apatinib and Sarcoma

Bone and soft tissue sarcomas are rare malignant tumors originated from mesenchymal tissues. They harbor more than 50 distinct subtypes and differ in pathological features and clinical courses. Despite the significant improvements in modern multi-modality treatment, the outcomes and overall survival rates remain poor for patients with advanced, refractory, metastatic, or relapsed diseases. The growth and metastasis of bone and soft tissue sarcoma largely depend on angiogenesis, and VEGF/VEGFR pathway is considered as the most prominent player in angiogenesis. Therefore, blockade of VEGF/VEGFR pathways is a promising therapeutic strategy to retard neovascularization. Several VEGFR inhibitors have been developed and revealed their favorable anti-neoplastic effects in various cancers, but such desirable anti-tumor effects are not obtained in advanced sarcomas because of multiple reasons, such as drug tolerance, short duration of response, and severe adverse effects. Fortunately, preclinical and clinical studies have indicated that apatinib is a novel promising VEGFR2 inhibitor showing potent anti-angiogenic and anti-neoplastic activities in advanced sarcomas. Especially, apatinib has showed notable characteristics in multidrug resistance reversal, tumor regression, vascular normalization, immunosuppression alleviation, and enhancement of chemotherapeutic and radiotherapeutic effects. However, apatinib also gets struck in dilemma of reversing multidrug resistance of chemotherapeutic agents while suffering drug resistance itself, and several difficulties should be tackled before full use of apatinib. In this review, we discuss the outstanding characteristics and main predicaments of apatinib as targeted therapy in advanced sarcomas. Bone and soft tissue sarcomas are rare but malignant tumors originated from mesenchymal tissues. They harbor more than 100 distinct subtypes and differ in features of pathologies and clinical courses. Despite the significant improvements in modern multi-modality treatment, the outcomes and overall survival rates remain poor for patients with advanced, refractory, metastatic, or relapsed lesions. The growth and metastasis of bone and soft tissue sarcoma largely depend on angiogenesis and VEGF/VEGFR pathways play a pivotal role in angiogenesis. Therefore, blockade of VEGF/VEGFR pathways is a promising therapeutic strategy. Several VEGFR inhibitors have been developed and verified in clinical trials but with unfavorable outcomes. Fort

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Bone Neoplasms; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neovascularization, Pathologic; Pyridines; Sarcoma

Cell-based  immunotherapy shows the therapeutic potential in sarcomas, in addition to angiogenesis-targeted tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI). Multi-antigen stimulated cell therapy-I (MASCT-I) technology is a sequential immune cell therapy for cancer, which composes of multiple antigen-loaded dendritic cell (DC) vaccines followed by the adoptive transfer of anti-tumor effector T-cells.. In this phase 1 study, we assessed MASCT-I plus camrelizumab (an ICI against PD-1) and apatinib (a highly selective TKI targeting VEGFR2) in patients with unresectable recurrent or metastatic bone and soft-tissue sarcoma after at least one line of prior systemic therapy. One MASCT-I course consisted of 3 DC subcutaneous injections, followed by 3 active T cell infusions administered 18-27 days after each DC injection. In schedule-I group, 3 DC injections were administered with a 28-day interval in all courses; in schedule-II group, 3 DC injections were administered with a 7-day interval in the first course and with a 28-day interval thereafter. All patients received intravenous camrelizumab 200 mg every 3 weeks and oral apatinib 250 mg daily.. From October 30, 2019, to August 12, 2021, 19 patients were enrolled and randomly assigned to schedule-I group (n = 9) and schedule-II group (n = 10). Of the 19 patients, 11 (57.9%) experienced grade 3 or 4 treatment-related adverse events. No treatment-related deaths occurred. Patients in schedule-II group showed similar objective response rate (ORR) with those in schedule-I group (30.0% versus 33.3%) but had higher disease control rate (DCR; 90.0% versus 44.4%) and longer median progression-free survival (PFS; 7.7 versus 4.0 months). For the 13 patients with soft-tissue sarcomas, the ORR was 30.8%, DCR was 76.9%, and median PFS was 12.9 months; for the 6 patients with osteosarcomas, the ORR was 33.3%, the DCR was 50.0%, and median PFS was 5.7 months.. Overall, MASCT-I plus camrelizumab and apatinib was safe and showed encouraging efficacy in advanced bone and soft-tissue sarcoma, and schedule-II administration method was recommended.. ClinicalTrials.gov, NCT04074564.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Humans; Pilot Projects; Protein Kinase Inhibitors; Sarcoma

There is no standard treatment for stage IV soft tissue sarcoma (STS) after the failure of Adriamycin-based chemotherapy. This phase II study (NCT03121846) assessed the efficacy and safety of apatinib (YN968D1), a new tyrosine kinase inhibitor that targets VEGFR-2, for patients with stage IV STS after chemotherapy failure.. Forty-two subjects with stage IV STSs who had failed chemotherapy and who received Apatinib were recruited between September 2015 and February 2018. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the PFS rate (PFR), objective response rate (ORR), and disease control rate (DCR) at week 12. Treatment-related adverse effects (AEs) were evaluated.. Forty-two subjects were evaluated for AEs and 38 subjects were evaluated for efficacy. At 12 weeks, the PFR, ORR, and DCR were 70%, 26.32% (10/38), and 86.84% (33/38), respectively. Regarding overall responses, the ORR and DCR were 23.68% (9/38) and 57.89% (22/38), respectively. The median PFS was 7.87 months, and the median overall survival (OS) was 17.55 months. The most common AEs included hypertension (n = 18, 42.86%), hand-foot-skin reaction (n = 15, 35.71%), apositia (n = 13, 30.95%), and proteinuria (n = 11, 26.19%). No subjects had grade 4 AEs and 11 subjects (26.19%) experienced grade 3 AEs, mainly hypertension, hand-foot-skin reaction, proteinuria, apositia, fatigue, pain, and dysgeusia. Notably, the subjects who experienced hypertension, hand-foot-skin reaction, or proteinuria had significantly longer OS than those without these AEs (P = 0.0003).. With the largest Chinese STS cohort to date, we report that apatinib show good efficacy in advanced STS subjects with significant higher ORR and some adverse events may predict prognosis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; China; Cohort Studies; Female; Humans; Male; Middle Aged; Pyridines; Sarcoma; Survival Rate; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2

Apatinib (YN968D1) is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2). We conducted a single-arm, nonrandomized phase II study (NCT03121846) to assess the efficacy and safety of apatinib in patients with stage IV sarcoma. We recruited 64 patients with stage IV sarcoma who had failed chemotherapy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were progression-free survival rate (PFR), objective response rate (ORR), and disease control rate (DCR) at week 12. Treatment-related adverse effects (AEs) were evaluated. Fifty-nine patients were assessed for efficacy and 64 patients for AEs. The median PFS was 7.93 months. At 12 weeks, the PFR was 74%, the ORR was 16.95% (10/59), and the DCR was 86.44% (51/59). The final ORR was 15.25% (9/59) and the DCR was 57.63% (34/59). Notably, 22 patients (34.38%) who developed hypertension, hand-foot-skin reaction, or proteinuria had significantly longer OS than those without these AEs (18.20 vs. 10.73 months; P = 0.002). We conclude that apatinib is effective and well tolerated in patients with advanced sarcoma. The development of hypertension, hand-foot-skin reaction, or proteinuria may indicate a favorable prognosis, representing a novel finding in sarcoma patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Child; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Progression-Free Survival; Protein Kinase Inhibitors; Pyridines; Sarcoma; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2; Young Adult

Sarcoma is a rare tumor with more than 50 histologic subtypes. Patients with advanced sarcoma have a poor prognosis. The aim of this study was to evaluate the efficacy and safety of apatinib, an oral vascular endothelial growth factor receptor-2 inhibitor, as salvage treatment for advanced bone and soft tissue sarcomas. From May 2017 to July 2018, a prospective, open-label, nonrandomized, clinical trial of apatinib was carried out in selected patients with advanced sarcoma. After apatinib dosing, progression-free survival (PFS), overall survival (OS), objective response rate, disease control rate, and treatment-related adverse events (AEs) were reviewed and evaluated. Patients were administered apatinib for at least 1 month. Median follow-up time was 6.00 months (1-13 months). The median PFS was 7.88 months, with the longest PFS of 13 months observed in a patient with epithelial sarcoma. The 3-month PFS rate was 66.44%. The median OS was 11.64 months with significant differences observed based on disease subtypes. Four patients achieved a partial response, and 36 patients achieved stable disease. The objective response rate was 8.88% (4/45), and the disease control rate was 88.89% (40/45). The most common grade 3/4 treatment-related AEs were hypertension (12.50%), hand-foot syndrome (6.67%), diarrhea (12.50%), fatigue (6.25%), and proteinuria (14.29%). One drug-related severe AE of thrombocytopenia (21×10/l) occurred 2 months after therapy. Apatinib treatment in our study exhibited objective efficacy in PFS, OS, and manageable toxicity in patients with advanced sarcoma. This result supports future randomized controlled trials to further define apatinib activity in stage IV sarcomas.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Child; Female; Follow-Up Studies; Humans; Male; Middle Aged; Non-Randomized Controlled Trials as Topic; Prognosis; Prospective Studies; Pyridines; Sarcoma; Survival Rate; Young Adult

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Humans; Neoplasm Recurrence, Local; Sarcoma

The study aimed to investigate the effectiveness and safety of the combination of immune checkpoint inhibitor, local interventional therapy, and anti-angiogenic therapy in patients with metastatic soft-tissue sarcoma (mSTS).. We retrospectively evaluated the medical records of patients with mSTS who started treatment between September 2018 and June 2020 at our hospital.. Overall, 33 patients with different subtypes of mSTS were included. Most primary tumors originated from the lungs, and the rest were scattered throughout the body. All patients were treated with camrelizumab combined with apatinib within 5 days of local interventional therapy using transarterial chemoembolization (TACE) or radiofrequency ablation (RFA). Primary end point was progression-free survival (PFS), and secondary end points were objective response rate (ORR), disease control rate (DCR), and patient safety.. The median PFS, median overall survival (OS), ORR, and DCR were 8.8 months, 18.5 months, 36.4%, and 75.8%, respectively. Patients (n = 20) treated with RFA combined with TACE showed better responses than those treated with RFA alone (n = 13), with mPFS of 9.3 and 7.9 months (P = 0.044) and mOS of 19.0 and 16.2 months (P = 0.043), respectively. Patients (n = 8) with alveolar soft part sarcomas showed excellent efficacy, with ORR, DCR, mPFS, and mOS of 62.5%, 87.5%, 11.5 months, and 22.5 months, respectively. Grades 3 or 4 treatment-related adverse events occurred in 12 of 33 patients.. Local intervention therapy combined with camrelizumab and apatinib is effective and safe for patients with mSTS and should be investigated in future clinical trials.

Topics: Antibodies, Monoclonal, Humanized; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Humans; Liver Neoplasms; Pyridines; Retrospective Studies; Sarcoma

The present study aims to examine the effects of apatinib combined with autophagy inhibitor 3-Methyladenine (3-MA) on the proliferation and apoptosis of human uterine sarcoma in FU-MMT-1 and MES-SA cells and its tumor inhibition effect in xenograft model of uterine sarcoma.. Different concentrations of 3-MA and apatinib were used to treat the uterine sarcoma cell lines (MES-SA and FU-MMT-1 cells). The cell viability was detected by CCK8 method. Flow cytometry was used to detect the apoptosis and cell cycle. Wound closure assay and Transwell assay were performed to measure the migration ability of cells. Western blot was used to determine the apoptosis proteins and autophagy proteins. A nude mice sarcoma xenograft model was established and treated with apatinib alone, 3-MA alone, or combined incubation of them. Tumor size of xenograft and the mice survival rate were measured.. Combination of 3-MA and apatinib significantly inhibited the proliferation and migration ability, but increased the apoptosis rate of uterine sarcoma cells compared to apatinib. The combination of 3-MA and apatinib significantly limited the tumor size of xenograft and increased the survival rate of mice compared to apatinib alone. Apatinib inhibited the PI3K/Akt/mTOR pathway, while 3-MA and the combination of 3-MA and apatinib significantly activated the PI3K/Akt/mTOR pathway and inhibited autophagy. Combination of 3-MA and apatinib increased apoptosis compared to apatinib alone. The expression of VEGFR-2 was not impacted by 3-MA.. Combination of apatinib and autophagy inhibitor 3-MA significantly inhibited the growth and migration of uterine sarcoma cells and xenograft. Autophagy inhibition may increase the antitumor effect of apatinib via the PI3K/Akt/mTOR pathway.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyridines; Sarcoma; Signal Transduction; TOR Serine-Threonine Kinases; Uterine Neoplasms; Xenograft Model Antitumor Assays

Background Previous studies have demonstrated the efficacy of apatinib and anlotinib for the treatment of sarcomas. However, more clinical data and evidence are needed to support clinical treatment selection and study design. Here, we evaluated the effectiveness and safety of these two drugs for the treatment of sarcomas. Methods We retrospectively reviewed the data of 110 patients with advanced osteosarcoma (n = 32) or soft tissue sarcoma (STS, n = 78) who received oral apatinib or anlotinib therapy during May 2016-February 2019 at two centers. Patients were divided into the apatinib and anlotinib groups. Results Among osteosarcoma patients, the objective response rates (ORRs) for the apatinib and anlotinib groups were 15.79% (3/19) and 7.69% (1/13), respectively. The disease control rates (DCRs) were 63.16% (12/19) and 30.77% (4/13), and the median progression-free survival (m-PFS) was 4.67 ± 3.01 and 2.67 ± 1.60 months, respectively. Among STS patients, ORRs for the apatinib and anlotinib groups were 12.24% (6/49) and 13.79% (4/29), respectively. The DCRs were 59.18% (29/49) and 55.17% (16/29), and m-PFS was 7.82 ± 6.90 and 6.03 ± 4.50 months, respectively. Regarding adverse events (AEs), apatinib was associated with a higher incidence of hair hypopigmentation and pneumothorax, while anlotinib was associated with a higher incidence of pharyngalgia or hoarseness. Conclusion Both apatinib and anlotinib were effective for the treatment of sarcomas. However, the effectiveness of the two drugs and associated AEs varied based on the histological type of sarcoma. These differences may be due to their different sensitivities to targets such as RET, warranting further study.

Topics: Adolescent; Adult; Antineoplastic Agents; Child; Female; Humans; Indoles; Kaplan-Meier Estimate; Male; Middle Aged; Osteosarcoma; Progression-Free Survival; Protein Kinase Inhibitors; Pyridines; Quinolines; Retrospective Studies; Sarcoma; Soft Tissue Neoplasms; Young Adult

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Child; China; Humans; Lung Neoplasms; Osteosarcoma; Pyridines; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome

Anti-angiogenesis Tyrosine kinase inhibitors (TKIs) have been proved to show promising effects on prolonging progression-free survival (PFS) for advanced sarcoma after failure of standard multimodal Therapy. Methylsulfonic apatinib is one of those TKIs which specifically inhibits VEGFR-2. This paper summarizes the experience of three Peking University affiliated hospitals in off-label use of apatinib in the treatment of extensively pre-treated sarcoma.. We retrospectively analysed files of patients with advanced sarcoma not amenable to curative treatment, who were receiving an apatinib-containing regimen between June 1, 2015 and December 1, 2016. Fifty-six patients were included: 22 osteosarcoma, 10 Ewing's sarcoma, 3 chondrosarcoma and 21 soft tissue sarcoma.. With median follow-up time of 6 months (range, 0.7-18.0 m), thirty-five (62.5%) patients had partial response, and disease was stable in 11 (19.6%). The 4-month and 6-month progression-free survival rates were 46.3 and 36.5%, respectively. The median duration of response was 3.8 months (95% CI 1.9-5.6 m), with much variability among disease subtypes. The median overall survival was 9.9 months (95% CI 7.6-12.2 m). Grade 3 and 4 toxicities were observed in 8 (14.3%) patients, the most common being hypertension, pneumothorax, wound-healing problems, anorexia, and rash or desquamation.. Apatinib might be effective, with a high objective response rate, in an off-label study of sarcoma patients with advanced, previously treated disease. The duration of response was consistent with reports in different subtypes of sarcomas. Prospective trials of apatinib in the treatment of selected subtypes of sarcomas are needed.. Retrospectively registered in the Medical Ethics Committee of Peking University People's Hospital, Peking University Shougang Hospital and Peking University International Hospital. The trial registration number is 2017PHB176-03 and the date of registration is January 20th 2017.

Topics: Adolescent; Adult; Antineoplastic Agents; Child; China; Follow-Up Studies; Humans; Middle Aged; Molecular Targeted Therapy; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Off-Label Use; Proportional Hazards Models; Protein Kinase Inhibitors; Pyridines; Sarcoma; Vascular Endothelial Growth Factor Receptor-2; Young Adult