Establishment and validation of a population pharmacokinetic model for apatinib in patients with tumors.

OBJECTIVE: This study aimed to develop a population pharmacokinetic (PPK) model for oral apatinib in Chinese oncology patients and investigate the factors influencing the pharmacokinetics of apatinib. METHODS: We gathered 199 blood concentration monitoring data points from 91 inpatient oncology participants receiving oral apatinib at the Third Affiliated Hospital of Soochow University. Covariates, such as age, gender, body weight, and indices of liver and renal function, were examined to assess their influence on the pharmacokinetic parameters of apatinib. The PPK model was developed using the nonlinear mixed-effects modeling procedure (NONMEM), and model validation was conducted using the bootstrap method and normalized prediction distribution error (NPDE) method. RESULTS: The structural model adopted a one-compartment structure with first-order elimination. Notably, aspartate aminotransferase (AST) and the co-administered drug type emerged as primary covariates affecting apatinib clearance (CL/F). The finalized model was expressed as CL/F (L/h) = 56.7 × (AST/26.6)-0.298 × Î¸, when apatinib was combined with monoclonal antibodies, θ was 1; when combined with paclitaxel, θ was 0.58; when combined with other drugs (e.g., platinum, capecitabine, or the combination of tegafur, gimeracil, and oteracil potassium), θ was 1.60; When used as monotherapy, θ was 1.38. V/F = 674 L, and the absorption rate constant (Ka) was fixed at 0.08 h-1. Bootstrap results affirmed the model's reliability and stability, while NPDE outcomes attested to the model's fit. CONCLUSION: Our study successfully established a PPK model for apatinib in oncology patients, revealing that liver function status and co-administered drug types significantly impacted apatinib CL/F. This finding underscored the potential necessity for dose adjustments to optimize efficacy, particularly in patients undergoing different chemotherapy regimens involving apatinib.

EGCG enhances antitumor effect of apatinib in nonsmall cell lung cancer by targeting VEGF signaling to inhibit glycolysis.

Nonsmall cell lung cancer (NSCLC), one of the most aggressive malignancies globally, is characterized by poor prognosis and limited life expectancy. Epigallocatechin-3-gallate (EGCG), a natural polyphenol found in green tea, has emerged as a promising anticancer agent due to its potent antitumor properties. However, the role and the underlying mechanisms of EGCG in NSCLC remain poorly understood. Hence, this research aimed to explore the effect of EGCG on the antitumor effect of apatinib in NSCLC through vascular endothelial growth factor (VEGF)-regulated glycolysis. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine staining, wound healing, transwell, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and flow cytometry assays were carried out to evaluate the proliferation, migration, invasion, and apoptosis of H1299 cells, respectively. Furthermore, western blot analysis was used to detect the expressions of VEGF, p-vascular endothelial growth factor receptor-2, hypoxia-inducible factor 1α, neuropilin-1, phosphorylated-phosphatidylinositol 3-kinase, and phosphorylated-AKT. The transfection efficiency of H1299 cells with VEGF overexpression plasmid was also assessed by western blot analysis. Glycolysis was analyzed by estimating extracellular acidification rate, lactate concentration, glucose uptake, and the expressions of lactate dehydrogenase A, pyruvate kinase M2, and hexokinase 2. The results demonstrated that VEGF activated glycolysis in NSCLC cells. EGCG alone and apatinib alone or in combination inhibited cell viability, proliferation, invasion, migration, and glycolysis whereas promoted apoptosis in NSCLC cells. EGCG regulated glycolysis levels in NSCLC through VEGF overexpression, and enhanced the antitumor effect of apatinib in NSCLC through VEGF-regulated glycolysis. Taken together, EGCG strengthened the protective effects of apatinib in NSCLC through glycolysis mediated by VEGF.

Targeting the VEGFR2 signaling pathway for angiogenesis and fibrosis regulation in neovascular age-related macular degeneration.

Neovascular age-related macular degeneration (nAMD) is characterized by abnormal blood vessel growth from the choroid, leading to complications and eventual blindness. Despite anti-VEGF therapy, subretinal fibrosis remains a major concern, as VEGF/VEGF receptor-2 (VEGFR2) signaling can contribute to both angiogenesis and fibrosis. For the identification of the aqueous humor proteome, we performed liquid chromatography with tandem mass spectrometry analysis. To investigate the potential therapeutic effects of targeting the VEGF signaling pathway using apatinib, a highly selective VEGFR2 tyrosine kinase inhibitor, this study employed in vitro (THP-1 conditioned media-treated ARPE-19 cells) and in vivo (laser-induced choroidal neovascularization mouse) models of nAMD. This study revealed elevated VEGFR2 protein levels in the aqueous humor of nAMD patients, suggesting a potential target to mitigate neovascularization and fibrosis in nAMD. Apatinib effectively reduced VEGFA and αSMA levels in both in vitro and in vivo models. Moreover, apatinib showed improvement in laser-induced subretinal hyper-reflective lesions. The action mechanism was linked to the inhibition of VEGFR2 activation, leading to the suppression of both angiogenesis and fibrosis through the downregulation of STAT3 phosphorylation. Therefore, the VEGFR2 signaling pathway appears to play a central role in the development of nAMD by regulating both angiogenesis and fibrosis.

Apatinib monotherapy for early non-small cell lung cancer: a case report.

Stage I non-small cell lung cancer (NSCLC) accounts for about 15% of incident cancer cases. Prognosis is poor, with a metastasis and recurrence rate of 38% within 2 years of surgery and an overall 5-year survival rate of 54-60%. Here, we report successful apatinib monotherapy of early NSCLC in a patient who had declined surgery, radiofrequency ablation, and immunotherapy. The patient received apatinib for 64 months without clinical, laboratory, or radiographic evidence of disease progression. The curative effect was judged to be stable and safe.The role of apatinib as monotherapy for patients with early stage NSCLC who are not candidates for surgery or radiotherapy, or as an adjunct to standard therapy, deserves further study.

Disitamab vedotin combined with apatinib in gastric cancer: A case report and review of literature.

BACKGROUND: In patients with human epidermal growth factor receptor 2 (HER2)-overexpressing gastric cancer (GC), the combination of HER2 targeting and a standard first-line chemotherapy regimen has been demonstrated to significantly improve their prognosis. However, in a proportion of patients, cancer progresses within a short period of time, and there is currently no standard treatment after disease progression. CASE SUMMARY: This study presents a case of a 51-year-old male with advanced GC who underwent radical resection (Billroth type II subtotal gastrectomy and gastrojejunostomy) and resection of liver metastases. Immunohistochemical staining revealed a HER2 score of 2+, a dMMR status, and a Ki67 proliferation index of 30% to 40%. The gene test results indicated the presence of ERBB2 amplification and a PD-L1 expression level of less than 5%. Since December 2021, the patient has experienced disease progression during both first-line (two cycles of KN026 combined with KN046) and second-line (five cycles of nivolumab combined with trastuzumab and SOX chemotherapy) treatment regimens. The patient's prognosis following the first and second lines of treatment was unfavorable, with progression occurring in a relatively short time. For third-line therapy, disitamab vedotin (RC48) plus apatinib was used. At the time of this report, the patient had achieved a progression-free survival (PFS) of 25.8 months, which exceeded the median survival time for patients with advanced GC. CONCLUSION: Despite the unfavorable prognosis associated with advanced GC, the implementation of personalized treatment approaches may still prove beneficial for select patients. In patients with HER2-positive GC with extensive metastatic involvement, the use of the HER2-targeted combination with apatinib has demonstrated the potential to prolong both PFS and overall survival.

A Phase II Clinical Study on Apatinib Plus Vinorelbine in Refractory HER2-Negative Breast Cancer and its Metabolic Implications of Drug Resistance.

BACKGROUND: Apatinib, a tyrosine-kinase inhibitor that targets the vascular endothelial growth factor receptor 2, contributes to the inhibition of angiogenesis. Vinorelbine, a semisyn-thetic vinca alkaloid, primarily inhibits metaphase mitosis of cancer cells through its interactions with tubulin. This study aimed to evaluate whether apatinib combined with vinorelbine was ef-fective and safe for refractory human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients who failed taxanes and/or anthracycline and analyze the possible mechanism of drug resistance through metabolomic analysis. METHODS: Eligible patients were HER2-negative, inoperable, locally advanced, or metastatic breast cancer patients who progressed after at least one chemotherapy regimen in this present prospective phase II study. Patients took oral apatinib (250-500 mg/day) plus intravenous infusion of vinorelbine (25 mg/m2 on day 1, day 8 at 3-week intervals). Objective response rate (ORR) was our primary endpoint, while disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and toxicity were our secondary endpoints. The exploratory purpose was to identify biomarkers or drug resistance mechanisms through metabolomics changes before and after the combination therapy. RESULTS: Between September, 2019 and June, 2022, a total of 34 patients were included. ORR and DCR were 32.4% (11/34) and 85.3% (29/34), respectively. The median PFS was 5.0 months (95% CI, 3.766-6.234), while the median OS was 13.0 months (95% CI, 8.714-17.286). Side effects included hematologic toxicity, gastrointestinal reaction, and sinus tachycardia, which were mild to moderate. The mainly disturbed metabolic pathways were the cAMP signaling pathway, the alanine/aspartate/glutamate metabolism, the central carbon metabolism in cancer, the beta-alanine metabolism, the butanoate metabolism, and the glyoxylate and dicarboxylate metabolism, which may lead to the resistance of patients to this combination therapy. CONCLUSION: Apatinib combined with vinorelbine is effective and safe in patients with locally advanced or metastatic refractory HER2-negative breast cancer. The findings of this study con-tribute to a better understanding of the metabolic effect of apatinib and vinorelbine therapy.

Apatinib has anti-tumor effects and induces autophagy in lung cancer cells with high expression of VEGFR-2.

Objectives: This study investigated the inhibitory effect of apatinib on lung cancer cells with high expression of vascular endothelial growth factor-2 (VEGFR-2) and on inducing cellular autophagy and drug resistance. Materials and Methods: The expression of VEGFR-2 was detected using western blotting and RT-PCR. Cell proliferation was measured using the CCK8 and colony formation assays. The cell apoptosis rate was determined using flow cytometry and tunnel assay. Cellular autophagy was detected by measuring the expression of LC3-II using Western blotting and cellular immunofluorescence. The inhibitory effect of apatinib on lung cancer cells and transplanted tumors was observed after treatment with the autophagy inhibitor chloroquine. Results: Apatinib dose-dependently inhibited the proliferation of H1975 and H446 cells; it induced apoptosis via the PARP and caspase-3 pathways in H1975 and H446 cells and effectively inhibited the growth of transplanted tumors. Apatinib induced autophagy in a dose-dependent manner in H1975 and H446 cells. The inhibitory effect of apatinib on cells and the promotion of apoptosis were significantly enhanced after treatment with chloroquine. Immunohistochemistry showed that combining apatinib with chloroquine could reduce the expression of CD31 and Ki67 and increase the expression of caspase-3. Conclusion: Apatinib inhibits proliferation and induces apoptosis in H1975 and H1446 lung cancer cells with high VEGFR2 expression and autophagy in H1975 and H446 cells.

Clinical efficacy and safety of targeted therapy, immunotherapy combined with chemotherapy for treating patients with advanced gastric cancer.

Objective: Exploring the clinical efficacy and safety of targeted therapy, immunotherapy combined with chemotherapy in the treatment of advanced gastric cancer. Methods: A retrospective analysis was performed on the medical records of 134 patients with advanced gastric cancer who visited Renmin Hospital, Hubei University of Medicine from January 2019 to December 2022. According to therapeutic regimens, enrolled patients were divided into the control group and the study group. Patients in the control group received chemotherapy intervention, while those in the study group were provided with a combined intervention of apatinib, PD-1 inhibitor and chemotherapy. We analyze the tumor control effect and incidence of adverse reactions in two groups of patients. Results: The disease control rate (DCR) of patients in the study group and the control group was 72.06% and 42.42%, with an overall response rate (ORR) of 8.82% and 4.55%, The differences are statistically significant(P<0.05). By the end of follow-up, the median progression-free survival (mPFS) and the median overall survival (mOS) of the control group patients were 3.0±0.266 and 5.0±0.224 months respectively; while the mPFS and mOS of the study group were 5.0±0.261 and 7.0±0.172 months respectively, the differences are statistically significant (P<0.05). However, there was no significant difference in adverse reactions between the two groups (P>0.05). Conclusion: The therapeutic regimen of apatinib, a PD-1 inhibitor combined with chemotherapy exhibits relatively high clinical efficacy and safety for the treatment of patients with advanced gastric cancer. It can be considered as an interventional option for this type of patient.

AB048. Evidence of effectiveness of neoadjuvant camrelizumab and apatinib in patients with recurrent high-grade gliomas.

BACKGROUND: Recurrent high-grade glioma (HGG) is a challenge with limited treatment options and a poor prognosis. We conducted an open-label phase II study: neoadjuvant camrelizumab and apatinib in patients with recurrent high-grade gliomas (NCT04588987), and interim analysis showed very promising results. We are further searching for evidence of the effectiveness of this strategy. METHODS: Patients with recurrent HGG received neoadjuvant treatment with camrelizumab (intravenous injection 200 mg on day 1) and apatinib (oral 250 mg per day on days 1-7), and 14 days later received surgery for recurrent tumor resection. Sequential therapy began 2 weeks after surgery with the biweekly camrelizumab (200 mg) and 4 weeks after surgery with the daily apatinib (250 mg) until investigator assessed progressive disease or unable to tolerate toxicity. The primary endpoint was overall survival (OS). When patients suspected progress during per-protocol treatment, re-surgery for resection of lesion was done, and the tissue was further examined. RESULTS: Between October 9, 2020, and March 30, 2024, 24 patients were enrolled [19 glioblastomas, one World Health Organization (WHO) grade 4 diffuse astrocytoma, three anaplastic astrocytoma, and one anaplastic oligodendroglioma]. Nineteen patients with interim analysis data, and showed the median progression-free survival (PFS) was 4.8 months [95% confidence interval (CI): 4.4-5.2], the median OS was 12.9 months (95% CI: 9.3-16.4) respectively, with a median follow-up time of 17.5 months (95% CI: 9.0-26.1). There were two patients who suspected progress and received second surgery. One patient showed real tumor progression with active tumor cells. While another patient the histology revealed mainly necrosis with inflammatory cells. Five patients initially showed increased enhancement on magnetic resonance imaging (MRI) but without increased symptoms, and showed continuous improvement when receiving further treatment. CONCLUSIONS: This immuno-target combination neoadjuvant therapy in recurrent HGG demonstrated encouraging efficacy and revealed some evidence of efficacy, and worth to further investigate.

A pH-Responsive Drug-Delivery System Based on Apatinib-Loaded Metal-Organic Frameworks for Ferroptosis-Targeted Synergistic Anti-Tumor Therapy.

Purpose: The efficacy of systemic therapy for hepatocellular carcinoma (HCC) is limited mainly by the complex tumor defense mechanism and the severe toxic side-effects of drugs. The efficacy of apatinib (Apa), a key liver cancer treatment, is unsatisfactory due to inadequate targeting and is accompanied by notable side-effects. Leveraging nanomaterials to enhance its targeting represents a crucial strategy for improving the effectiveness of liver cancer therapy. Patients and Methods: A metal polyphenol network-coated apatinib-loaded metal-organic framework-based multifunctional drug-delivery system (MIL-100@Apa@MPN) was prepared by using metal-organic frameworks (MOFs) as carriers. The nanoparticles (NPs) were subsequently characterized using techniques such as X-ray diffraction (XRD), transmission electron microscopy (TEM), zeta potential measurements, and particle size analysis. In vitro experiments were conducted to observe the drug release kinetics and cytotoxic effects of MIL-100@Apa@MPN on HepG2 cells. The in vivo anti-tumor efficacy of MIL-100@Apa@MPN was evaluated using the H22 tumor-bearing mouse model. Results: The formulated MIL-100@Apa@MPN demonstrates remarkable thermal stability and possesses a uniform structure, with measured drug-loading (DL) and encapsulation efficiency (EE) rates of 28.33% and 85.01%, respectively. In vitro studies demonstrated that HepG2 cells efficiently uptake coumarin-6-loaded NPs, and a significant increase in cumulative drug release was observed under lower pH conditions (pH 5.0), leading to the release of approximately 73.72% of Apa. In HepG2 cells, MIL-100@Apa@MPN exhibited more significant antiproliferative activity compared to free Apa. In vivo, MIL-100@Apa@MPN significantly inhibited tumor growth, attenuated side-effects, and enhanced therapeutic effects in H22 tumor-bearing mice compared to other groups. Conclusion: We have successfully constructed a MOF delivery system with excellent safety, sustained-release capability, pH-targeting, and improved anti-tumor efficacy, highlighting its potential as a therapeutic approach for the treatment of HCC.

The combination of apatinib and antigen-specific DC-induced T cells exert antitumor effects by potently improving the immune microenvironment of osteosarcoma.

Objective: Osteosarcoma (OS) is the most common primary bone sarcoma with a high propensity for local invasion and metastasis. Although the antitumor effect of apatinib has been well confirmed in advanced OS, the synergistic effect of apatinib and immunotherapies has not yet been elucidated. Methods: In this study, we established tumour-bearing mice and observed tumour size with low and high doses of apatinib treatments. The expression of 17 cytokines, including vascular endothelial growth factor (VEGF), was detected by protein microarray analysis. Moreover, we designed apatinib and antigen-specific dendritic cell (DC)-T combination treatment for tumour-bearing mice. Tumour growth was detected by statistical analysis of tumour size and microvessel density (MVD) counting, the protein expression of VEGF by western blotting, the cytokines interleukin 6 (IL-6), IL-17 and interferon-gamma (IFN-γ) by enzyme-linked immunosorbent assay (ELISA), and the numbers of myeloid-derived suppressor cells (MDSCs) and tumour-infiltration macrophages (TAMs) by flow cytometry. Results: The results showed that apatinib efficiently suppressed tumour growth, and high-dose apatinib achieved a stronger effect. The same was true for DC-T immunotherapy. However, their combination treatment revealed a better oncolytic effect. Meanwhile, apatinib or DC-T treatment inhibited the expression of VEGF and the proangiogenic mediators IL-6 and IL-17 but increased IFN-γ production. Combination therapy further reduced/increased these effects. In addition, the combination treatment reduced MDSC but enhanced TAM-M1 ratios in the OS microenvironment. These findings indicated that apatinib and antigen-specific DC-T combination therapy was more efficient in oncolysis by regulating pro-/anti-angiogenic inducers and improving the immune state in the OS microenvironment. Conclusion: This study proved that it was feasible to employ immunotherapy with therapeutic agents in OS treatment, which may provide a new approach in addition to the combination of surgery with chemotherapy in tumour treatment.

Efficacy and safety of camrelizumab plus apatinib in patients with advanced esophageal squamous cell carcinoma previously treated with immune checkpoint inhibitors (CAP 02 Re-challenge): A single-arm, phase II study.

BACKGROUND: With the increasing use of immune checkpoint inhibitors (ICIs) in advanced esophageal squamous cell carcinoma (ESCC), there remains an unmet need for options to address disease progression after prior ICIs. This single-arm phase II study evaluated the efficacy and safety of re-challenge with camrelizumab plus apatinib in patients with advanced ESCC who were previously treated with ICIs. METHODS: This study enrolled patients aged 18-75 years with unresectable locally advanced, locally recurrent, or distant metastatic ESCC who received prior ICIs. Patients received intravenous camrelizumab 200 mg every 2 weeks and oral apatinib 250 mg daily until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was the investigator-assessed confirmed objective response rate (ORR). RESULTS: Between September 1, 2021 and March 29, 2023, 49 eligible patients were enrolled and received treatment. Among the 49 patients, the confirmed ORR was 10.2 % (95 % CI 3.4-22.2), the disease control rate (DCR) was 69.4 % (54.6-81.7), the median progression-free survival (PFS) was 4.6 months (95 % CI 3.8-6.5) and overall survival (OS) was 7.5 months (5.5-13.6). Grade ≥ 3 treatment-related adverse events occurred in 17 patients (34.7 %). No treatment-related deaths occurred. CONCLUSIONS: This study showed that the confirmed ORR was modest and did not reach clinically meaningful improvement for patients with ESCC who were previously treated with ICIs, with a manageable safety profile.

Response to hepatic arterial infusion chemotherapy combined with camrelizumab and targeted therapy in advanced primary hepatic neuroendocrine carcinoma: a case report and literature review.

Background: Primary hepatic neuroendocrine carcinoma (PHNEC), which often lacks distinctive radiological features or specific clinical symptoms, is extremely rare. In this report, we describe a rare case of PHNEC that was successfully treated with hepatic arterial infusion chemotherapy (HAIC) combined with camrelizumab and targeted therapy. Case Description: This report describes the treatment of a 53-year-old male with PHNEC in China. The patient was admitted for persistent upper right quadrant abdominal pain. Dynamic contrast-enhanced abdominal computed tomography (CT) and magnetic resonance imaging (MRI) both detected multiple masses, enlarged portal lymph nodes, and retroperitoneal lymph nodes. Histological and immunohistochemistry of the largest mass biopsy specimen from the right liver lobe confirmed the neuroendocrine tumor of the liver. The patient underwent HAIC with a modified fluorouracil and oxaliplatin (mFOLFOX) regimen. Meanwhile, the patient received camrelizumab (200 mg, intravenously, q3w) apatinib (250 mg, oral, daily) within 7 days after the start of HAIC. CT and MRI showed a marked decrease in the size of the largest mass of the liver and the portal lymph nodes, indicating a partial response of the tumor. Conclusions: PHNEC is a very rare tumor, and the treatment for its advanced type is controversial and remains to be standardized. HAIC combined with camrelizumab and targeted therapy may be an effective and safe therapeutic option for patients with PHNEC.

Low-dose apatinib optimizes the vascular normalization and enhances the antitumor effect of PD-1 inhibitor in gastric cancer.

Background: Apatinib is a tyrosine kinase inhibitor that has shown potential in combination with immune checkpoint inhibitors (ICIs) in gastric cancer (GC); however, its role in GC is unclear. This research aims to investigate the effect of low-dose apatinib in GC, and analyze the mechanisms of its underlying action. Methods: A mouse model of GC was established, and the experimental mice were divided into different groups for different treatment: group NS (normal saline), group A (low-dose apatinib 50 mg/kg), group B (high-dose apatinib 200 mg/kg), group C [programmed cell death protein 1 (PD-1) inhibitor monotherapy], and group D (PD-1 inhibitor combined with low-dose apatinib). After 14 days of treatment, the tumor and blood samples were collected from all mice for histological and cytokine detection. Results: Compared with the control group, mice in the low-dose apatinib group showed smaller tumor volumes and slower growth. CD31/α-smooth muscle actin (α-SMA) double staining revealed significantly higher coverage of perivascular cells in the low-dose apatinib group by contrast to the control and high-dose apatinib groups, suggesting that low-dose apatinib may alleviate hypoxia. Compared to the high-dose apatinib group, the expression of hypoxia inducible factor 1 alpha (HIF1α) significantly decreased in the low-dose apatinib group. Hematoxylin and eosin (HE) staining results showed a higher proportion of necrotic tumor tissues in the group of mice treated with low-dose apatinib combined with PD-1 inhibitor than in other groups. In addition, this combined treatment significantly reduced the expression of NG2 and HIF1α in mouse tumor tissues, indicating a more normalized vascular density, and also increased the proportion of CD8+ T cells. Conclusions: Low-dose apatinib enhances the antitumor effect of PD-1 inhibitor by normalizing tumor-related blood vessels, alleviating intratumor hypoxia and altering immunosuppressive microenvironment (IM).

Efficacy of bevacizumab combined with apatinib in the treatment of advanced metastatic gastric cancer.

OBJECTIVE: To evaluate the clinical efficacy and safety of bevacizumab combined with apatinib in the treatment of advanced metastatic gastric cancer, providing insights for treatment decisions. METHODS: We conducted a single-center retrospective study involving patients with metastatic gastric cancer treated with apatinib, with or without bevacizumab, between August 2018 and April 2021 at Nanchang Medical College. Data on efficacy, adverse events, response rates, and quality of life were collected and compared. RESULTS: No significant differences were observed in complete remission, partial response, stable disease, disease progression, objective response rate, or disease control rate between the groups (all P>0.05). The median progression-free survival was 9.23 months in the control group and 9.94 months in the observation group (P=0.587). Median overall survival (OS) was 19.64 months in the control group and 26.44 months in the observation group (P=0.187). Univariate and multivariate analyses identified combination therapy with apatinib and bevacizumab, primary lesion resection, and number of metastatic organs as independent prognostic factors for OS. Scores for role, emotional, somatic, cognitive, and social functions were significantly higher in the observation group post-intervention (all P<0.05). CONCLUSIONS: In patients with advanced metastatic gastric cancer, combined therapy with bevacizumab and apatinib significantly improved OS, enhanced response rates, and increased rates of early and maximal tumor shrinkage.

Combination of arsenic trioxide and apatinib synergistically inhibits small cell lung cancer by down-regulating VEGFR2/mTOR and Akt/c-Myc signaling pathway via GRB10.

BACKGROUND: Small cell lung carcinoma (SCLC) is characterized by -poor prognosis, -high predilection for -metastasis, -proliferation, and -absence of newer therapeutic options. Elucidation of newer pathways characterizing the disease may allow for development of targeted therapies and consequently favorable outcomes. METHODS: The current study explored the combinatorial action of arsenic trioxide (ATO) and apatinib (APA) in vitro and in vivo. In vitro models were tested using -H446 and -H196 SCLC cell lines. The ability of drugs to reduce -metastasis, -cell proliferation, and -migration were assessed. Using bioinformatic analysis, differentially expressed genes were determined. Gene regulation was assessed using gene knock down models and confirmed using Western blots. The in vivo models were used to confirm the resolution of pathognomic features in the presence of the drugs. Growth factor receptor bound protein (GRB) 10 expression levels of human small cell lung cancer tissues and adjacent tissues were detected by IHC. RESULTS: In combination, ATO and APA were found to significantly reduce -cell proliferation, -migration, and -metastasis in both the cell lines. Cell proliferation was found to be inhibited by activation of Caspase-3, -7 pathway. In the presence of drugs, it was found that expression of GRB10 was stabilized. The silencing of GRB10 was found to negatively regulate the VEGFR2/Akt/mTOR and Akt/GSK-3ß/c-Myc signaling pathway. Concurrently, absence of metastasis and reduction of tumor volume were confirmed in vivo. The immunohistochemical results confirmed that the expression level of GRB10 in adjacent tissues was significantly higher than that in human small cell lung cancer tissues. CONCLUSIONS: Synergistically, ATO and APA have a more significant impact on inhibiting cell proliferation than each drug independently. ATO and APA may be mediating its action through the stabilization of GRB10 thus acting as a tumor suppressor. We thus, preliminarily report the impact of GRB10 stability as a target for SCLC treatment.

Clinical efficacy of Apatinib combined with Epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) in nonsmall cell lung cancer after EGFR-TKI resistance.

Objective: To evaluate the efficacy and safety of Apatinib combined with epidermal growth factor receptor - tyrosine kinase inhibitor (EGFR-TKI) in the treatment of patients with non-small cell lung cancer (NSCLC) and acquired EGFR-TKI resistance. Methods: Clinical records of 106 patients with NSCLC at Shanxi Tumor Hospital of the Chinese Academy of Medical Sciences Cancer Hospital from January 2017 to October 2020, with acquired drug resistance after EGFR-TKI treatment were retrospectively analyzed. Among them, 52 patients received Apatinib combined with EGFR-TKI (Apatinib group), and 54 patients received a standard chemotherapy (pemetrexed combined with platinum) (chemotherapy group). Clinical efficacy indicators, follow-up results, and adverse reactions in both groups were compared. Results: There was no significant difference in the objective response rate and disease control rate between the two groups (P>0.05). The progression free survival (PFS) of the Apatinib group was significantly longer than that of the chemotherapy group (10.5 months vs. 5.7 months; P<0.05). There was no significant difference in adverse reactions between the two groups (P>0.05). Conclusions: Compared with standard chemotherapy, Apatinib combined with EGFR-TKI has the same efficacy in treating NSCLC patients with EGFR-TKI resistance, and was associated with longer PFS with no significant increase in adverse reactions.

Efficacy and safety of apatinib in the treatment of patients with platinum­resistant ovarian cancer: A systematic review and network meta­analysis.

At present, the optimal therapeutic approach for the treatment of platinum-resistant recurrent ovarian cancer remains to be fully elucidated. The present systematic review and network meta-analysis aimed to elucidate the relative efficacy and safety of apatinib, administered either as monotherapy or in conjunction with chemotherapy, compared with chemotherapy alone, for the treatment of platinum-resistant recurrent ovarian cancer. The PubMed, Embase and Wanfang Data electronic databases were searched, where the search spanned from the conception of the databases until April 2023. A quality evaluation was conducted and R software was used for network meta-analysis. Following inclusion and exclusion criteria screening, the present analysis included 17 clinical trials, combining data from 1,228 patients with platinum-resistant recurrent ovarian cancer categorized into the following three treatment cohorts: i) 555 patients who received apatinib plus chemotherapy; ii) 229 patients who received apatinib alone; and iii) 444 patients who underwent conventional chemotherapy. Results of the present study demonstrated that the co-administration of apatinib with either tegiol [odds ratio (OR), 2.54; 95% CI, 1.06-6.11] or etoposide (OR, 2.12; 95% CI, 1.20-3.74) significantly improved the objective response rate (ORR) compared with that following apatinib monotherapy. By contrast, gemcitabine monotherapy resulted in inferior ORR efficacy compared with that following apatinib (OR, 0.47; 95% CI, 0.23-0.95). In addition, combinations of apatinib with etoposide (OR, 1.32; 95% CI, 1.06-1.64) or paclitaxel (OR, 1.52; 95% CI, 1.04-2.23) demonstrated a significantly improved disease control rates (DCR) compared with those following apatinib alone. According to the area under the cumulative ranking analysis, apatinib and paclitaxel in combination was the most efficacious treatment modality in terms of DCR. In terms of safety, the incidence of adverse events, such as hand-foot syndrome [relative risk (RR), 4.23; 95% CI, 1.80-9.95] and hypertension (RR, 4.80; 95% CI, 1.53-15.05), was found to be significantly higher in patients treated with apatinib-containing therapies, compared with those treated with chemotherapy alone. Consequently, the present meta-analysis highlighted the potential of apatinib, particularly in combination with chemotherapy, as a therapeutic strategy for patients with platinum-resistant recurrent ovarian cancer.

Characteristics and patient-reported outcomes of long-term cancer survivors after apatinib-based therapy: an online survey.

BACKGROUND: Data on long-term cancer survivors treated with apatinib are lacking. This study aimed to describe the characteristics of long-term cancer survivors after apatinib-based therapy, and to know about their satisfaction degree with apatinib and severity of depression and insomnia. METHODS: Patients with solid tumors who had received apatinib-based therapy for at least 5 years were invited to complete an online questionnaire. Characteristics of patients and treatment, knowledge of apatinib, satisfaction degree, and severity of depression and insomnia assessed by Patient Health Questionnaire-9 and Insomnia Severity Index were collected. RESULTS: Between December 8, 2023 and March 1, 2024, a total of 436 patients completed the online questionnaire. Most patients were satisfied with the efficacy (96.6%) and safety (93.1%) of apatinib, were willing to continue apatinib treatment (99.5%), and would recommend apatinib to other patients (93.3%). Continuous apatinib treatment resulted in significant negative impact on daily life, work, or study in only two (0.5%) patients. Almost all patients currently had no or mild depression (97.0%) and insomnia (97.9%) problems. The most common patient-reported adverse events were hand-foot syndrome (21.3%) and hypertension (18.3%). CONCLUSIONS: Our survey showed a high satisfaction degree with apatinib in long-term cancer survivors. Long-term apatinib treatment resulted in almost no negative impact on patient's quality of life.

Camrelizumab Combined with Apatinib for Portal Vein Tumor Thrombus in Advanced Hepatocellular Carcinoma: Two Case Reports.

Aims/Background: Portal vein tumor thrombus (PVTT) is a common complication of primary hepatocellular carcinoma (HCC). HCC typically infiltrates intrahepatic vessels, particularly the portal vein, leading to the formation of PVTT, marking advanced-stage HCC and correlating with poor prognosis. PVTT often complicates local treatment strategies such as surgical resection and affects the efficacy of interventions. Combination therapy, including immunotherapy and targeted therapy, shows promise in HCC treatment, but management options for HCC patients with PVTT are incompletely characterized. This study aims to investigate the efficacy and safety of camrelizumab + apatinib in treating HCC patients with PVTT. Case Presentation: Two cases of HCC with PVTT were presented. Patient 1, a 51-year-old male with a history of hepatitis B virus, was diagnosed with stage IIIA HCC and treated with camrelizumab + apatinib, achieving complete response (CR) after six cycles. Patient 2, a 50-year-old male with stage IIIA HCC, also underwent the same treatment and achieved CR after four cycles but died due to acute cardiac disease. Results: Our research found that camrelizumab + apatinib effectively shrank the size of filling defects and significantly prolonged patients' progression-free survival. In addition, no adverse effects were observed during the treatment process. However, despite the manageable safety profile demonstrated by combination therapy, further clinical research is needed to validate its long-term efficacy and safety. Conclusion: Camrelizumab + apatinib produced satisfactory efficacy and safety among the HCC patients with PVTT, providing clinical evidence for future treatment.