: FivePrime Therapeutics; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Merrimack; Research grant / Funding (institution): Genetech/Roche; Research grant / Funding (institution): Boston Biomedical. S. Cascinu: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly. M. Ryu: Honoraria (self), Advisory / Consultancy: ONO; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Taiho; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Daehwa. K. Lee: Honoraria (self), Travel / Accommodation / Expenses: BMS; Honoraria (self): Eli Lilly; Research grant / Funding (institution): ALX Oncology; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): ASLAN Pharmaceuticals; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Green Cross Corp.; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharmacyclics. A. McGinn: Shareholder / Stockholder / Stock options, Full / Part-time employment: LSK BioPharma. N. Sankar: Shareholder / Stockholder / Stock options, Full / Part-time employment: LSK BioPharma. N. Boku: Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Eli Lilly; Honoraria (self): Chugai. All other authors have declared no conflicts of interest.

70P - New therapy for intrahepatic cholangiocarcinoma targeted to cancer associated fibroblasts

BackgroundThe microenvironment such as cancer associated fibroblasts (CAFs) was reported to be involved in progression of intrahepatic cholangiocarcinoma (ICC). Nintedanib (BIBF1120) is a tyrosine kinase inhibitor of PDGFR, FGFR and VEGFR which is approved for idiopathic pulmonary fibrosis. And nintedanib was reported to suppress liver fibrosis in mouse through the suppression of hepatic stellate cells activation (Ozturk Akcora B, et al. Sci Rep. 2017 Mar 14;7:44545). Therefore, we hypothesized that nintedanib can inhibit the activity of CAFs of ICC. The purpose of this study is to clarify the effect of CAFs on ICC and develop a new therapy for ICC targeted to CAFs. MethodsCAFs were established from surgically resected ICC tissues. The effect of nintedanib on proliferation and expression of alpha smooth muscle actin (αSMA) of CAFs was examined. The effect of CAF-CM (conditioned medium of CAFs) and nintedanib-CAF-CM (CM of CAFs treated with nintedanib) on proliferation and invasion of ICC cell lines (HuCCT1, RBE) was examined. The humoral factors of CAF-CM and nintedanib-CAF-CM were analyzed using cytokine array and ELISA. The effect of nintedanib and gemsitabine (GEM) treatment on xenograft model co-implanted with HuCCT1 and CAFs was examined in vivo. ResultsNintedanib(1µM) suppressed the proliferation of CAFs and expression of αSMA in CAFs. CAF-CM significantly promoted the proliferation and invasion of ICC cell lines. But in nintedanib-CAF-CM, all of those cancer promoting effects were cancelled. In cytokine array and ELISA of CAF-CMs, expression of IL-6, IL-8, VEGF, VCAM1, and Osteopontin were suppressed in nintedanib-CAF-CM compared with CAF-CM. HuCCT1 + CAFs xenograft was increased more than HuCCT1 alone in vivo. Combination treatment with nintedanib (30mg/kg) and GEM (50mg/kg) inhibited HuCCT1 + CAFs xenograft growth than nintedanib or GEM alone in vivo. The xenograft treated with nintedanib and GEM showed reduction of both αSMA-positive staining in stroma and proportion of Ki-67 positive ICC cells. ConclusionsNintedanib suppressed CAFs activity and the production of cancer-promoting cytokines produced by CAFs. Combination therapy with nintedanib and GEM may be a new promising therapy to overcome refractory ICC. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

P2.01-20 Anlotinib vs. Docetaxel in Advanced Non-Squamous NSCLC (EGFR Wild-Type) After Progression on Platinum-Based Chemotherapy: A Trial Protocol

Anlotinib, an oral VEGFR, FGFR, PDGFR and c-Kit tyrosine kinase inhibitor, showed significantly longer overall survival in a phase 3 trial. In the multi-center, open-label, randomized controlled ALTER-L023 trial, we compared anlotinib with docetaxel as second-line treatment in patients with advanced non-squamous EGFR wild-type non-small cell lung cancer (NSCLC) previously given platinum-based doublet chemotherapy. This multi-center, open-label, randomized controlled ALTER-L023 trial was conducted at 10 hospitals in China. Eligible patients with previously treated non-squamous EGFR wild-type NSCLC were randomly assigned (1:1) to receive anlotinib (12 mg QD from day 1 to 14 of a 21-day cycle) or docetaxel (75mg/m2, on day 1 of a 21-day cycle) till progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS), that was defined as the time from randomization to disease progression or death. The secondary endpoints included objective response rate, disease control rate, duration of response and safety. Based on a two-sided log-rank test at 5% significance level, a power of 80% and a median PFS of 6 months for anlotinib versus 3 months for docetaxel, the simple size was estimated at 77 patients. Allowing for 15% dropouts, the sample size was set at 88 patients (44 patients in both groups). Clinical trial information: NCT03703596 Section not applicable Section not applicable

Phase I Study of Apatinib in Combination with Gefitinib As First-Line Treatment in Patients with EGFR-Mutant Advanced Non-Squamous Non-Small Cell Lung Cancer

Background: Dual blockade of the EGFR and VEGFR pathways in EGFR-mutant NSCLC have shown enhanced anti-tumor efficacy versus a (v)EGFR inhibitor alone. This phase I study evaluated the safety, pharmacokinetic (PK) profile and antitumor activity of apatinib, an orally effective VEGFR-2 tyrosine kinase inhibitor (TKI), plus gefitinib as a first-line treatment for EGFR-mutant advanced NSCLC. Methods: Advanced non-squamous NSCLC patients with the EGFR 19 deletion or the 21 L858R mutation who met this study's eligibility criteria were included. There were two cohorts. Cohort A: apatinib 500mg + gefitinib 250mg. Cohort B: apatinib 250mg + gefitinib 250mg. The primary endpoint was safety profile. Other endpoints included PK analysis, objective response rate (ORR) and progression free survival (PFS). Exploratory analysis was conducted using next generation sequencing of plasma circulating-tumor DNA with samples collected at baseline, best of response and after progression disease. Findings: Between July 2016 and April 2017, 13 patients with NSCLC were enrolled in this study. Six patients were enrolled in Cohort A and seven in Cohort B. Most adverse events (AEs) were grade 1-2 and the treatment-related AEs (TRAEs) were similar in both cohorts: rash (100% v 71.4%), diarrhea (66.7% v 71.4%), hypertension (66.7% v 71.4%), proteinuria (66.7% v 42.9%), and hand-foot skin reaction (33.3% v 28.6%). The area under the plasma concentration-time curve (AUC) for the steady state of apatinib was 2864.73 ± 2605.54 ng/ml*h in Cohort A and 2445.09 ± 1550.89 ng/ml*h Cohort B. Median follow-up was 29.7 months. The ORR was 80.0% and the median PFS was 19.2 months in Cohort and it 83.3% and 13.4 months in Cohort B. Patients without a concomitant mutation at baseline had a longer PFS compared with those with a detected concomitant mutation (20.99 months v 13.21 months, P=0.0624). The EGFR-T790M mutation remained the dominant resistance mechanism. Interpretation: Apatinib (500mg) plus gefitinib (250mg) had a tolerable safety profile and promising antitumor activity for EGFR-mutant NSCLC patients in the first-line setting. Phase III trials of apatinib (500mg) plus gefitinib (250mg) are warranted. Funding: This work was supported by National Key R&D Program of China (Grant number: 2016YFC0905500, 2016YFC0905503), The Science and Technology Planning Project of Guangdong Province of China (Grant number: 2017B020227001)，Natural Science Foundation of Guangdong Province of China (Grant number: 2018A0303130243) and The 5010 Clinical Research Foundation of Sun Yat-sen University (Grant number: 2016001). Li Zhang has received research support from the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDA12020101 to J.D.). Yan Huang has received research support from Science and Technology Program of Guangzhou (201704020072). Yunpeng Yang was supported by Outstanding Young Talents Program of Sun Yat-sen University Cancer Center (16zxyc03) and Central Basic Scientific Research Fund for Colleges-Young Teacher Training Program of Sun Yat-sen University (17ykpy85). Declaration of Interest: All authors declare no competing interests. Ethical Approval: This trial has been approved by the institutional review boards (ID: 2016-FXY-023) and the independent ethics committees of Sun Yat-sen University Cancer Center (Ethic approval ID: 5010-2016-03). And other participating centers have also obtained the approval from their institutional review boards/independent ethics committees before enrollment. All patients will be required to sign the informed consent form before enrollment.

Nivolumab for the Treatment of Patients with Metastatic Non-Clear Cell Renal Cell Carcinoma (nccRCC): A Single-Institutional Experience and Literature Meta-Analysis.

Nivolumab alone and in combination with ipilimumab is approved for the treatment of patients with metastatic renal cell carcinoma (RCC) who received prior vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKI) and those who are treatment naive, respectively. However, the clinical activity of nivolumab in non-clear cell RCC (nccRCC) is unknown, as these patients were excluded from the trials. We reviewed the records of patients who received nivolumab for nccRCC and ccRCC with >20% rhabdoid with the primary endpoint to assess the objective response rate (ORR). We assessed radiographic response using RECIST, v1.1. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). We also reviewed the literature to identify studies reporting on the clinical activity of immune checkpoint inhibitors in nccRCC, and performed a meta-analysis of proportions for ORR and disease control rate (DCR). Twelve patients (30%) had papillary histology, 11 (27.5%) had unclassified, 8 (20%) had ccRCC with rhabdoid component, 5 (12.5%) had chromophobe, 3 (7.5%) had translocation, and 1 (2.5%) had mucinous tubular and spindle cell carcinoma. Overall, seven patients (21.6%, 95% confidence interval [CI], 8.7%-37.9%) had an objective response, including three patients (8.8%, 95% confidence interval [CI], 1.9%-23.7%) who achieved a complete remission. At a median follow-up of 24.5 monoths (95% CI, 17.7-32.6), median PFS was 4.9 monoths (95% CI, 3.53-10.27) and median OS was 21.7 monoths (95% CI, 7.83 mo to not reached). There were no treatment-related deaths. We also identified two retrospective studies reporting best ORR in patients with nccRCC receiving PD-1/PD-L1 checkpoint blockade. The ORR and DCR for the total cohort were, respectively, 18.6% (95% CI, 11.9%-26.4%) and 53.4% (95% CI, 44.2%-62.5%). Nivolumab demonstrated activity in unclassified nccRCC and ccRCC with >20% rhabdoid; further randomized clinical trials are warranted. This article reports on the clinical activity and safety of immune checkpoint inhibitors in non-clear cell kidney cancer. The retrospective data with the meta-analysis provides a summary that will help guide the treatment of this rare and heterogeneous group of kidney cancers.

Pro-angiogenesis effect and transcriptome profile of Shuxinyin formula in zebrafish

BackgroundAngiogenesis plays a critical role in ischemia disease like coronary heart disease. Shunxinyin formula has been developed for treating coronary heart disease according to the principle of traditional Chinese medicine while its underlying mechanism is not fully elucidated. PurposeHere, we hypothesize Shuxinyin formula could promote angiogenesis and microcirculation, and the underlying mechanism is also investigated. MethodsWe established the chemical profile of Shuxinyin (SXY) extract utilizing a UHPLC-Q/Exactive analysis system and evaluated its pro-angiogenesis effect in zebrafish model. The underlying mechanisms were investigated by combination of pharmacological experiments with transcriptome analysis in zebrafish. Zebrafish treated with VEGF was served as the positive control in present study. ResultsWe found SXY significantly enhanced the sub-intestinal vessel plexus (SIVs) growth in zebrafish. Co-treatment and post-treatment SXY attenuated VEGF receptor tyrosine kinase inhibitor II (VRI)-induced deficiency of intersegmental vessels (ISVs) in a concentration dependent manner. Post-treatment VEGF, which is a well-known angiogenesis driver, also partially ameliorated VRI-induced ISVs deficiency. In addition, SXY inhibited the down-regulation of VEGF receptors, including kdr, flt1 and kdrl, induced by VRI in zebrafish. The pro-angiogenesis effect of SXY on VRI-induced ISVs deficiency was suppressed by PI3K and JNK inhibitors, and Akt inhibitor abolished the pro-angiogenesis effect of SXY. The transcriptome profile of SXY preventing from VRI-induced vascular growth deficiency revealed that the underlying mechanisms were also co-related to cell junction, apoptosis and autophagy. ConclusionWe could conclude that SXY presented pro-angiogenesis effect and the action mechanisms were involved in VEGF/PI3K/Akt/MAPK signaling pathways, cell junction, apoptosis and autophagy.

De novo Design of Indole Derivatives as VEGFR-2 Tyrosine Kinase Inhibitors†

Protein tyrosine kinase(PTK) is an especially important target for anticancer drug design due to its crucial role in the modulation of growth factor signaling.Vascular endothelial growth factor receptor-2(VEGFR-2) tyrosine kinase plays a pivotal role in modulating angiogenesis,as well as the proliferation and migration of endothelium.Compounds that inhibit the activity of VEGFR-2 tyrosine kinase are potential chemotherapeutics to treat tumors.In this study,based on the crystal structure of VEGFR-2 tyrosine kinase,de novo drug design was employed to develop a series of indole compounds.Absorption,distribution,metabolism,excretion and toxicity(ADMET) and molecular docking were used to screen the designed compounds.Finally,ten molecules which have lower binding energy were obtained,a 10 ns molecular dynamics(MD) calculation was performed to study the complex of the compound which has the lowest binding energy and VEGFR-2 tyrosine kinase,and then the binding models were analyzed.These new chemical entities could be lead compounds for anticancer.This result will provide theoretical basis for molecular structure improvement,molecular design,and molecular synthesis of VEGFR-2 tyrosine kinase inhibitors.

Brivanib, a multitargeted small-molecule tyrosine kinase inhibitor, suppresses laser-induced CNV in a mouse model of neovascular AMD.

In age-related macular degeneration (AMD), choroidal neovascularization (CNV), a major pathologic feature of neovascular AMD (nAMD), affects 10% of patients, potentially causing serious complications, including vision loss. Vascular endothelial growth factor receptor 2 (VEGFR2) and fibroblast growth factor receptor 1 (FGFR1) contribute to the pathogenesis of CNV. Brivanib is an oral selective dual receptor tyrosine kinase (RTK) inhibitor of FGFRs and VEGFRs, especially VEGFR2 and FGFR1. In this study, brivanib inhibited zebrafish embryonic angiogenesis without impairing neurodevelopment. In a mouse CNV model, brivanib intravitreal injection blocked phosphorylation of FGFR1 and VEGFR2 and reduced CNV leakage, area, and formation without causing intraocular toxicity. Moreover, brivanib oral gavage reduced CNV leakage and area. Accordingly, brivanib remained at high concentrations (above 14,000 ng/ml) in retinal/choroidal/scleral tissues following intravitreal injection. Similarly, brivanib remained at high concentrations (over 10,000 ng/ml) in retinal/choroidal/scleral tissues following oral gavage. Finally, in vitro cell experiments demonstrated that brivanib inhibited the proliferation, migration and tube formation of microvascular endothelial cells. In conclusion, our study suggested that brivanib treatment could be a novel therapeutic strategy for nAMD.

SU5416 does not attenuate early RV angiogenesis in the murine chronic hypoxia PH model

BackgroundRight ventricular (RV) angiogenesis has been associated with adaptive myocardial remodeling in pulmonary hypertension (PH), though molecular regulators are poorly defined. Endothelial cell VEGFR-2 is considered a “master regulator” of angiogenesis in other models, and the small molecule VEGF receptor tyrosine kinase inhibitor SU5416 is commonly used to generate PH in rodents. We hypothesized that SU5416, through direct effects on cardiac endothelial cell VEGFR-2, would attenuate RV angiogenesis in a murine model of PH.MethodsC57 BL/6 mice were exposed to chronic hypoxia (CH-PH) to generate PH and stimulate RV angiogenesis. SU5416 (20 mg/kg) or vehicle were administered at the start of the CH exposure, and weekly thereafter. Angiogenesis was measured after one week of CH-PH using a combination of unbiased stereological measurements and flow cytometry-based quantification of myocardial endothelial cell proliferation. In complementary experiments, primary cardiac endothelial cells from C57 BL/6 mice were exposed to recombinant VEGF (50 ng/mL) or grown on Matrigel in the presence of SU5416 (5 μM) or vehicle.ResultSU5416 directly inhibited VEGF-mediated ERK phosphorylation, cell proliferation, and Kdr transcription, but not Matrigel tube formation in primary murine cardiac endothelial cells in vitro. SU5416 did not inhibit CH-PH induced RV angiogenesis, endothelial cell proliferation, or RV hypertrophy in vivo, despite significantly altering the expression profile of genes involved in angiogenesis.ConclusionsThese findings demonstrate that SU5416 directly inhibited VEGF-induced proliferation of murine cardiac endothelial cells but does not attenuate CH-PH induced RV angiogenesis or myocardial remodeling in vivo.

Neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors: A meta-analysis.

To explore the association of peripheral neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) use in patients with cancer. Published data search up to November 2018 reporting peripheral neuropathy in patients with cancer treated with VEGFR-TKIs was performed. The primary outcome was presence of peripheral neuropathy at the end of the trial. Random-effects meta-analysis was performed to estimate relative risk (RR) of individual treatment. Thirty randomized clinical trials (RCTs) including 12,490 patients with cancer were included in this analysis. Eight studies compared VEGFR-TKIs with placebo and the remaining studies compared VEGFR-TKIs with the standard chemotherapeutic regimen. When compared against placebo, VEGFR-TKIs were associated with a higher risk of peripheral neuropathy (RR 1.76; 95% confidence interval [CI] 1.13-2.75, p = 0.01). Similarly, a stronger association was noted for sensory neuropathy with VEGFR-TKIs monotherapy (RR 1.61; 95% CI 1.09-2.37, p = 0.02). Risk of peripheral neuropathy with VEGFR-TKIs was higher even when they were compared against control (either placebo or standard chemotherapeutic agents) (RR 1.08; 95% CI 1.01-1.15, p = 0.03). High-grade neuropathy (RR 1.28; 95% CI 1.06-1.54, p <0.01) and high-grade sensory neuropathy (RR 1.38; 95% CI 1.09-1.74, p < 0.01) were noted more frequently with VEGFR-TKIs treatment compared against control. VEGFR-TKIs therapy appeared to be associated with an increased risk of neuropathy.

Safety of combining vascular endothelial growth factor receptor tyrosine-kinase inhibitors with chemotherapy in patients with advanced non-small-cell lung cancer: A PRISMA-compliant meta-analysis.

Background:Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) have been developed for targeted therapies in non–small-cell lung cancer (NSCLC); moreover, some drug-related toxic reactions among cancer patients have been reported. A meta-analysis of randomized controlled trials (RCTs) to definite the incidence and the risk of grade ≥3 adverse events (AEs), serious and fatal AEs (SAEs and FAEs), with VEGFR-TKIs in advanced/metastatic NSCLC patients was performed.Methods:A comprehensive literature search was conducted for the clinical trials published up to December 2017. Qualified studies allotted patients with advanced/metastatic NSCLC to receive either chemotherapy alone or in combination with VEGFR-TKIs. Data were extracted by 2 authors.Results:Eighteen RCTs of VEGFR-TKIs plus chemotherapy, involving 8461 advanced NSCLC patients were included. The proportion of patients with grade ≥3 AEs was increased with the addition of VEGFR-TKIs (relative risk, 1.35; 95% confidence interval [CI] 1.19–1.52; incidence, 68.1% vs 50.1%; P < .001). The most common grade ≥3 AEs was neutropenia (24.9% vs 15.4%, P < .001). Addition of VEGFR-TKIs was also related to the increased risk of SAEs (relative risk, 1.34; 95% CI 1.14–1.56; incidence, 37.8% vs 27.9%; P < .001) and FAEs (relative risk, 2.16, 95% CI 1.47–3.19; incidence, 3.4% vs 1.8%). Subgroup analysis suggested there was no difference in the rates of SAEs and FAEs in the second-line settings. No evidence of bias was found between the literatures. The study was registered with PROSPERO (CRD42018099654).Conclusions:In comparison with chemotherapy alone, the addition of VEGFR-TKIs in advanced NSCLC patients was related to the increased risk of grades ≥3 AEs, SAEs, and FAEs, especially in the first-line settings. Physicians should be aware of some specific grade ≥3 adverse effect, especially haematologic adverse events, and it is also necessary to monitor cancer patients receiving VEGFR-TKIs.

A phase I study of pazopanib with weekly paclitaxel and carboplatin in advanced solid tumors.

3021 Background: Pazopanib (pazo) is an oral tyrosine kinase inhibitor of VEGFR, PDGFR and c-Kit. It is a weak inhibitor of CYP3A4 and CYP2C8 and may decrease paclitaxel (P) clearance. Daily pazo with P and carboplatin (C) every 21 days was not feasible on a previous study. We hypothesized that pazo dosed intermittently and on a different day from P and C may be tolerable. We sought to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of pazo with weekly P and C. Methods: Using a 3+3 standard design, a schedule of P 60-80 mg/m2 and C AUC2 on days 1, 8, and 15 with pazo 400-800 mg on days 2-5, 9-12, and 16-26 on a 28-day cycle was evaluated. Pazo alone could be continued if P and C were omitted due to maximal benefit or toxicity. PK was collected during cycles 1 and 2. Results: 34 patients (pts) were treated over 6 dose levels (Table). Mean age 57 (37-79). Tumor types: breast (22), lung (3) and other (9); 27 had prior platinum. Delay in starting cycle 2 due to grade 3 neutropenia was a DLT at dose level 2 and 5. Pts on 5A missed dosing during C1 and C2 due to neutropenia and required subsequent growth factor, and this was deemed unlikely to be sustainable long-term. All grade toxicities included anemia (62%), neutropenia (59%), and thrombocytopenia (56%). Protocol-defined MTD was not determined. PK analysis showed a dose proportional increase in pazo concentration, consistent with previous reports. Pazo did not alter the PK of C. Cmax of P was higher C2D1 vs C1D1; mean Cmax ratio between C2D1:C1D1 was 1.63 (95% CI:1.29-1.96). There were 11 objective responses (3 CRs, 8 PRs). Five breast pts were on pazo alone for a median of 9 cycles (2-52) with CR (2), PR (2) and SD (1); a squamous cell of unknown primary in CR received 22 cycles. Clinical trial information: NCT01407562. Conclusions: PK confirm that pazo is a weak inhibitor of CYP3A4 and CYP2C8. Myelosuppression was a major adverse event at all dose levels. MTD was not determined. Antitumor activity was achieved with this alternate combination schedule and sustained responses from sequential pazo monotherapy was observed.[Table: see text]

Systemic therapy for advanced clear cell renal cell carcinoma (ccRCC) after progression on immune-oncology plus VEGF targeted therapy combinations (IO-VEGF).

4576 Background: IO-VEGF combinations are the backbone for current and future therapeutic developments in RCC with several IO-VEGF regimens reporting positive results in phase 3 trials. However, limited data exists on outcomes to subsequent therapy in patients progressing on IO-VEGF regimens. Methods: A retrospective analysis was performed on patients with ccRCC at the Memorial Sloan Kettering Cancer Center and Cleveland Clinic Cancer Institute who initiated systemic therapy post IO-VEGF regimens including combinations with VEGFR tyrosine kinase inhibitors (IO-TKI) and combinations with anti-VEGF monoclonal antibodies (IO-mAB). Patients treated on unreported clinical trials were excluded from the outcomes analysis. The primary objective was to evaluate the overall survival (OS) post IO-VEGF. The secondary objectives included objective response rate (ORR) and progression-free survival (PFS) according to RECIST v1.1. Kaplan-Meier methods and the log-rank test were used to evaluate time from start of systemic therapy post IO-VEGF to the event of interest. Results: Fifty-nine patients were treated after discontinuation of IO-VEGF regimens. Prior IO-VEGF regimens included IO-mAB (n = 35, 59%) and IO-TKI (n = 24, 41%). IMDC scores at the start of next line of therapy were favorable in 20%, intermediate in 60% and poor in 20%. Next line of therapy included VEGFR-TKI monotherapy (n = 45, 76%), VEGFR-TKI based combinations (n = 6, 10%), mTOR inhibitors (n = 3, 5%), and unreported clinical trials (n = 5, 9%). VEGFR-TKI containing regimens (n = 51) included cabozantinib (n = 22), axitinib (n = 17), lenvatinib/everolimus (n = 4), pazopanib (n = 4), and others (n = 4). Median OS was 24.5 months (95% CI 12-NE) with a 12 months OS rate of 63%. The ORR was 27% (14/51) and the median PFS was 6.8 months (95% CI 4.8-11). No difference in post IO-VEGF OS was observed when comparing IO- TKI vs IO-mAB (log rank p = 0.7). Conclusions: Post combination IO-VEGF treatment, most patients received VEGFR-TKIs. In this setting, VEGFR-TKIs continue to show clinical activity similar to historic experiences of patients post VEGF monotherapy.

Anti-angiogenic therapies for gastric cancer.

Tumor angiogenesis plays an important role in cancer cell proliferation and metastasis. In gastric cancer, among the numerous clinical trials investigating various anti-angiogenic therapies, such as antivascular endothelial growth factor (VEGF) or anti-VEGF receptor (VEGFR)-2 monoclonal antibodies, VEGF-Trap and VEGFR tyrosine kinase inhibitors, the anti-VEGFR-2 antibody ramucirumab was shown to prolong overall survival not only as a single agent but also in combination with paclitaxel as a second-line chemotherapy. Additionally, apatinib, a selective VEGFR-2 tyrosine kinase inhibitor, prolonged survival as a third-line or later treatment option in patients with advanced gastric cancer. Preliminary results of studies investigating ramucirumab plus immune checkpoint inhibitors in gastric cancer were encouraging, and further investigations are ongoing. In China, apatinib in combination with cytotoxic agents is being investigated for systemic chemotherapy or maintenance therapy as an earlier treatment option. The clinical activity in gastric cancer of the multikinase inhibitor regorafenib was suggested in a randomized phase II study. A global phase III trial comparing regorafenib with placebo is currently ongoing. Further studies of anti-angiogenic therapy combined with not only chemotherapy but also immune checkpoint inhibitors are also being pursued, providing hope for improved survival in patients with gastric cancer.

A multicenter, single-armed, prospective phase II study of apatinib combined with chemotherapy neoadjuvant for locally advanced gastric cancer.

e15508 Background: Molecular targeted therapy has made great progress in the treatment of gastric cancer. In some previous studies, apatinib, an oral small molecular of VEGFR-2 tyrosine kinase inhibitor, had been confirmed can improve OS and PFS with an acceptable safety profile in patients with advanced gastric cancer refractory to two or more lines of prior chemotherapy. However, there is limited evidence about the safety and feasibility of apatinib combined with SOX regimen as neoadjuvant therapy for locally advanced gastric cancer (LADG). Methods: This is a multicenter, single-armed, prospective study. Patients with LAGC (cT2-4N+M0) without prior anti-cancer strategies were included. Patients were received 3 to 5 cycles (21 days a cycle) of neoadjuvant therapy using S-1 (po, 40-60 mg bid, day1-day14), oxaliplatin (iv, 130 mg/m2, day1), and apatinib (po, 500 mg qd). Apatinib was prohibited in the last cycle. The operation should be performed 2 to 4 weeks later of the neoadjuvant therapy. The primary outcome was safety of the neoadjuvant therapy. The secondary outcomes included R0 resection rate, objective response rate (ORR), and disease control rate (DCR). Results: A total of 30 patients from 7 centers in China were recruited between Sep. 1, 2017 and Aug. 31, 2018. There were 21 males and 9 females. The median age was 66 years (range 41-75 years). There were 25 patients with tumor response evaluation, 18 patients had partial response (PR), 6 patients had stable disease (SD), and 1 patient had progressive disease (PD). The ORR and DCR were 72.0% (18/25) and 96.0% (24/25), respectively. 10 patients discontinued the study (withdrew consent 8 patients, physical deterioration in performance status 1 patient, and Disease progression 1 patient). 20 patients received gastric surgery, the R0 resection rate was 100%, 3 patients had postoperative complication: one had intestinal obstruction and two had pneumonia (all Clavien-Dindo classification less than grade II). All patients were included for safety analysis. The incidence of adverse events (AEs) and grade 3/4 AEs were 56.7% (17/30) and 6.7% (2/30), respectively. The most common AEs were leucopenia (33.3%), liver function damage (6.7%), up-GI hemorrhage (6.7%), and hypertension (6.7%). Conclusions: This prospective study shows that neoadjuvant therapy using apatinib plus SOX brings clinical benefit to LAGC with a high disease control rate and tolerable adverse reactions. This study is registered at ClinicalTrials.gov and carries the following ID number: NCT 03192735. Clinical trial information: NCT 03192735.

Outcomes of patients with metastatic clear-cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors

BackgroundImmune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor–receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy. Patients and methodsThis is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists' review using Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan–Meier method were used. ResultsSeventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti–programmed death ligand-1 (PD-(L)1) monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab and 25 (36%) received combination anti–PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity. ConclusionsIn this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI.

Grade III meningioma with gastro-intestinal tract and brain metastases: case report and review of the literature

BackgroundMeningioma is the most common adult primary intracranial tumor. Malignant meningioma is a rare variant of meningioma. The prognosis for the patients with these tumors is poor, due to the tumor’s capacity for relapse and to develop distant metastases. These tumors can present the same evolutionary course as aggressive carcinoma.Case descriptionWe report the case of distant brain and gastro-intestinal tract (GIT) metastases. A 78-year-old patient developed malignant meningioma with a Ki-67 proliferative index of 40%. According to guidelines, surgery followed by postoperative radiotherapy (RT) was performed. Three months after the end of RT, he presented histologically proven meningioma distant brain and GIT metastases.ConclusionsTo our knowledge, this is the first case of meningioma GIT metastases. Also, we report the difficulty to confirm the diagnosis of meningioma metastases. Indeed, malignant meningioma has the same histopathological features as melanoma or carcinoma. The standard of care for the management of malignant meningioma is gross total surgery followed by postoperative radiotherapy. Metastatic meningioma is uncommon and no guidelines for the management of recurrent or metastatic meningioma have yet been published. However, several studies reported systemic therapeutic options such as antibody against VEGF, somatostatin analogs, PDGF-R, and VEGF-R tyrosine kinase inhibitors, in the case of recurrent or metastatic meningioma. We also made a review of the actual literature of systemic treatment options for metastatic meningioma.

Risk of hand-foot skin reaction associated with vascular endothelial growth factor–tyrosine kinase inhibitors: A meta-analysis of 57 randomized controlled trials involving 24,956 patients

Multiple randomized controlled trials have assessed hand-foot skin reaction (HFSR) caused by vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). We performed a meta-analysis to determine the incidence and the relative risk (RR) of HFSR associated with these agents. Databases were searched for relevant studies. Statistical analyses were conducted to calculate the summary incidences, RR, and 95% confidence intervals (CIs) by using random-effects or fixed-effects models according to the heterogeneity of the included studies. A total of 24,956 patients from 57 studies were included. The overall incidence of all-grade and high-grade HFSR associated with VEGFR-TKIs was 35.0% (95% CI, 28.6%-41.6%) and 9.7% (95% CI, 7.3%-12.3%), respectively. The use of VEGFR-TKIs significantly increased the risk of developing all-grade (RR, 5.09; 95% CI, 3.52-7.35; P<.001) and high-grade (RR, 9.42; 95% CI, 5.59-15.90; P<.001) HFSR. Subgroup analyses revealed that the risk of HFSR was significantly increased according to tumor type, VEGFR-TKI, trial phase, treatment regimen, and control therapy. No evidence of publication bias was observed. High heterogeneity in most studies. High risk of HFSR is prone to develop in cancer patients receiving VEGFR-TKIs.

Expression of Concern: Antitumor Activity of Sorafenib in Human Cancer Cell Lines with Acquired Resistance to EGFR and VEGFR Tyrosine Kinase Inhibitors.

Expression of Concern: Antitumor Activity of Sorafenib in Human Cancer Cell Lines with Acquired Resistance to EGFR and VEGFR Tyrosine Kinase Inhibitors.