apatinib and Neoplasms

Metastasis is one of the main issues in cancer treatment and it has been documented that angiogenesis plays an important role in this process. Studies showed that vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have elevated expression in tumors and are involved in tumor progression and metastasis; suggesting their potential for being a therapeutic target. In this regard, Apatinib or YN968D1, a specific inhibitor of VEGFR-2 has been suggested as a promising therapeutic agent for cancer that can prevent tumor angiogenesis and metastasis. Furthermore, this drug can sensitize resistant tumor cells to chemotherapy drugs and increase the effectiveness of conventional chemotherapy drugs. Recent studies have shown that Apatinib has beneficial implications as a post-second and third-line therapy agent in a variety of cancers. Furthermore, Apatinib has the capacity to promote the overall survival and progression-free survival of cancer patients. This review discussed about, the molecular mechanisms and clinical relevance underlying the therapeutic potential of Apatinib in cancer treatment.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Apoptosis; Cell Proliferation; Chemotherapy, Adjuvant; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Neoplasms; Protein Kinase Inhibitors; Pyridines; Vascular Endothelial Growth Factor Receptor-2

Apatinib (YN968D1) is a novel and highly selective tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor-2 (VEGFR-2) and is approved as a third-line and subsequent-line treatment for advanced gastric adenocarcinoma or gastroesophageal junction adenocarcinoma in China. Apatinib is also widely studied in other solid tumors. With the increase in clinical research of apatinib, its adverse effects have also received widespread attention. Hence, this article summarizes the pharmacological properties of apatinib and reviews its clinical use in advanced or metastatic cancers. We highlight the common adverse reactions of apatinib in clinical applications and we also clarify the corresponding prevention and intervention measures. Overall, this review will help us better understand the safety and efficacy of apatinib treatment.

Topics: Antineoplastic Agents; China; Humans; Neoplasms; Pyridines; Vascular Endothelial Growth Factor A

Apatinib [Aitan

Topics: Antineoplastic Agents; Humans; Neoplasms; Protein Kinase Inhibitors; Pyridines; Stomach Neoplasms; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2

Aberrant proangiogenic pathways have long been implicated in tumorigenesis and metastasis. Antiangiogenic therapies have shown efficacy in the treatment of a variety of solid tumors including lung, breast, colon, glioblastomas, and other solid tumor types. Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), is an orally bioavailable agent currently being studied in multiple tumor types. Apatinib has shown a survival benefit in gastric cancer in a phase III trial and non-small cell lung cancer in a phase II trial. With a favorable side effect profile and improved outcomes, apatinib has demonstrated a substantial potential to augment therapeutic options in a variety of tumor types.

Topics: Administration, Oral; Angiogenesis Inhibitors; Clinical Trials as Topic; Humans; Neoplasms; Neovascularization, Pathologic; Pyridines; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2

As tumor angiogenesis is one of the hallmarks of cancer, the inhibition of vascular endothelial growth factor signaling has become an attractive anticancer approach. Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor-2, has demonstrated encouraging anticancer activity across a broad range of malignancies, including gastric cancer, non-small-cell lung cancer, breast cancer, and hepatocellular carcinoma. In this up-to-date review, focus is not only on the structure, mechanisms, and pharmacokinetics of apatinib, but also on summarizing clinical trials and making recommendations of apatinib for patients with advanced solid tumors.

Topics: Angiogenesis Inhibitors; Animals; Humans; Molecular Structure; Molecular Targeted Therapy; Neoplasms; Neovascularization, Pathologic; Pyridines; Signal Transduction; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2

APPEASE is a phase I study to assess the safety, dosing, and efficacy of rivoceranib (a selective, small-molecule inhibitor of VEGFR2) in combination with pembrolizumab. We aimed to treat patients with metastatic malignancies who have progressed through at least first-line therapy, with pembrolizumab 200 mg every 3 weeks, as well as escalating doses of rivoceranib until disease progression or unacceptable toxicity.. Five patients were enrolled on the starting dose of rivoceranib 300 mg once daily. There were no dose-limiting toxicities observed in combination with pembrolizumab. The dose of rivoceranib was not escalated due to study closure. We note a treatment related grade 3 adverse event (AE) rate of 40%, predominantly in urothelial cancer patients, with no deaths related to treatment related AEs. The disease control rate was 75% (3 of 4) and the median progression free survival (PFS) was 3.6 months. Tumor shrinkage was noted in patients who were previously progressing on pembrolizumab alone. Apatinib 300 mg is safe and demonstrates anti-tumor activity in advanced solid tumors in combination with pembrolizumab. Further dose escalation and efficacy need to be investigated in larger disease-specific patient populations.. Clinical trial registration number: NCT03407976. Date of registration: January 17, 2018.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Humans; Neoplasms

Apatinib is a small-molecule tyrosine kinase inhibitor for the treatment of recurrent or progressive advanced-stage gastric adenocarcinoma or gastroesophageal junction cancer. The in vitro inhibition studies suggested that apatinib exerted potent inhibition on CYP3A4 and CYP2C9. To evaluate the potential of apatinib as a perpetrator in CYP450-based drug-drug interactions in vivo, nifedipine and warfarin were, respectively, selected in the present study as the probe substrates of CYP3A4 and CYP2C9 for clinical drug-drug interaction studies. Since hypertension and thrombus are common adverse effects of vascular targeting anticancer agents, nifedipine and warfarin are usually coadministered with apatinib in clinical practice.. A single-center, open-label, single-arm, and self-controlled trial was conducted in patients with advanced solid tumors. The patients received a single dose of 30 mg nifedipine on Day 1/14 and a single dose of 3 mg warfarin on Day 3/16. On Day 9-21, the subjects received a daily dose of 750 mg apatinib, respectively. The pharmacokinetics of nifedipine and warfarin in the absence or presence of apatinib was, respectively, investigated.. Compared with the single oral administration, coadministration with apatinib contributed to the significant increases of AUC. Concomitant apatinib administration resulted in significant increases in systemic exposure to nifedipine and S-warfarin. Owing to the risk of pharmacokinetic drug-drug interactions based on CYP3A4/CYP2C9 inhibition by apatinib, caution is advised in the concurrent use of apatinib with either CYP2C9 or CYP3A4 substrates.

Topics: Administration, Oral; Adolescent; Adult; Aged; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Female; Humans; Male; Middle Aged; Neoplasms; Nifedipine; Pyridines; Warfarin; Young Adult

The lethal effects of multiple antigen-specific cellular therapy (MASCT) may be enhanced by blocking PD-1 in vitro and vascular endothelial growth factor receptor 2 inhibitor (apatinib). We analyzed the pooled data from our phase I/II trials to determine the toxicity and efficacy of PD-1 blockade (SHR-1210)-activated MASCT (aMASCT) alone or in combination with apatinib in advanced solid tumors.. Patients with advanced solid tumors received aMASCT alone (n = 32) or aMASCT plus apatinib (500 mg q.d., n = 38) after standard treatment. The safety profile was the primary end point. The secondary end points were antitumor response, progression-free survival (PFS), and overall survival (OS). The circulating T cells were quantified before and after aMASCT infusion.. Treatment-related adverse events (AEs) occurred in 18/32 (56.3%) and 25/38 (65.8%) patients in the aMASCT and aMASCT plus apatinib groups, respectively. No serious AEs were reported, and apatinib did not increase immunotherapy-related toxicity. The objective response rate (34.2% and 18.8%) and PFS (median 6.0 and 4.5 months, P = 0.002) were improved in the aMASCT plus apatinib group compared with the aMASCT group; however, the OS was not improved (median 10.0 and 8.2 months, P = 0.098). Multivariate analyses indicated that two or more cycles of aMASCT treatment was an independent and favorable prognostic factor of PFS and OS. The circulating T cells increased and Tregs decreased in both groups after one cycle of aMASCT treatment.. Treatment with aMASCT plus apatinib was safe and effective for the management of advanced solid tumors.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Dendritic Cells; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Immunotherapy; Male; Middle Aged; Neoplasms; Programmed Cell Death 1 Receptor; Prospective Studies; Pyridines; Receptor, ErbB-2; Survival Analysis; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory

Apatinib is an oral tyrosine kinase inhibitor approved in China for the treatment of patients with advanced metastatic gastric cancer. The approved dosing schedule is 850 mg once daily. The objective of this study was to develop a population pharmacokinetic (popPK) model of apatinib and determine factors that affect its pharmacokinetics.. A popPK model for apatinib was developed using data from 106 individuals, including healthy volunteers and patients with malignant solid tumors. The potential influence of demographic, patient, and laboratory characteristics on oral apatinib pharmacokinetics were investigated in a covariate analysis. The extent of the impact of significant covariates on the exposure of apatinib was evaluated using simulations.. The increase in apatinib exposure was less than proportional to dose. The pharmacokinetics of apatinib in gastric cancer patients were significantly different from those in patients with other cancer types. Dosing of apatinib in various cancer subpopulations may require adjustments to optimize efficacy and benefits to patients.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; China; Dose-Response Relationship, Drug; Female; Healthy Volunteers; Humans; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Neoplasms; Protein Kinase Inhibitors; Pyridines; Socioeconomic Factors; Young Adult

YN968D1 (Apatinib) selectively inhibits phosphorylation of VEGFR-2 and tumor angiogenesis in mice model. The study was conducted to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, and antitumor activity in advanced solid malignancies.. This dose-escalation study was conducted according to the Chinese State Food and Drug Administration (SFDA) recommendations in patients with advanced solid tumors to determine the MTD for orally administered apatinib. Doses of continuously administered apatinib were escalated from 250 mg. Treatment continued after dose-escalation phase until withdrawal of consent, intolerable toxicities, disease progression or death.. Forty-six patients were enrolled. Hypertension and hand-foot syndrome were the two dose-limiting toxicities noted at dose level of 1000 mg. MTD was determined to be 850 mg once daily. Pharmacokinetic analysis showed early absorption with a half-life of 9 hours. The mean half-life was constant over all dose groups. Steady-state conditions analysis suggested no accumulation during 56 days of once-daily administration. The most frequently observed drug-related adverse events were hypertension (69.5%, 29 grade 1-2 and 3 grade 3-4), proteinuria (47.8%, 16 grade 1-2 and 6 grade 3-4), and hand-foot syndrome (45.6%, 15 grade 1-2 and 6 grade 3-4). Among the thirty-seven evaluable patients, PR was noted in seven patients (18.9%), SD 24 (64.9%), with a disease control rate of 83.8% at 8 weeks.. The recommended dose of 750 mg once daily was well tolerated. Encouraging antitumor activity across a broad range of malignancies warrants further evaluation in selected populations.. ClinicalTrials.gov unique identifier: NCT00633490.

Topics: Adult; Aged; Antineoplastic Agents; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms; Pyridines; Tomography, X-Ray Computed; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2

Topics: Humans; Infant; Irinotecan; Neoplasms; Pyridines; Temozolomide

Apatinib is widely used in Chinese cancer patients. As the in vivo drug disposition of apatinib has large individual differences, adverse events are prone to occur. Cytochrome P450 (CYP)3A5 and cancer types maybe the main factors affecting this individual differences. The objective of our study was to establish a population pharmacokinetics (PK) model of apatinib in adult cancer patients, and to explore optimal dosage regimens for individualized treatment.. Adult patients with various types of cancer treated with apatinib were enrolled. The concentration of apatinib in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. CYP3A5 genotype was determined using TaqMan allelic discrimination technique. The population PK model was developed by NONMEM V7.4. The dosing regimen was optimized based on Monte Carlo simulations.. A population PK model of apatinib in adult cancer patient was established. CYP3A5 genotype and systemic cancer type (digestive system cancers, nondigestive system cancers) were the most significant covariates for PK parameters. Patients with CYP3A5*1 expressers (CYP3A5*1/*1 and CYP3A5*1/*3) had lower apparent clearance and apparent volume of distribution than patients who do not express CYP3A5*1 (CYP3A5*3/*3). Patients with nondigestive system cancer had higher apparent volume of distribution and absorption rate constant than digestive system cancer. The results of dose simulation suggest that the apatinib dose in patients who do not express CYP3A5*1 should be 33.33-50.00% higher than that in CYP3A5*1 expressers.. A population PK model of apatinib in adult cancer patients was established. CYP3A5 genotype and systemic cancer type had concurrent effects on PK parameters. CYP3A5 patients who do not express CYP3A5*1 required higher doses.

Topics: Adult; Cytochrome P-450 CYP3A; Genotype; Humans; Immunosuppressive Agents; Neoplasms; Pharmacogenetics; Pyridines; Tacrolimus

This study aimed to evaluate the underlying pharmacological mechanisms of Apatinib anti-bladder cancer via network pharmacology and experimental verification.. Network pharmacology was used to screen the possible signaling pathways of Apatinib in bladder cancer, and the most likely pathway was selected for in vitro validation. CCK-8 and colony formation assay were used to detect the effect of Apatinib on the proliferation of bladder cancer cells. Hoechst staining and flow cytometry detected apoptosis of bladder cancer cells induced by Apatinib. Western blot was performed to distinguish the effect of Apatinib on the expression levels of key targets.. Apatinib can affect many signaling pathways and the correlation of the PI3K-AKT signaling pathway was the greatest. In vitro experiments showed that Apatinib could inhibit bladder cancer cell proliferation, induce apoptosis, and up-regulate the expression of apoptosisrelated proteins Cleaved-PARP and down-regulate the expression of Bcl-2. Furthermore, Apatinib could decrease the protein expression of VEGFR2, P-VEGFR2, P-PI3K and P-AKT.. Apatinib could promote apoptosis of bladder cancer cells by inhibiting the VEGFR2- PI3K-AKT signaling pathway.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Neoplasms; Network Pharmacology; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction

The effectual clinical benefits of immune checkpoint inhibitor (ICI) are hampered by a high rate of innate resistance, and VEGFA may contribute to ICI treatment resistance. In this study, we endeavored to assess the tumor microenvironment (TME) in VEGFA-overexpressed human tumors and mouse tumor models, and to explore whether anti-angiogenesis therapy can overcome the innate resistance to ICI in hyperangiogenesis mouse tumor models and the underlying mechanism. Effect of VEGFA on clinical prognosis and TME was analyzed using TCGA data. The VEGFA-overexpressed mouse breast and colon subcutaneous models were established. PD-1 mAb or apatinib alone and combination therapy were used. Immunohistochemistry and immunofluorescence were used to assess angiogenesis and hypoxia. Flow cytometry, RNA sequencing and MCP-counter were applied to detect tumor immunomicroenvironment. High level of VEGFA mRNA in human tumors is related to poor prognosis and hypoxic, angiogenic and immunosuppressive TME. Upregulation of VEGFA increased the degree of malignancy of tumor cells in vitro and in vivo. VEGFA-overexpressed models were characterized by hypoxic, hyperangiogenic and immunosuppressive TME and indicated innate resistance to ICI. In tumor-bearing mice without VEGFA overexpression, the combination therapy had no synergistic anti-tumor effect compared to monotherapy. However, apatinib alleviated hyperangiogenesis and hypoxia in TME and converted the immunosuppressive TME into an immunostimulatory one in VEGFA-overexpressed tumors. Thus, anti-angiogenesis therapy could improve the efficiency of ICI in VEGFA-overexpressed tumors. Revealing whether there is hypervascularization in tumor tissues may help to clarify the adoption of anti-angiogenesis and ICI combination therapy or ICI monotherapy in cancer treatment.

Topics: Animals; B7-H1 Antigen; Cell Line, Tumor; Disease Models, Animal; Female; Humans; Immunity, Innate; Immunohistochemistry; Immunotherapy; Mice; Mice, Inbred BALB C; Neoplasms; Neovascularization, Pathologic; Prognosis; Programmed Cell Death 1 Receptor; Pyridines; Tumor Microenvironment; Vascular Endothelial Growth Factor A

Apatinib has been approved for the treatment of advanced gastric adenocarcinoma and gastric-esophageal junctional adenocarcinoma, but its efficacy is unknown for other advanced solid tumors.. We retrospectively reviewed the use of apatinib for multiple advanced-stage non-gastric cancers. Ninety-two patients from 7 hospitals who received additional treatment except apatinib more than once were enrolled.. The primary end-point was the overall response rate (ORR), and the secondary end-points included progression-free survival (PFS), disease control rate (DCR), overall survival, and adverse reactions. We categorized all the patients into six groups according to their cancer type.. In the lung cancer group, the ORR was 9% (95% confidence interval [CI], 3%-23%), DCR was 88% (95% CI, 74%-96%), and median PFS was 3 months (95% CI, 1.9-5.4 months). In the cervical cancer group, the ORR was 25% (95% CI, 3%-65%), DCR reached 100%, and median PFS was 3.5 months (95% CI, 0.6-9.0 months). There were different ORRs between the other cancer groups. In addition, the most common adverse effect of apatinib was palmar-plantar erythrodysesthesia syndrome (37%), followed by proteinuria (14%) and hypertension (13%).. These results suggest that apatinib might be effective for not only gastric cancer but also other carcinomas including lung cancer, colorectal cancer, cervical cancer, liver cancer, breast cancer, and nasopharyngeal cancer. Thus, apatinib is a promising targeted drug for multiple types of cancer.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neoplasms; Prognosis; Pyridines; Retrospective Studies; Survival Rate; Young Adult

In recent years, targeted therapy has received widespread attention. Among these therapies, anti-angiogenic targeted drugs have become one of the hotspots of research. Apatinib is a novel oral small molecule anti-angiogenic agent that has been clinically tested in a variety of solid tumours. The aim of this study was to investigate the efficacy of apatinib in patients with advanced malignant tumours and failure of standard therapy.. We collected 41 patients with advanced malignant tumours in our department; all tumours were pathologically confirmed as malignant. All patients received apatinib after failure of standard therapy: 500 mg/dose, one dose/d, orally 30 min after a meal, until progressive disease or intolerable adverse reactions occurred. When there was a second- or third-degree adverse reaction associated with apatinib during treatment, apatinib treatment could be suspended or reduced to 250 mg/dose. Clinical efficacy and progression-free survival were assessed according to RECIST1.1, and adverse reactions were observed.. Efficacy assessment was available for 31 patients with a median progression-free survival time of 2.66 months; the objective response rate and disease control rates were 16.1 and 64.5%, respectively. The disease control rates of the patients with lower Eastern Cooperative Oncology Group scores (1-2 points) and with fewer metastatic sites (< 3 sites) were higher than those of the patients with higher scores (3 points) and with more metastatic sites (≥3 sites), respectively (all P < 0.05). The most common adverse reactions were hypertension, neutropenia and hand-foot syndrome.. For patients with advanced malignant tumours with failure of standard therapy, administration of apatinib can still result in good efficacy. The efficacy of apatinib is better in patients with a higher performance status and lower degree of tumour progression.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Female; Humans; Male; Middle Aged; Neoplasms; Progression-Free Survival; Protein Kinase Inhibitors; Pyridines; Young Adult

Topics: Antineoplastic Agents; Humans; Neoplasms; Neovascularization, Pathologic; Pyridines; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2