Low-dose Apatinib Research Articles

50P Camrelizumab (Cam) combined with gemcitabine and cisplatin (GP) plus low-dose apatinib in first-line treatment of advanced biliary tract cancer (BTC)

50P Camrelizumab (Cam) combined with gemcitabine and cisplatin (GP) plus low-dose apatinib in first-line treatment of advanced biliary tract cancer (BTC)

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

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. 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. 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. 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).

The efficiency and safety of low-dose apatinib combined with oral vinorelbine in pretreated HER2-negative metastatic breast cancer.

Apatinib is an oral small-molecule tyrosine kinase inhibitor that blocks vascular endothelial growth factor receptor-2. Oral vinorelbine is a semisynthetic chemotherapeutic agent of vinorelbine alkaloids. Apatinib and oral vinorelbine have been proved to be effective in the treatment of metastatic breast cancer (mBC). At present, several small sample clinical trials have explored the efficacy of apatinib combined with oral vinorelbine in the treatment of mBC. This retrospective study included 100 human epidermal growth factor receptor-2 (HER2)-negative mBC patients who received low-dose apatinib (250 mg orally per day) plus oral vinorelbine until disease progression or intolerance during February 2017 and March 2023. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), and safety were analyzed by SPSS 26.0 software and GraphPad Prism 8 software. Cox proportional hazards regression model for univariate and multivariate was used to identify factors significantly related to PFS and OS. The median follow-up time for this study was 38.1 months. Among 100 patients with HER2-negative mBC, 66 were hormone receptor (HR)-positive/HER2-negative and 34 were triple-negative breast cancer (TNBC). The median PFS and OS were 6.0 months (95% CI, 5.2-6.8 months) and 23.0 months (95% CI, 19.9-26.1 months). There were no statistical differences in PFS (p = 0.239) and OS (p = 0.762) between the HR-positive /HER2-negative and TNBC subgroups. The ORR, CBR, and DCR were 21.0%, 58.0%, and 78.0%, respectively. Ninety-five patients (95.0%) experienced varying grades of adverse events (AEs) and 38.0% of patients for Grades 3-4. The most common Grades 3-4 AEs that we observed were neutropenia (30.0%) and leukopenia (25.0%). Low-dose apatinib combined with oral vinorelbine demonstrates potential efficacy and well tolerated for pretreated HER2-negative mBC.

Camptothecin enhances the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma

Apatinib has been shown to apply to a variety of solid tumors, including advanced hepatocellular carcinoma. Preclinical and preliminary clinical results confirmed the synergistic antitumor effects of apatinib in combination with anti-programmed death-1 (PD-1) inhibitors. In this study, we investigated camptothecin (CPT) enhances the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma. CPT combined with a PD-1 inhibitor enhances the anti-tumor effects of low-dose apatinib in hepatocellular carcinoma which was evaluated in making use of the H22 mouse model (n = 32), which was divided into four groups. Immunohistochemical staining and western blotting were used to detect nuclear factor erythroid 2-related factor 2 (Nrf2) as well as sequestosome 1 (p62), vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), PD-1, and programmed cell death ligand 1 (PD-L1). The results showed that the average size of the tumor of the combination group (Group D) was significantly less than that of the apatinib + PD-1 inhibitor group (Group C). The expression levels of Nrf2, p62, VEGFA, VEGFR2, PD-1, and PD-L1 in the apatinib + PD-1 inhibitor group(Group C) were lower than those in the control group (Group A) (P < 0.05). The expression levels of these genes in the apatinib + PD-1 inhibitor group (Group C) were significantly lower in the combination group (Group D) (P < 0.05). There was no obvious difference in body weight and liver and kidney functions between the four groups of mice. In conclusion, CPT improves the anti-tumor effect of low-dose apatinib combined with PD-1 inhibitor on hepatocellular carcinoma

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.

A real-world study of the effectiveness and safety of apatinib-based regimens in metastatic triple-negative breast cancer

PurposeThis investigation sought to examine the efficacy and safety of low-dose apatinib used alongside chemotherapy in the clinical management of patients with metastatic triple-negative breast cancer (TNBC) within a real-world setting, whilst comparing the outcomes with those treated solely with chemotherapy.MethodsThis case series study analyzed clinical data and treatment outcomes of 163 patients with metastatic TNBC who underwent rescue treatment at the Medical Oncology Department of Clinical Oncology, Fujian Cancer Hospital, School of Fujian Medical University, China, between October 2011 and January 2023. All the patients underwent rescue treatment with either chemotherapy alone or apatinib (250 mg/day) combined with chemotherapy. The study’s primary outcome was progression-free survival (PFS), whereas the secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety profiles.ResultsThe study was designed to compare two groups [1]. Out of the 163 TNBC patients who participated in the study, 107 individuals (65.6%) received treatment based on chemotherapy, whereas 56 patients (34.4%) were given treatment based on a combination of low-dose apatinib (250 mg/day) and other treatments, including chemotherapy. After propensity score matching (PSM), the objective response rate (ORR) and disease control rate (DCR) of patients with advanced triple-negative breast cancer (TNBC) who received apatinib-based treatment were 50.0 and 90.0%, respectively, while they were 6.7 and 20.0%, respectively, for the chemotherapy-based group (P < 0.001). The group that received apatinib-based treatment showed superior results in both PFS and OS compared to the group that received chemotherapy. The median PFS and OS for the apatinib-based group were 7.8 and 20.3 months, respectively, while they were only 2.2 months and 9.0 months, respectively, for the chemotherapy-based group (P < 0.001) [2]. Patients who were administered combo therapies, including PD-1 inhibitors, were excluded. In total, 97 patients received chemotherapy alone, while 34 patients were treated with apatinib in combination with chemotherapy. After propensity score matching (PSM), the ORR and DCR for the total group who received combo therapies were 44.4 and 81.5%, respectively, while they were 11.1 and 22.2%, respectively, for the chemotherapy alone group (P < 0.001). The group receiving both apatinib and chemotherapy displayed notable advantages over the group solely receiving chemotherapy in regards to PFS and OS for the entirety of the population. The PFS was found to be 7.8 months in comparison to 2.1 months (P < 0.001) and the OS was 21.1 months in contrast to 9.0 months (P < 0.001). Apatinib combined with chemotherapy induced grade 3/4 hematological toxicities, including neutropenia (8.8%) and thrombocytopenia (2.9%). Additionally, non-hematological toxicities were commonly observed, such as Hand-foot syndrome (35.3%), proteinuria (26.5%), hypertension (61.8%), higher alanine aminotransferase levels (26.5%), and fatigue (35.3%). The most frequent non-hematological grade 3/4 toxicities were Hand-foot syndrome (2.9%) and hypertension (5.9%). The study did not report any fatal adverse effects.ConclusionsThe combination of low-dose apatinib with chemotherapy has proven to be more effective than chemotherapy alone in treating metastatic triple-negative breast cancer (TNBC). Additionally, the occurrence of grade 3/4 non-hematologic toxicities was significantly lower compared to the recommended dose of apatinib.

Low-dose apatinib in subjects with renal impairment: A pharmacokinetics study

ObjectiveIn patients with renal impairment, we studied apatinib and its major metabolites (M1–1, M1–2, M1–6, and M9–2) for pharmacokinetics. MethodsSubjects with different renal functions were given a single oral dose of apatinib mesylate tablets of 250 mg. Pharmacokinetic samples were collected at 1 hour before dosing,0.25, 0.5, 1, 2, 3, 4, 6, 8, 24, 48, 72, and 96 h after dosing. The pharmacokinetic parameters of apatinib and its major metabolites were calculated by noncompartmental analysis. ResultsComparing PK parameters of the mild or moderate renal impairment group with the healthy group: the geometric mean ratios of maximum observed drug concentration (Cmax), the area under the plasma drug concentration-time curve from time 0 to the final quantifiable time (AUC0-t), and the area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0–inf) were all about one. No significant effect of mild and moderate renal impairment on apatinib pharmacokinetics was observed. Mild and moderate renal impairment was also not observed to have a significant effect on the pharmacokinetics of metabolites M1–1, M1–2, and M1–6. However, mild and moderate renal impairment had a certain increase in exposure to the metabolite M9–2. Considering that M9–2 has no inhibitory effect on protein tyrosine kinase, it has no clinical significance. In addition, the proportion of cumulative excretion of apatinib and its major metabolites was small and almost negligible in all three groups of subjects. ConclusionPatients with mild and moderate renal impairment do not need to adjust the dose of apatinib when using low dose (250 mg) apatinib.

Efficacy of the low dose apatinib plus deep hyperthermia as third-line or later treatment in HER-2 negative advanced gastric cancer.

Aim: To observe the efficacy of the low dose apatinib plus deep hyperthermia as third-line or later treatment for patients with human epidermal growth factor receptor 2 (HER-2) negative advanced gastric cancer. Methods: 80 eligible patients with HER-2 negative advanced gastric cancer admitted to Jingjiang People's Hospital Affiliated with Yangzhou University-from March 2021 to March 2022 were selected, and they were divided into the control group (n = 40, apatinib) and experimental group (n = 40, apatinib plus deep hyperthermia) on the basis of random number table method. The levels of serum carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), and vascular endothelial growth factor (VEGF) were monitored, and the efficacy of the two groups was analyzed by referring to Karnofsky performance status (KPS), overall survival (OS) and disease control rate (DCR) before and after treatment. Results: The levels of CEA, CA199, and VEGF in both groups were lower after treatment than before (p < 0.05), and lower (CEA: 8.85 ± 1.36 vs. 12.87 ± 1.23, CA199: 34.19 ± 4.68 vs. 50.11 ± 5.73, VEGF: 124.8 ± 18.03 vs. 205.9 ± 19.91) in the experimental group than in the control group (p < 0.05). The DCR and KPS of the patients in the experimental group were significantly higher (DCR: 62.50% vs. 40.00%; KPS: 83.25 ± 1.15 vs. 76.25 ± 1.17) than in the control group (p < 0.05). In survival analysis, patients with control group had shorter OS than the experimental group. (median 5.65 vs. 6.50months; hazard ratio [HR], 1.63 [95% confidence interval (CI) 1.02-2.60], p = 0.0396). Conclusion: The application of low-dose apatinib plus deep hyperthermia for patients with HER-2 negative gastric cancer who failed second-line treatment should be a promising option.

Efficacy and Safety of Low-Dose Apatinib Combined with Chemotherapy as Second-Line Treatment for Advanced Gastric Cancer: A Meta-Analysis

Introduction: At present, there are several studies on low-dose apatinib combined with chemotherapy as a second-line treatment of advanced gastric cancer (AGC), but the conclusions are controversial. Therefore, this meta-analysis aimed to evaluate the efficacy and safety of low-dose apatinib combined with chemotherapy as a second-line treatment of AGC. Methods: Nine databases were searched for records on apatinib combined with chemotherapy in treating AGC from inception to June 2022. The observation group received low-dose apatinib combined with chemotherapy, while the controls received chemotherapy alone or other non-placebo treatments. Outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events. The relative risk (RR) and weighted mean difference (WMD) were used as effect sizes. Results: Eight studies involving 679 patients were included in this meta-analysis. The results of the meta-analysis showed that the observation group was superior to the controls in terms of ORR (RR = 1.38, 95% confidence interval [CI]: 1.05–1.81, p = 0.02), DCR (RR = 1.35, 95% CI: 1.20–1.53, p < 0.001), OS (WMD = 4.72, 95% CI: 0.71–8.72, p < 0.001), and PFS (WMD = 2.67, 95% CI: 1.7–3.63, p < 0.001). There were no significant differences between the two groups in adverse events of any grade except hypertension (RR = 2.82, 95% CI: 2.07–3.84, p < 0.001), hand-mouth syndrome (RR = 1.84, 95% CI: 1.84–2.48, p < 0.001), and proteinuria (RR = 3.63, 95% CI: 2.31–5.7, p < 0.001). Conclusion: Low-dose apatinib combined with chemotherapy as a second-line therapy is more effective in improving the efficacy of AGC compared to chemotherapy alone. However, this option has the potential to increase the risk of hypertension, hand-mouth syndrome, and proteinuria.

The anti-tumor efficiency of low-dose apatinib-based chemotherapy in pretreated HER2-negative breast cancer with brain metastases

Background More than half of the metastatic breast cancer patients with brain metastases (BCBM) are HER-2 negative, and the prognosis of HER2-negative BCBM is dismal. But few clinical trials have investigated systemic therapies for this subgroup of patients. Methods This real-world study included 58 HER2-negative BCBMs who received low-dose apatinib (250 mg daily) in combination with chemotherapy between 18 March 2017 and 31 December 2021. The objective response rate (ORR) of the central nervous system, clinical benefit rate (CBR), progression-free survival of central nervous system (CNS-PFS) and overall survival (OS) were analyzed. Univariate and multivariate Cox regression model was used to estimate the prognostic factors for CNS-PFS and OS. Results At the cut-off date, the median follow-up time was 28.2 months. Of the 58 patients, 36 patients were HR+/HER2-, and 22 patients were TNBC. The CNS-ORR was 17.2% (95%CI 9.6% to 28.9%) and the CBR was 53.4% (95%CI 40.8% to 65.7%). The median duration of CNS-PFS for the entire cohort was 6.4 months, and the median OS was 10.7 months. The median CNS-PFS and OS were not affected by hormone receptor status, disease-free survival, the number of prior lines of therapy and local treatment. The most common grade 2–3 adverse events associated with low-dose apatinib were hypertension (20.6%), elevated bilirubin (10.4%), hypothyroidism (10.3%), and hand-foot skin reaction (10.3%). Conclusion Apatinib-based chemotherapy demonstrates potential feasibility with acceptable tolerance for HER2-negative BCBM. Its clinical application in BCBM still needs further verification.

Camrelizumab plus low-dose apatinib and SOX in the first-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma: A single-arm, dose escalation and expansion study (SPACE study).

365 Background: The dose escalation phase was presented early, and confirmed that the recommended phase II dose (RP2D) was camrelizumab (200 mg, d1) plus apatinib (250 mg, qd), S-1(40 mg, bid, d1-14) and oxaliplatin (130 mg/m2, d1) every 3 weeks followed by camrelizumab (200 mg, d1) plus apatinib (250 mg, qd) every 3 weeks. Methods: Patients (pts) aged 18-75 years, with unresectable or potentially resectable G/GEJ adenocarcinoma, HER2-negative or unknown HER2 status and no previous systemic therapy, were enrolled to receive combination therapy. Primary endpoint was Objective response rate (ORR) by RECIST 1.1, secondary endpoints included progression free survival (PFS), overall survival (OS), disease control rate (DCR), surgical resection rate and safety. Results: From Jun, 2020 to July 2022, 35 pts were enrolled (9 pts in dose escalation phase, 26 pts in dose expansion phase), with a median follow-up of 8.0 months (95% CL, 6.7-12.2). Median age (range) was 59(19-68), 94.3% (33/35) were male, 20% (7/35) were diagnosed with GEJ adenocarcinoma, 60% (21/35) had liver metastases. At data cutoff, 33 pts were included in the efficacy analysis. The ORR was 90.9%, with 30 (90.9%) PR. SD were 1 (3.0%) with a DCR of 93.9%. In addition, 9 pts showed an unconfirmed PR with a confirmed ORR of 80.8%. Median PFS was 10.2 months (95% CI, 5.5-22.3), with the median OS not reached yet. Conversion to resectable G/GEJ adenocarcinoma was identified in 9 (25.7%) pts. Of them, 2 pts were observed complete pathology response. 94.3% pts experienced treatment related adverse event (TRAE), with 45.7% being grade ≥3. The most frequent grade ≥3 TRAE were GGT increased (31.4%, 11/35), rash (11.4%, 4/35), alkaline phosphatase increased (11.4%, 4/35)、neutrophil count decreased (8.6%, 3/35). No new safety signal was identified. Conclusions: Camrelizumab plus apatinib and SOX followed by camrelizumab plus apatinib demonstrated encouraging antitumor activity and manageable toxicity as first line therapy for patients with G/GEJ adenocarcinoma. Clinical trial information: ChiCTR2000034109 .

Retracted: Low-Dose Apatinib Improves the Prognosis of Patients with Recurrent High-Grade Gliomas.

[This retracts the article DOI: 10.1155/2022/3181133.].

Low-dose apatinib combined with camrelizumab and the SOX regimen in the neoadjuvant treatment of locally advanced gastric/gastroesophageal junction adenocarcinoma (SPACE-neo): a protocol for an open-label, single-arm, clinical trial

Neoadjuvant chemotherapy with S-1 plus oxaliplatin (SOX regimen) has shown promising results in pathological response rate and survival rate in patients with locally advanced resectable gastric cancer (LAGC). We previously carried out the SPACE study to assess efficacy and safety of low-dose apatinib combined with camrelizumab and the SOX regimen as a first-line treatment of advanced gastric/gastroesophageal junction adenocarcinoma (AGC/GEJC). The preliminary results demonstrated a high objective response rate. However, the SPACE study was conducted in patients with AGC, but the efficacy of LAGC patients is not yet known. The SPACE-neo study is designed to investigate whether this combination could improve outcomes in patients with locally advanced gastric/gastroesophageal junction cancer (LAGC/GEJC) as neoadjuvant therapy. SPACE-neo is a prospective, open-label, single-arm study conducted in China at the First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital). Thirty-two patients with human epidermal growth factor receptor 2 (HER2)-negative or HER2-unknown LAGC/GEJC confirmed by histopathology or cytology will be recruited. Included patients shall be clinically staged as M0 and either T3 to T4 or N+ assessed by ultrasound endoscopy and thoracoabdominal-enhanced computed tomography or magnetic resonance imaging. The patients will receive three cycles of this combined regimen as a neoadjuvant treatment. Each patient will receive screening visits within 2 weeks before the first cycle and planned visits before every cycle of treatment. Key monitoring data include imaging data, pathological findings, and adverse events associated with neoadjuvant and surgical treatment. The primary endpoints are major pathological response (MPR) and safety. MPR is the proportion of patients whose residual tumor cells make up less than 10% of the primary tumor from among the total cohort. Clopper-Pearson method will be used to estimate the 95% confidence interval of MPR and safety data will be reported as descriptive statistical analysis. The SPACE-neo trial aims to evaluate the safety and preliminary efficacy of this regimen in the neoadjuvant treatment of LAGC/GEJC. It is hoped that the study can achieve a higher pathological response rate and longer survival rate. ChiCTR.gov.cn: ChiCTR2100049305.

Low- dose Apatinib promotes vascular normalization and hypoxia reduction and sensitizes radiotherapy in lung cancer.

Abnormal vascular network of tumor can create a hypoxic microenvironment, and reduce radiotherapy sensitivity. Normalization of tumor vasculature can be a new therapeutic strategy for sensitizing radiotherapy. This study aimed to explore the effect of apatinib on vascular normalization, as well as the syngeneic effect with radiotherapy on lung cancer. Lewis lung carcinoma (LLC) xenograft-bearing female C57BL/6 mice were treated with different doses of apatinib (30, 60, and 120 mg/kg per day) and/or radiation therapy (8Gy/1F) and then sacrificed to harvest tumor tissue for immunohistochemical test. Further 18 F-FMISO micro- PET in vivo explored the degree of hypoxia. Immunohistochemistry of CD31 and alpha-smooth muscle actin (α-SMA) proved that low-dose apatinib can normalize vasculature in tumor, especially on Day 10. Tissue staining of hypoxyprobe-1 and 18 F-FMISO micro- PET in vivo showed that 60 mg/kg/day of apatinib significantly alleviates hypoxia. Moreover, this study further proved that low-dose apatinib (60 mg/kg/day) can enhance the radio-response of LLC xenograft mice. Our data suggested that low- dose apatinib can successfully induce a vascular normalization window and function as a radio- sensitizer in the lung cancer xenografts model.

Low-Dose Apatinib Improves the Prognosis of Patients with Recurrent High-Grade Gliomas.

Objective To evaluate the efficacy, safety, and prognostic value of low-dose apatinib in combination with temozolomide in the treatment of primary or recurrent high-grade gliomas (HGGs). Methods A retrospective analysis of patients with postoperative and recurrent HGGs treated in our hospital from April 1, 2018, to April 30, 2020. Patients should be treated by combination therapy (surgery + radiotherapy + chemotherapy). Patients who received apatinib combined with temozolomide chemotherapy were allocated to the research group (RG), while patients who received temozolomide chemotherapy alone were allocated to the control group (CG). The efficacy and toxic side effects were compared between the two groups. Results There were 67 qualified patients retrieved, including 37 cases in the RG and 30 cases in the CG. There were no significant differences in objective remission rate (ORR) or disease control rate (DCR) between the control group and the study group (P > 0.05). However, the overall improvement of clinical efficacy in the observation group was better than that in the control group (P < 0.05). There was no significant difference in the incidence of adverse effects between the two groups (P > 0.05). There were no significant differences in overall survival (OS) or progression-free survival (PFS) between the two groups (P > 0.05). Conclusion Low-dose apatinib combined with temozolomide and radiotherapy for HGGs is effective in improving efficacy, relieving brain edema, reducing the use of glucocorticoid drugs, and improving patients' quality of life. It has mild adverse effects and is well tolerated by patients.

Retrospective study on the efficacy and safety of low dose apatinib in reversing chemotherapy resistance in sarcoma

Objective: To explore whether apatinib can reverse the chemotherapy resistance of patients with advanced sarcoma. Methods: The clinical data of advanced sarcoma patients after chemotherapy who received the original chemotherapy regimen combined with low-dose apatinib in Cancer Center of Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology from May 2018 to November 2021 were collected retrospectively to evaluate the efficacy and safety of this regimen. The primary end point was progression-free survival (PFS), and the secondary end points were objective response rate (ORR), disease control rate (DCR), overall survival (OS) and adverse events (AE). The patients were grouped according to the diagnosis: osteosarcoma, soft tissue sarcoma and undifferentiated small round cell sarcoma. And the benefits of combination treatment was investigated with the stratified analysis of best outcome of combined therapy, lines of chemotherapy received, best response and PFS of original chemotherapy. Results: A total of 30 patients were included in this study, including 20 males and 10 females. The mean age was (25.6±14.7) years. There were 9 cases of osteosarcoma, 11 cases of soft tissue sarcoma and 10 cases of undifferentiated small round cell sarcoma. No patient achieved complete response, 8 patients (26.7%) achieved partial response, 19 patients (63.3%) achieved disease stability, the ORR was 26.7%(8/30), and the DCR was 90.0%(27/30). The median PFS and OS were 4.1 and 13.1 months respectively. Among the three different subtypes of sarcoma, the ORR of osteosarcoma was 44.4% (4/9), the median PFS was 4.1 months, and the median OS was not yet achieved; the ORR of undifferentiated small round cell sarcoma was 40% (4/10), the median PFS was 6.4 months, and the median OS was 10.9 months; No response was observed in soft tissue sarcoma, and the median PFS and median OS was 3.5 and 7.3 months respectively. Patients who achieved objective response had better PFS than patients with stable disease (12.8 vs 3.8 months, P=0.015), and patients with PFS≥ 6 months of original chemotherapy had better PFS benefits (12.7 vs 2.7 months, P<0.001). However, the number of original chemotherapy lines and the best response of original chemotherapy had no significant effect on the PFS of this combination regimen. In terms of safety, the related toxicity of apatinib was no more than grade 2, and the grade 4 chemotherapy-related adverse reactions was mainly hematological toxicity, of which 2 patients interrupted treatment because of febrile neutropenia. Conclusion: Low dose apatinib is effective in reversing chemotherapy resistance of osteosarcoma and undifferentiated small round cell sarcoma with acceptable adverse reactions.

Camrelizumab plus low-dose apatinib and SOX in the first-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma: A single-arm, dose-escalation and expansion study.

e16053 Background: The combination of camrelizumab, an anti-PD-1 monoclonal antibody, and apatinib, a selective VEGFR-2 inhibitor, has shown synergistic antitumor effects in G/GEJ adenocarcinoma patients. We aimed to evaluate the safety and efficacy of camrelizumab combined with low-dose apatinib and SOX in the first-line treatment of advanced G/GEJ adenocarcinoma. Methods: In this study (ChiCTR2000034109), eligible patients were diagnosed as unresectable or potentially resectable G/GEJ adenocarcinoma, HER2-negative or unknown HER2 status, and treatment-naive with inhibitors of VEGFR or PD-1/PD-L1. In dose escalation phase, 9 patients (3 in each group) were given with camrelizumab (200 mg, d1), apatinib (250 mg, qod/qd), and SOX regimen (oxaliplatin, 100/130 mg/m2, d1; S-1, 40 mg, bid, d1-14) every 3 weeks. Afterwards, the optimal combination integrated with safety and efficacy would be applied in dose expansion phase for another 33 patients. After up to 6-8 cycles of quadruple therapy, patients with complete response (CR)/partial response (PR)/stable disease (SD) would continue camrelizumab plus apatinib therapy until disease progression, intolerable toxicities, physician/patient withdrawal, or up to 2 years of camrelizumab therapy. The safety and efficacy were assessed by investigators per CTCAE v5.0 and RECIST v1.1, respectively. The primary endpoints were maximum tolerated dose and objective response rate (ORR). Results: From Jun 12, 2020 to Jul 26, 2021, no patient reported any dose-limiting toxicity in the dose escalation phase, thus another 11 eligible patients had been enrolled to receive quadruple therapy with apatinib (250 mg, qd) and oxaliplatin (130 mg/m2, d1). The patients were characterized with a median age of 59 years (range, 46-57), 30% GEJ adenocarcinoma, 100% lymph node metastasis, and 45% liver metastases. As of Nov 30, 2021, with a median follow-up of 10.9 months (range, 4.2-17.6), safety and efficacy were assessed in 19 evaluable patients, with overall response of 18 PR and 1 SD. Confirmed ORR and DCR were 94.7% (95% CI, 71.9%-99.7%) and 100% (95% CI, 79.1%-100%), respectively. The median PFS, median DOR and estimated 1-year OS rate were 8.3 months (95% CI, 6.1-10.5), 6.7 months (95% CI, 5.9-7.5) and 59.0%, respectively, with the median OS not reached yet. Conversion surgery had been conducted in 2/19 (10.5%) patients, with one case of pathological CR and one clinical CR. Grade 3-4 treatment-related adverse events occurred in 45% of patients, with rash ranking the most frequent. No new safety signal was identified. Conclusions: Camrelizumab combined with low-dose apatinib and SOX showed high level of safety and efficacy in the first-line treatment of advanced G/GEJ adenocarcinoma. Clinical trial information: ChiCTR2000034109.

Efficacy and safety of low-dose apatinib in advanced hepatocellular carcinoma.

4104 Background: Apatinib, a tyrosine kinase inhibitor, has shown promising effects on advanced hepatocellular carcinoma (HCC) recently. However, studies on its efficacy and safety are limited with controversial findings. Therefore, this study aimed to reveal the efficacy and safety of low-dose apatinib for the treatment of advanced HCC in the real world. Methods: Between January 2017 and August 2020, 178 patients with advanced HCC treated with apatinib at three different institutions were included for the present study. 174 patients received oral apatinib 250 mg daily and 4 received 500 mg daily until disease progression. 25 and 103 patients were also treated with immunotherapy and transcatheter arterial chemoembolization (TACE) at least once, respectively. Tumor response and adverse reactions were evaluated according to RECIST 1.1 and CTCAE 5.0 respectively. Survival curves were analyzed using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic value of variables in a univariate and multivariate setting. Results: During the 24-month follow-up period, 0 (0%), 28 (15.73%), 103 (57.87%) and 47 (26.40%) patients achieved a compete response (CR), partial response (PR), stable disease (SD), and progressive disease (PR), respectively. The overall response rate (ORR) and disease control rate (DCR) were 15.73% and 73.60% respectively. Interestingly, among the 28 patients with PR, 27 received apatinib as the first or second line treatment and 21 received immunotherapy or TACE as a combined treatment, indicating early application of apatinib and combination treatment could provide better efficacy. Kaplan-Meier analysis revealed the median overall survival (OS) and progressive-free survival (PFS) were 16.0 and 7.0 months respectively, which are significantly higher than previously reported survival of sorafenib in advanced HCC. Univariate Cox analysis indicated medication lines, distant metastasis, aplpha fetoprotein (AFP) level, portal vein tumor thrombus (PVTT) and combination therapy significantly affected OS and PFS. Multivariate Cox analysis confirmed third-line treatment (HR = 3.21; 95%CI = 1.54–6.68; p= 0.002), and PVTT (HR = 1.75; 95%CI = 1.13–2.70; p= 0.011) were independently associated with worse PFS. In contrast, apatinib combined with immunotherapy (HR = 0.52; 95%CI = 0.32–0.83; p= 0.008) or TACE (HR = 0.27; 95%CI = 0.18–0.40; p&lt; 0.001) were independently associated with better PFS. Similar findings were also present on OS. The most common treatment-related adverse events were hypertension (29.21%), fatigue (16.85%), hand and foot syndrome (16.29%), vomiting (14.04%), liver dysfunction (6.18%), and proteinuria (6.74%). No severe (grade ≥3) adverse events were observed. Conclusions: Low-dose apatinib is able to provide effective and safe treatment for advanced HCC. Early application of apatinib and combination treatment could provide even better efficacy.

Low-dose apatinib combined with neoadjuvant chemotherapy in the treatment of early-stage triple-negative breast cancer (LANCET): A single-center, single-arm, phase II trial.

e12613 Background: Anti-angiogenic therapy combined with chemotherapy could improve pathologic complete response for breast cancer. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits VEGF receptor 2. We assessed the efficacy and safety of the combination therapy of apatinib and standard chemotherapy in patients with triple negative breast cancer (TNBC). Methods: This single-arm, phase II study enrolled patients aged 18-70 years with previously untreated stage IIA-IIIB TNBC. Patients received oral apatinib at a dose of 250 mg once daily and intravenously docetaxel every three weeks for four cycles, followed by epirubicin plus cyclophosphamide every three weeks for four cycles. The primary endpoint was the pathological complete response (pCR) rate in the breast and lymph nodes. Secondary endpoints included objective response rate, event-free survival (EFS), overall survival (OS), and safety. Results: Between August 1, 2018 and March 10, 2021, we screened 34 patients and enrolled 31 patients. At the date of cut-off on December 31, 2021, the median follow-up time was 22.9 months (range: 10.1-41.6 months). The pCR in both breast and lymph nodes were achieved in 17 (54.8%; 95%CI: 36.0–72.7) of 31 patients. Objective responses were achieved in 29 patients (93.5%; 95%CI: 78.6-99.2), and disease control was achieved in 31 patients (100%; 95%CI: 88.8–100.0). The 2-year EFS and 2-year OS were 90.9% and 94.4%, respectively. The five most common treatment-related adverse events were fatigue (51%), hypertension (41%), anorexia (39%), hand-foot syndrome (35%), and diarrhea (32%). Few grade 3 or more adverse events were observed. Conclusions: The combination of apatinib with docetaxel followed by the epirubicin plus cyclophosphamide showed excellent efficacy and manageable toxicities; further randomized controlled phase III trials are warranted. Clinical trial information: NCT03243838.

Studies of the Efficacy of Low-Dose Apatinib Monotherapy as Third-Line Treatment in Patients with Metastatic Colorectal Cancer and Apatinib's Novel Anticancer Effect by Inhibiting Tumor-Derived Exosome Secretion.

Simple SummaryWe assessed the efficacy and safety of low-dose apatinib monotherapy as a third-line treatment in patients with metastatic colorectal cancer. The ORR and DCR were 4.0% (2/50) and 70% (35/50), and the median PFS and OS were 4.7 months and 10.1 months, which demonstrated comparable survival outcomes, significant improvements to the patient’s quality of life, and tolerable adverse reactions. We also disclosed a novel role of apatinib’s anticancer effect, i.e., inhibiting tumor-derived exosome release. Our results indicated that apatinib treatment inhibited exosome secretion through the regulation of MVB biogenesis, transport, and fusion by regulating LAMP2, RAB11, Snap23, and VAMP2. This novel regulatory mechanism provides a new perspective for the antitumor effect of apatinib in CRC treatment.Antiangiogenic therapy is an important treatment strategy for metastatic colorectal cancer (mCRC). We carried out a clinical study of low-dose apatinib (250 mg) monotherapy as a third-line treatment in patients with mCRC and assessed its efficacy and safety. It demonstrated that low-dose apatinib had comparable survival outcomes, significantly improved the patient quality of life, and caused tolerable adverse reactions. To further investigate the underlying mechanism of the effects of apatinib in CRC besides angiogenesis, we performed RNA-seq, and our results suggested that apatinib may have other potential antitumor mechanisms in CRC through multiple pathways, including exosomes secretion. In RKO and HCT116 cells, apatinib significantly reduced exosomes secretion by targeting multivesicular body (MVB) transport. Further studies have indicated that apatinib not only promoted the degradation of MVBs via the regulation of LAMP2 but also interfered with MVB transport by inhibiting Rab11 expression. Moreover, apatinib inhibited MVB membrane fusion by reducing SNAP23 and VAMP2 expression. In vivo, apatinib inhibited orthotopic murine colon cancer growth and metastasis and reduced the serum exosomes amount. This novel regulatory mechanism provides a new perspective for the antitumor effect of apatinib beyond angiogenesis inhibition.