Apatinib Administration Research Articles

Apatinib beyond first progression is associated with prolonged overall survival in patients with advanced breast cancer: Results from an observational study.

In the present study, the efficacy and safety of a low dose of apatinib in the treatment of patients with advanced breast cancer (ABC) in a real-world setting were assessed, the impact of continuous anti-angiogenic therapy beyond progression was determined and the factors associated with efficacy were evaluated. A total of 63 patients with ABC who were treated with apatinib and for whom several lines of treatment had failed were retrospectively analyzed in Tangshan People's Hospital (Tangshan, China) between January 2016 and October 2022. Apatinib was administered orally combined with chemotherapy, endocrine therapy, targeted therapy or monotherapy at a dose of 250 mg per day. Apatinib administration was continued in certain patients beyond first progressive disease (PD), and these patients were defined as the continued anti-angiogenic treatment beyond first progression (CABF) group, while those who discontinued apatinib were defined as the non-CABF group. In the evaluation of the first efficacy, the objective response rate was 33.3%. A total of 26 patients continued to receive apatinib post-first PD and were allocated to the CABF group. The median overall survival (OS) time of the 63 patients was 16 months. Log-rank univariate analysis revealed that the OS time was significantly associated with molecular subtype (P=0.014), CABF (P=0.004), and the neutrophil-to-lymphocyte ratio (NLR) (P=0.011). Multivariate Cox regression analysis revealed that being in the non-CABF group and a high NLR were independent risk factors for lower OS time (P=0.017 and P=0.041, respectively). These results support the continued administration of low-dose apatinib beyond progression and the use of NLR as an easily accessible prognostic marker in patients with ABC treated with apatinib.

Camrelizumab combined with apatinib for unresectable, metastatic esophageal squamous cell carcinoma: a single-center, single-arm, prospective study.

The prognosis for esophageal cancer (EC), a common malignant tumor, is poor. The new oral small-molecule tyrosine kinase inhibitor apatinib has shown an excellent therapeutic effect on treating EC. Camrelizumab is a humanized programmed death 1 (PD-1) inhibitor with high affinity. Immune checkpoint inhibitors combined with chemotherapy have become the standard first-line treatment for advanced EC. The new combination strategy of anti-angiogenic therapy combined with immunotherapy has great application prospects in the treatment of tumors. We aimed to assess camrelizumab in combination with apatinib as a new combination regimen for advanced or metastatic esophageal squamous cell carcinoma (ESCC). In this study, we recruited patients with an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, with pathologically confirmed unresectable, locally advanced, locally recurrent, or metastatic ESCC. Each patient received an intravenous infusion of camrelizumab 200 mg and oral administration of apatinib 250 mg once a day, every 21 days, as a cycle until disease progression, intolerance, or death. The primary endpoint was the objective response rate (ORR), while the Kaplan-Meier method and LIFETEST procedure were used to estimate survival functions for overall survival (OS) and progression-free survival (PFS). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used to evaluate adverse events. Between December 1, 2019 and July 31, 2022, 35 patients were enrolled, with 29 patients in the efficacy and safety analysis. The ORR was 34.5%, and the disease control rate (DCR) reached 82.8%. Median OS was 13.8 months (95% CI: 11.2-16.2), and the estimated 6-, 9-, and 12-month OS rates were 85.5% (95% CI: 65.7-94.3%), 80.9% (95% CI: 60.3-91.5%), and 67.0% (95% CI: 43.8-82.4%), respectively. Median PFS was 9.5 months (95% CI: 7.0-13.6). The most prominent grade ≥3 adverse events associated with treatments were alanine aminotransferase (ALT) increase (10.3%), hypertension (10.3%), and reactive cutaneous capillary endothelial proliferation (CCEP) (6.9%), and no deaths occurred due to adverse events. Among patients with advanced or metastatic ESCC, camrelizumab combined with apatinib showed a reasonable remission rate and survival benefit with a manageable safety profile.

TIPS-13 A PHASE II STUDY OF NEOADJUVANT CAMRELIZUMAB AND APATINIB IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMAS

Abstract BACKGROUND A single arm clinical trial (NCT04588987) about combination therapy of programmed cell death protein 1 blockades camrelizumab with antiangiogenic agent apatinib has been initiated to investigate their effectiveness for patients with recurrent high-grade Gliomas (HGG). METHODS Patients with recurrent HGG will receive single-dose intravenous injection of camrelizumab (200 mg) and daily oral administration of apatinib (250 mg/day for 7 days) 14 days before surgery for recurrent tumor. Sequential therapy will begin 2 weeks after surgery with the biweekly injection of camrelizumab and 4 weeks after surgery with the daily administration of apatinib. RESULTS Up to date (March 9, 2023), 18 patients are enrolled (13 for recurrent glioblastomas and 5 for anaplastic astrocytoma), with a medial follow-up time is 19 months. The median cycles of postoperative combination therapies were 4.5 cycles (95%CI: 3.87-5.12 ), with median progression-free survival of 4.0 months (95%CI: 2.78-5.28 ). One patient (1/18, 5.5%) discontinue the combination treatment because the patient often underwent the extended periods of hospitalization because of unacceptable liver dysfunction, and the other patient (1/18, 5.5%) withdraw the from the trail after receiving the surgery. All enrolled patients appeared one or more treatment-related adverse effects. The most common adverse effects were constipation(58%), hypertension (52%), leukocytopenia (52%), and nausea (47%). CONCLUSION the short-term results indicated that the combination therapy might be beneficial for patients with recurrent HGG and improve the patients’ overall survivals. We will present our detailed progress and results on the conference.

SYST-04 PRELIMINARY REPORT OF A CLINICAL TRIAL EVALUATING THE SAFETY AND EFFICIENCY OF NEOADJUVANT CAMRELIZUMAB AND APATINIB IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMAS: A PROSPECTIVE, PHASE II, SINGLE-ARM STUDY

High-grade glioma is the most common malignant primary brain tumor in the central nervous system. Multiple strategies such as surgery, radiotherapy, and chemotherapy have been used, but the prognosis of patients with high-grade glioma remains poor. No standard treatment exists for recurrent gliomas; however, combination therapies of programmed cell death protein 1 blockades with antiangiogenic agents have demonstrated promising effects in different solid tumors. We have initiated a clinical trial designed to evaluate the safety and efficiency of neoadjuvant therapy using camrelizumab and apatinib in patients with recurrent highgrade gliomas. In this prospective, Phase II, singlearm study, patients with recurrent highgrade gliomas will receive singledose intravenous injection of camrelizumab (200 mg) and daily oral administration of apatinib (250 mg/day for 7 days) 14 days before surgery for recurrent tumor. Sequential therapy will begin 2 weeks after surgery with the biweekly injection of camrelizumab and 4 weeks after surgery with the daily administration of apatinib. Treatment of camrelizumab and apatinib will be continued until disease progression or unacceptable toxicity or death. The trial is planned to enroll 30 patients. Up-to date (March 31, 2022), 12 patients had been enrolled, in which, 9 were GBM. Three patients died, while 4 cases on trial more than 6 months, the longest already 1 year. Although an evaluation is still impossible to be conducted yet, some patients have shown a promising outcome. We will present updated results on the meeting. These preliminary data suggest that this study would be worthwhile. This study was approved by the Ethics Committee of Sun Yatsen University Cancer Center (Guangzhou, China; approval No. SLB202014901). This study was registered with ClinicalTrials.gov under identifier NCT04588987.

RHO KINASE BLOCKADE ALLEVIATE BLOOD PRESSURE ELEVATION AND INHIBIT VASCULAR REMODELING IN APATINIB-INDUCED HYPERTENSION TO BE CONFERMED

Objective: Hypertension is one of the major adverse effects of tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factors. However, the mechanism underlying TKIs-induced hypertension remains unclear. Here, we evaluated BP responses at different doses of apatinib, a TKI used for anti-tumor therapy, in normotensive Wistar–Kyoto rats. Furthermore, we explored the role of the RhoA/Rho kinase (ROCK) emodellin pathway in elevation of blood pressure (BP) induced by apatinib, a selective TKI approved in China for treatment of advanced or metastatic gastric cancer. A non-specific ROCK inhibitor, Y27632, was then combined with apatinib and its efficacy in alleviating apatinib-induced hypertension was evaluated. Design and method: Normotensive female Wistar–Kyoto rats were exposed to two different doses of apatinib, or apatinib combined with Y27632, or vehicle for two weeks. BP was monitored by a tail-cuff plethysmography system. The mRNA levels and protein expression in the RhoA/ROCK pathway were determined, and vascular emodelling assessed. Results: Administration of either a high or low dose of apatinib was associated with a rapid rise in BP, reaching a plateau after 12 days. Apatinib treatment mediated upregulation of RhoA and ROCK 2 in the mid-aorta, more significant in the high dose group. However, ROCK1 expression showed no statistically significant differences. Furthermore, the mRNA level of GRAF3 decreased dose-dependently. Apatinib administration was also associated with decreased levels of MLCP, and elevated endothelin-1 (ET-1) and collagen 1, which was accompanied with increased mid-aortic media. However, treatment with Y27632 attenuated the above changes. Conclusions: Results of the present study indicated that apatinib treatment increased BP and promoted vascular emodelling by activating the RhoA/ROCK emodellin pathway. However, Y27632, a non-specific ROCK inhibitor, reversed apatinib-induced increase in BP and vascular emodelling. Therefore, RhoA/ROCK activation could be the underlying mechanism of apatinib-induced hypertension, while ROCK inhibitors could be potential therapeutic drugs.

Initial or salvage treatment with apatinib shows promise against radioiodine-refractory differentiated thyroid carcinoma.

ObjectiveSorafenib and lenvatinib have been recommended as standard tyrosine kinase inhibitors (TKIs) for progressive radioiodine-refractory differentiated thyroid carcinoma (RR-DTC). However, their efficacy remains limited with unresolved drug resistance. Therefore, we conceived this open-label study based on real-world evidence to investigate the efficacy and safety of apatinib in patients with progressive RR-DTC.MethodsOff-label use of apatinib as either initial treatment or salvage treatment for sorafenib resistance was investigated. The primary endpoint was progression-free survival (PFS) and the secondary endpoints included objective response rate (ORR), overall survival (OS), and safety.ResultsFor all 28 enrolled patients, the median PFS was 15.1 months, with an ORR of 69.6%. The median OS was not reached at the data cut-off. In detail, the median PFS of 17.3 months and the ORR of 75% were determined in patients with TKI-naive RR-DTC (initial treatment group, n = 14). And, in patients with first-line sorafenib-resistant RR-DTC (salvage treatment group, n = 14), a median PFS of 12.0 months was reached, with an ORR of 45.5%. In the salvage treatment group, the median OS from the start of apatinib administration was 20.6 months, reaching 89.1 months from sorafenib treatment initiation. Adverse events at grade 3 or higher occurred in 64.3% of all subjects treated with apatinib.ConclusionsThis study demonstrated that apatinib shows promise against RR-DTC with tolerable toxicity, representing a novel initial treatment for progressive RR-DTC and effective salvage treatment for RR-DTC resistant to sorafenib.

Initial report of a clinical trial evaluating the safety and efficiency of neoadjuvant camrelizumab and apatinib in patients with recurrent high-grade gliomas: A prospective, phase II, single-arm study

Background and Aim: High-grade glioma is the most common malignant primary brain tumor in the central nervous system. Multiple strategies such as surgery, radiotherapy, and chemotherapy have been used, but the prognosis of patients with high-grade glioma remains poor. No standard treatment exists for recurrent gliomas; however, combination therapies of programmed cell death protein 1 blockades with antiangiogenic agents have demonstrated promising effects in different solid tumors. Therefore, since the end of 2020, a clinical trial designed to evaluate the safety and efficiency of neoadjuvant therapy using camrelizumab and apatinib in patients with recurrent high-grade gliomas has been carried out in our institution. Methods/Design: In this prospective, Phase II, single-arm study, patients with recurrent high-grade gliomas will receive single-dose intravenous injection of camrelizumab (200 mg) and daily oral administration of apatinib (250 mg/day for 7 days) 14 days before reoperation for tumor resection. Sequential therapy will begin 2 weeks after surgery with the biweekly injection of camrelizumab and 4 weeks after surgery with the daily administration of apatinib. Treatment of camrelizumab and apatinib will be continued until disease progression or unacceptable toxicity or death. The primary outcome measure will be the median overall survival rate. Secondary outcome measures will include progression-free survival rate at 6 months and at 12 months and other measures. The trial is planned to enroll 30 patients. This study was approved by the Ethics Committee of Sun Yat-sen University Cancer Center (Guangzhou, China; approval No. SL-B2020-149-01) on July 27, 2020. Results and Conclusions: Although an evaluation is still impossible to be conducted yet, 11 patients had been enrolled by the end of January 2022. Some patients have shown a promising outcome. These preliminary data suggest that this study would be worthwhile. We hope that this study will provide scientific evidence to better care of patients with recurrent high-grade glioma. Trial registration: This study was registered with ClinicalTrials.gov under identifier NCT04588987 on October 19, 2020.

Rho kinase inhibition ameliorates vascular remodeling and blood pressure elevations in a rat model of apatinib-induced hypertension.

Objectives:Hypertension is one of the major adverse effects of tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factors. However, the mechanism underlying TKIs-induced hypertension remains unclear. Here, we explored the role of the RhoA/Rho kinase (ROCK) signaling pathway in elevation of blood pressure (BP) induced by apatinib, a selective TKI approved in China for treatment of advanced or metastatic gastric cancer. A nonspecific ROCK inhibitor, Y27632, was then combined with apatinib and its efficacy in alleviating apatinib-induced hypertension was evaluated.Methods:Normotensive female Wistar–Kyoto rats were exposed to two different doses of apatinib, or apatinib combined with Y27632, or vehicle for 2 weeks. BP was monitored by a tail-cuff plethysmography system. The mRNA levels and protein expression in the RhoA/ROCK pathway were determined, and vascular remodeling assessed.Results:Administration of either a high or low dose of apatinib was associated with a rapid rise in BP, reaching a plateau after 12 days. Apatinib treatment mediated upregulation of RhoA and ROCK II in the mid-aorta, more significant in the high-dose group. However, ROCK I expression showed no statistically significant differences. Furthermore, the mRNA level of GRAF3 decreased dose-dependently. Apatinib administration was also associated with decreased levels of MLCP, and elevated endothelin-1 (ET-1) and collagen I, which were accompanied with increased mid-aortic media. However, treatment with Y27632 attenuated the above changes.Conclusion:These findings suggest that activation of the RhoA/ROCK signaling pathway could be the underlying mechanism of apatinib-induced hypertension, while ROCK inhibitor have potential therapeutic value.

Clinical effectiveness of apatinib at different doses in patients with advanced gastric cancer as the third-line or further treatment: Results from a post-marketing phase IV study.

e16037 Background: Apatinib, a highly selective VEGFR2 inhibitor, has shown a clinical benefit as third-line or further-line treatment in patients with gastric cancer in a randomized phase III study with the initial dose of 850mg. However, the study was conducted in a small scale (n = 267) under standardized conditions. Here, we assessed exposure and effectiveness of apatinib at different doses using data collected from a post-marketing phase IV study that included a broader patient population with a larger sample size. Methods: Patients with advanced or metastatic advanced gastric cancer or gastroesophageal junction adenocarcinoma who were aged 18-75 with ECOG performance status of 0-2 and failed at least two lines of chemotherapy were enrolled. Apatinib was recommended with an initial dose of 850 mg q.d orally, while the initial dose was determined at the discretion of the investigators. Administration of apatinib regarding the initial dose, duration of treatment, dose modification, average daily exposure dose (ADED) and its effect on progression-free survival (PFS) and overall survival (OS) were analyzed. Results: A total of 2004 patients were included in the intention-to-treat population. The median age was 59 (range, 19-85) years, 71.8% of patients were male, 84.2% had ECOG performance status of 0-1; 96.4% had stage IV disease, and 98.8% had metastases, among which 34.2% with more than 2 metastases. Five patients did not receive therapy. Compared to 5.5% of patients with the initial dose > 500mg, 94.1% was given at the initial dose≤500mg; 8.6% had ADED > 500mg and 91.1% had ADED ≤500mg. The median duration of treatment was 56 days. Treatment interruption and discontinuation, and dose reduction occurred in 34.4%, 24.5%, and 13.7% of patients due to adverse events, respectively. Survival analyses in the initial dose ≤500mg/ > 500mg subgroups showed median PFS of 2.6 months (95%CI 2.20-2.79) vs 2.7 months (95% CI 1.91-3.32), median OS of 5.6 months (95% CI 5.26-5.95) vs 5.9 months (95% CI 4.40-6.87). In the ADED ≤500mg/ > 500mg subgroups, the median PFS was 2.6 months (95% CI 2.14-2.76) vs 3.0 months (95% CI 2.27-3.61), and median OS was 5.7 months (95% CI 5.32-6.08) vs 6.1 months (95% CI 5.36-7.72). Conclusions: In conclusion, more than 90% of the patients received a lower dose regimen, which indicate dosage of 500mg or lower is a tolerated exposure. Furthermore, dose at 500mg or lower produced similar efficacy to that more than 500mg. Clinical trial information: NCT02426034.

Apatinib in patients with recurrent or metastatic adenoid cystic carcinoma of the head and neck: a single-arm, phase II prospective study.

Background:Apatinib, a vascular endothelial growth factor receptor (VEGFR) blocker, has demonstrated encouraging antitumor activities and tolerable toxicities in various cancer types. Recurrent or metastatic adenoid cystic carcinoma of the head and neck (R/MACCHN) carries a poor prognosis, and treatment options are currently limited. This study was conducted to explore the antitumor activity and safety of apatinib in patients with R/MACCHN.Methods:In this phase II single-arm, prospective study, patients aged 15–75 years with incurable R/MACCHN received apatinib at a 500 mg dose once daily until intolerance or progression occurred. The primary endpoint was the 6-month progression-free survival (PFS) rate based on RECIST version 1.1. The secondary endpoints included response rate, overall survival (OS), and safety. Efficacy was assessed in all dosed patients with at least one post-baseline tumor assessment.Results:Among 68 patients treated with apatinib, 65 were evaluable for efficacy analysis, with a median follow-up time of 25.8 months. The 6-month, 12-month, and 24-month PFS rates were 92.3% [95% confidence interval (CI): 83–97.5%], 75.2% (95% CI: 61.5–84.0%) and 44.7% (95% CI: 32.3–57.5%), respectively. The objective response rate (ORR) and disease control rate (DCR), as assessed by investigators, were 46.2% (95% CI: 33.7–59.0%) and 98.5% (95% CI: 91.7–100.0%), respectively. The median duration of response was 17.7 months [interquartile range (IQR) 14.0–20.9]. The 12-month and 24-month OS rates were 92.3% (95% CI: 83.0–97.5%) and 82.3% (95% CI: 70–90.4%), respectively. The most common adverse events of grades 3–4 were hypertension (5.9%), proteinuria (9.2%), and hemorrhage (5.9%). One patient developed a fatal hemorrhage.Conclusion:An encouraging PFS, a high ORR, and a manageable safety profile were observed in this study. It seems that the administration of apatinib in R/MACCHN is likely to have a clinically meaningful therapeutic benefit and warrants further investigation.This study was prospectively registered in ClinicalTrials.gov (NCT02775370; date of registration: 17 May 2016; date of first patient enrollment: 25 May 2016)

Apatinib in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma of the Head and Neck: A Single-Arm, Phase II Study

Background: Apatinib, a vascular endothelial growth factor receptor (VEGFR) blocker, has demonstrated encouraging antitumor activities and tolerable toxicities in various types of cancer. Recurrent or metastatic adenoid cystic carcinoma of the head and neck (R/MACCHN) carries a poor prognosis, and treatment options are currently limited. The high VEGFR expression in R/MACCHN makes antiangiogenesis a potential effective treatment in patients with R/MACCHN. This study was conducted to explore the antitumor activity and safety of apatinib in patients with R/MACCHN. Methods: In this phase II single-arm, prospective study, patients aged 15-75 years with incurable R/MACCHN received apatinib at a dose of 500 mg once daily until intolerance or progression occurred. The primary endpoint was the 6-month progression-free survival (PFS) rate, which was based on RECIST version 1·1. The secondary endpoints included response rate, overall survival (OS) and safety. Efficacy was assessed in all dosed patients with at least one post-baseline tumor assessment. Findings: Among 68 patients treated with apatinib, 65 were evaluable for efficacy analysis, with a median follow-up time of 25·8 months. The 6-month, 12-month and 24-month PFS rates were 92·3% (95% confidence interval [CI]: 83–97·5%), 75·2% (95% CI: 61·5-84·0%) and 44·7% (95% CI: 32·3-57·5%), respectively. The objective response rate (ORR) and disease control rate (DCR), as assessed by investigators, were 46·2% (95% CI: 33·7–59·0%) and 98·5% (95% CI: 91·7–100·0%), respectively. The median duration of response was 17·7 months (interquartile range [IQR], 14·0-20·9). The 12-month and 24-month OS rates were 92·3% (95% CI: 83·0-97·5%) and 82·3% (95% CI: 70-90·4%), respectively. The most common adverse events of grades 3–4 were hypertension (5·9%), proteinuria (9·2%) and hemorrhage (5·9%). One patient developed a fatal hemorrhage. Interpretation: An encouraging PFS, a high ORR and a manageable safety profile were observed in this study. It seems that the administration of apatinib in R/MACCHN is likely to have a clinically meaningful therapeutic benefit and warrants further investigation. Trial Registration: Registered under http://www.clinicaltrials.gov (NCT02775370) Funding Statement: This work was supported by Shanghai Municipal Commission of Health and Family Planning (grant number 201640158)；the Clinical Research Program of 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine and the Shanghai Shenkang Hospital Development Center Refractory Diseases Project (project number 16CR2004A); Clinical Research Program of 9th People's Hospital, Shanghai Jiao Tong University School of Medicine (program number JYLJ201825). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This investigator-initiated phase II study was approved by the ethics committee of Shanghai Ninth People’s Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, and performed according to Good Clinical Practice Guidelines. All patients provided written informed consent before enrollment.

Apatinib attenuates phenotypic switching of arterial smooth muscle cells in vascular remodelling by targeting the PDGF Receptor-β.

Apatinib (YN968D1) is a small‐molecule tyrosine kinase inhibitor（TKI）which can inhibit the activity of vascular endothelial growth factor receptor‐2 (VEGFR‐2). It has been reported that apatinib has anti‐tumour effect of inhibiting proliferation and inducing apoptosis of a variety of solid tumour cells, whereas its effect on vascular smooth muscle cells (VSMC) remains unclear. This study investigated the effect of apatinib on phenotypic switching of arterial smooth muscle cells in vascular remodelling. Compared to the vehicle groups, mice that were performed carotid artery ligation injury and treated with apatinib produced a reduction in abnormal neointimal area. For in vitro experiment, apatinib administration inhibited VSMC proliferation, migration and reversed VSMC dedifferentiation with the stimulation of platelet‐derived growth factor type BB (PDGF‐BB).In terms of mechanism, with the preincubation of apatinib, the activations of PDGF receptor‐β (PDGFR‐β) and phosphoinositide‐specific phospholipase C‐γ1 (PLC‐γ1) induced by PDGF‐BB were inhibited in VSMCs. With the preincubation of apatinib, the phosphorylation of PDGFR‐β, extracellular signal‐related kinases (ERK1/2) and Jun amino‐terminal kinases (JNK) induced by PDGF‐BB were also inhibited in rat vascular smooth muscle cell line A7r5. Herein, we found that apatinib attenuates phenotypic switching of arterial smooth muscle cells induced by PDGF‐BB in vitro and vascular remodelling in vivo. Therefore, apatinib is a potential candidate to treat vascular proliferative diseases.

An Oral Small Molecule VEGFR2 Inhibitor, Apatinib, in Patients with Recurrent or Refractory Cervical Cancer: A Real World Study.

To evaluate the efficacy and safety of apatinib, an oral antiangiogenic drug, in patients with recurrent or refractory cervical cancer as salvage treatment, we retrospectively analyzed the medical records of recurrent or refractory cervical cancer patients admitted to the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Hunan Cancer Hospital, from October 1, 2016, to December 31, 2017. Patients who progressed within 6 months after the last treatment were given apatinib orally at a dose of 250 mg daily until disease progression or unacceptable toxicity. Twenty-nine patients were enrolled in our retrospective study. Up to February 1, 2019, the median follow-up time was 18 months. The median progression-free survival was 128 days (95% confidence interval (CI): 20–540 days), and the median overall survival was 9 months (95% CI: 4–23 months). The longest period of apatinib administration was 540 days. No complete response was observed, 5 (17.2%) patients achieved partial response, and 11 (37.9%) achieved stable disease. The objective response rate and disease control rate were 17.2% and 55.1%, respectively. The most common adverse events were hypertension (G1, 65.5%, 19/29), mucositis (G1, 55.2%, 16/29), hand-foot syndrome (G1-2, 44.8%, 13/29), and proteinuria (G1-2, 20.7%, 6/29). Grade 3 proteinuria occurred in only one patient (3.4%, 1/29). Apatinib single-agent use might be an effective and tolerable choice as salvage therapy for patients with recurrent or refractory cervical cancer.

Apatinib prevents natural killer cell dysfunction to enhance the efficacy of anti-PD-1 immunotherapy in hepatocellular carcinoma.

Apatinib, a selective vascular endothelial growth factor receptor 2-tyrosine kinase inhibitor, has demonstrated activity against a wide range of solid tumors, including advanced hepatocellular carcinoma (HCC). Preclinical and preliminary clinical results have confirmed the synergistic antitumor effects of apatinib in combination with anti-programmed death-1 (PD-1) blockade. However, the immunologic mechanism of this combination therapy remains unclear. Here, using a syngeneic HCC mouse model, we demonstrated that treatment with apatinib resulted in attenuation of tumor growth and increased tumor vessel normalization. Moreover, our results indicated that natural killer cells, but not CD4+ or CD8+ T cells mediated the therapeutic efficacy of apatinib in HCC mouse models. As expected, the combined administration of apatinib and anti-PD-1 antibody into tumor-bearing mice generated potent immune responses resulting in a remarkable reduction of tumor growth. Furthermore, increased interferon-γ and decreased tumor necrosis factor-α and interleukin-6 levels were observed, suggesting the potential benefits of combination therapy with PD-1 blockade and apatinib in HCC.

<p>Effects of Apatinib on the Pharmacokinetics of Nifedipine and Warfarin in Patients with Advanced Solid Tumors</p>

Background and PurposeApatinib 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.MethodsA 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.ResultsCompared with the single oral administration, coadministration with apatinib contributed to the significant increases of AUC0–48h and Cmax of nifedipine by 83% (90% confidence interval [CI] 1.46–2.31) and 64% (90% CI 1.34–2.01), respectively. Similarly, coadministration with apatinib contributed to the significant increases of AUC0-t and Cmax of S-warfarin by 92% (90% CI 1.68–2.18) and 24% (90% CI 1.10–1.39), respectively.ConclusionConcomitant 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.

The suppressing effects of VEGF-mediated angiogenesis at different administration sequences of apatinib and transarterial embolization in vivo.

BackgroundTo investigate the suppressing effects of vascular endothelial growth factor (VEGF)-mediated angiogenesis at different treatment schedules by applying apatinib combined with transarterial embolization (TAE).MethodsForty ideal liver cancer rat models were randomly divided into four groups based on different administration methods of apatinib [control group (CG): TAE only; Combined Group 1 (CG1): apatinib administration 3 days pre-TAE; Combined Group 2 (CG2): apatinib administration simultaneously with TAE; Combined Group 3 (CG3): apatinib administration 3 days post-TAE]. The characteristics of liver cancer, the expression of VEGF and microvascular density (MVD) as determined by CD34, and the overall survival (OS) were compared among the groups.ResultsThe tumor sizes of the liver on the 10th day after treatment were significantly larger when compared to the baseline sizes (P<0.05), and tumor growth in the combined groups was significantly slower than that of CG (P<0.05). The OS of rats was significantly different between the combined groups and control group (P<0.05), which were 19.9±3.21, 31.2±6.48, 27.1±5.59, and 25.9±6.06 days in groups CG, CG1, CG2 and CG3, respectively. Significant differences were observed between groups CG1 and CG3. The expression levels of VEGF in groups CG1, CG2 and CG3 were 45.6±9.88, 70.8±14.11 and 75.3±9.82, and were significantly lower than that in control groups (85.8±11.26). The MVD in CG (109.7±10.32) reached the peak value when compared to those in the three combined groups (46.4±19.22, 75.7±15.97, and 90.5±12.71, all P<0.05). Furthermore, overexpression of VEGF and MVD showed significant positive correlation with poor OS.ConclusionsThese findings demonstrated that apatinib treatment enhanced anti-tumor effects of TAE via reducing tumor angiogenesis, suppressing tumor growth, and prolonging the OS of rats with liver tumors. Early administration of apatinib showed better therapeutic effects.

Apatinib-loaded CalliSpheres Beads for embolization in a rabbit VX2 liver tumor: characterization in vitro, pharmacokinetics and tumor response in vivo

Apatinib mesylate is an oral antiangiogenic agent that can inhibit activation of vascular endothelial growth factor receptor-2 tyrosine kinase. However, its therapeutic use in liver cancer is restricted due to severe systemic toxicity. Our work aimed to construct apatinib-loaded CalliSpheres Beads (CBAPA) and investigate its application in transarterial chemoembolization (TACE) of liver cancer. The established stock solution containing 20, 40 or 60 mg apatinib were fully mixed with 100–300 μm CalliSpheres Beads (CB) for 2 hours, respectively. The highest loading efficiency at 30 min after combination in 20 mg group (maximum 70.7%). Further, apatinib can be steadily released from CBAPA in vitro release test. For pharmacokinetics and tumor response in vivo, sixty New Zealand white rabbits with VX2 liver tumor were assigned into four groups: sham (NS) group, apatinib solution alone (APA) group, CB group and CBAPA group. Apatinib was measured in plasma and liver tissue by high performance liquid chromatography–tandem mass spectrometry. Compared to APA group, the administration of apatinib by TACE with CBAPA resulted in low systemic concentration. In addition, intratumoural apatinib concentration was higher than adjacent hepatic parenchyma in the CBAPA group. Compared to other three groups, CBAPA group achieved lower tumor growth rate and improved survival time. In conclusion, these findings provide a basis for the potential application of apatinib-loaded CalliSpheres Beads in liver cancer.

Application effect of apatinib in patients with failure of standard treatment for advanced malignant tumours

BackgroundIn 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.MethodsWe 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.ResultsEfficacy 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.ConclusionFor 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.

Safety and Efficacy of Drug-Eluting Bead Transarterial Chemoembolization Combined with Apatinib in Patients with Advanced Hepatocellular Carcinoma

The goal of this study was to determine the clinical efficacy and safety of drug-eluting bead (DEB) transarterial chemoembolization (TACE) in combination with apatinib administration in patients with advanced hepatocellular carcinoma (HCC). From December 2015 to May 2017, a total of 32 patients with advanced HCC treated with DEB-TACE combined with apatinib were consecutively enrolled in this study. The treatment response and laboratory outcomes were assessed at the first- and third month after DEB-TACE therapy. Overall survival, progression-free survival, and adverse events were also analyzed and assessed. The objective response rate and disease control rate were 62.5% and 96.9% at the first month after treatment, respectively. At the third month after the first therapy, a slightly higher objective response rate (68.8%) and lower disease control rate (90.6%) were achieved. There were no differences in the levels of aspartate aminotransferase, alanine aminotransferase, serum albumin, or total bilirubin at M1 or M3 compared to M0 (all p> 0.05) The median progression-free survival was 9.5 months (95% confidence interval, 8.1-10.9 months), and the median overall survival was 22.0 months (95% confidence interval, 20.2-23.9 months). Among the 32 patients, 2 had hypertension and 1 had grade 3 diarrhea; the rest of the patients had mild to moderate adverse reactions that were acceptable, and no serious adverse reactions occurred. DEB-TACE combined with apatinib is a safe and promising treatment approach for patients with advanced HCC.

Apatinib exerts anti-tumor activity to non-Hodgkin lymphoma by inhibition of the Ras pathway

Apatinib is a tyrosine kinase inhibitor that selectively targets vascular endothelial growth factor receptor-2 (VEGFR-2). Although apatinib has shown promising anti-tumor activity against several types of tumor, its role and underlying mechanism against non-Hodgkin lymphoma (NHL) remain to be explored. Here, we report that apatinib dramatically inhibited in vitro the proliferation of various human NHL cell lines, including Burkitt lymphoma (BL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL), in a dose-dependent manner. Moreover, administration of apatinib markedly delayed tumor growth in vivo in a xenograft mouse model derived from human DLBCL OCI-ly3 cells, in association with significantly prolonged survival of tumor-bearing mice. Mechanistically, apatinib suppressed activation of VEGFR2 (manifested by reduced VEGFR2 phosphorylation), accompanied by inhibition of the Ras pathway (reflected by down-regulation Ras, Raf, pMEK1/2, pERK1/2) in OCI-ly1 (GCB subtype of DLBCL) and SU-DHL2 (ABC subtype of DLBCL) cells. Of note, apatinib sharply impaired angiogenesis in vivo in tumor tissues. Together, these results indicate that apatinib displays a marked cytotoxic activity against various types of NHL cells (including BL, MCL, and GCB- or ABC-DLBCL) both in vitro and in vivo. They also suggest that anti-NHL activity of apatinib might be associated with inhibition of tumor cell growth and induction of apoptosis as well as anti-angiogenesis by targeting VEGFR2 and its downstream Ras/Raf/MEK/ERK pathway.