Combination Of Apatinib Research Articles

Apatinib combined with PD-L1 blockade synergistically enhances antitumor immune responses and promotes HEV formation in gastric cancer.

Apatinib, an antiangiogenic drug, has shown beneficial effects only in a fraction of advanced gastric cancer (GC) patients. Given the recent success of immunotherapies, combination of apatinib with immune checkpoint inhibitor may provide sustained and potent antitumor responses. Immunocompetent mice with subcutaneous MFC tumors grown were given a combination of apatinib and anti-PD-L1 antibody therapy. GC tissues from patients undergoing curative resection in China were collected, and the density of HEVs, MSI status and tumor-infiltrated lymphocytes were analyzed by immunohistochemical staining. Combined apatinib and PD-L1 blockade therapy synergistically delayed tumor growth and increased survival in MFC-bearing immunocompetent mice. The combination therapy promoted antitumor immunity by increasing the ratio of CD8+ cytotoxic T cells to Foxp3+ Treg cells, the accumulation of CD20+ B cells and the Th1/Th2 cytokine ratio (IFN-γ/IL-10). The combination therapy induced the formation of HEVs through activation of LTβR signaling, thus promoting CD8+ cytotoxic T cell and CD20+ B cell infiltration in tumors. In clinical GC samples, the density of HEVs positively correlated with the intratumoral infiltration of CD8+ cytotoxic T cells and CD20+ B cells. MSI-high GC showed a higher density of HEVs, CD8+ cytotoxic T cells and CD20+ B cells than MSS/MSI-low GC. GC patients with high densities of HEVs, CD8+ cytotoxic T cells and CD20+ B cells had an improved prognosis with superior overall survival. Combining apatinib with PD-L1 blockade treatment synergistically enhances antitumor immune responses and promotes HEV formation in GC.

Regulatory Effects of Apatinib in Combination with Piperine on MDM-2 Gene Expression, Glutathione Peroxidase Activity and Nitric Oxide level as Mechanisms of Cytotoxicity in Colorectal Cancer Cells.

Purpose: Apatinib has been utilized in colon cancer therapies but its efficiency and molecularmechanism are not fully understood. Chemotherapy in combination with non-toxic compoundscan be an effective treatment strategy for cancer. Consequently, this study was carried out toevaluate the effects of apatinib and piperine on colorectal cancer (CRC) cell line and theirpotential anti-cancerous mechanisms in vitro. Methods: The effects of apatinib and piperine on HCT-116 CRC cells were detected byassessing cell viability using MTT assay. The potential cytotoxic mechanisms of apatinib andpiperine were investigated by evaluating MDM-2 gene expression ratio using real-time PCRassay. Moreover, the glutathione peroxidase (GPX) activity and nitric oxide (NO) levels wereassessed by colorimetric assays. Results: The proliferation rate of CRC cells decreased by increasing the concentrations ofpiperine or apatinib. When HCT-116 cells were treated with different concentrations of apatinibin combination with piperine, the synergistic effects were observed (combination index < 1).In HCT-116 cells treated with apatinib and piperine at the concentrations of 0.5×IC50 and0.2×IC50, the MDM-2 gene expression was downregulated and NO levels increased comparedto the untreated control cells and related single treatments. In addition, GPX activity significantlydecreased in combination treatment at 0.5×IC50 concentration of both agents versus singletreatments. Conclusion: Apatinib in combination with piperine could significantly inhibit the growth ofCRC cells. These cytotoxic effects were induced by regulation of MDM-2 gene expression andinhibition of antioxidant marker.

P86.17 Continuous Administration of Low-Dose Apatinib Combined With WBRT for Non-Small Cell Lung Cancer With Symptomatic Brain Metastases

Symptomatic multiple brain metastases occur in non-small cell lung cancer patients (NSCLC) who are without driver mutations or are resistant to epidermal growth factor tyrosine kinase (EGFR-TKI) are often associated with a unfavourable prognosis. Whole brain radiation therapy (WBRT) which comes with many complications and unsatisfactory effects, is the only option for the treatment. Previous studies have shown that antiangiogenesis combined with WBRT can improve efficiency and prolong survival. This study evaluated the effects and safety of apatinib combined with WBRT in NSCLC patients with symptomatic multiple brain metastases. We performed a retrospective review of 13 patients with multiple brain metastases from NSCLC treated with apatinib (125mg or 250mg, QD, oral) and WBRT. Intracranial objective response rate (IORR), peritumoral edema volumetric measurement, karnofsky performance status (KPS) and adverse events (AEs) were evaluated. Median intracranial progression-free survival (mIPFS) and median overall survival (mOS) were also analyzed. Thirteen patients with NSCLC who were diagnosed with symptomatic multiple brain metastases received apatinib combined with WBRT were inclued, including 1 lung squamous cell carcinoma (LSCC) and 12 lung adenocarcinoma. Six patients were EGFR-TKI resistant, while the other six were without driver mutations. Until the last follow-up in March 2020, 5 patients died, and 8 patients were still alive. The IORR was 84.6% (11/13) and intracranial disease control rate (IDCR) was 100% (13/13). The median edematous volume decreased by 87.96% (range 42% to 98%, p < 0.001), the average KPS score increased from 62.31 ± 12.35 to 82.31 ± 9.27 (t = -8.83, P < 0.001). The mIPFS was 6.7 months [95% confidence interval (CI): 4.3 - 9.1], and the mOS was 8.8months (95% CI: 5.8 - 11.8). The most commonly adverse events of apatinib combination WBRT included grade 1/2 fatigue (3, 23.1%), inappetence (3, 23.1%), hypertension (2, 15.4%) and leukopenia (2, 15.4%), and no grade 3/4 AEs were observed. This retrospective study suggests that NSCLC patients with multiple brain metastases treated with apatinib combined with WBRT, achieved encouraging therapeutic effects, showed a significant reduction in tumor size and peritumoral edema, enjoyed an improved KPS score and experienced prolonged survival time. Apatinib combined with WBRT is well tolerated and may be a potential choice for relapsed or drug-resistant advanced NSCLC patients with symptomatic multiple brain metastases.

P86.02 Pyrotinib Combined with Apatinib for HER2-Mutant Non-Small Cell Lung Cancer: Interim Analysis from a Phase II Clinical Study

Currently, there has been no approved tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC) harboring HER2 mutations, resulting in an unmet need of this molecular entity. We performed this phase II study to assess the efficacy and safety of pyrotinib combined with apatinib in HER2-mutant advanced NSCLC patients who had failed to prior treatment. Patients with metastatic HER2-mutant lung adenocarcinomas who had been pretreated with chemotherapy or other TKIs were enrolled to administer pyrotinib (dose of 400mg once daily) in combination with apatinib (dose of 250mg once daily) for 28-day cycles. The primary endpoint was objective response rate (ORR), and the second endpoint included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR), overall survival (OS) and safety. The trial was approved by ethics committee and registered to Chinese Clinical Trial Registry (ChiCTR1900021684). All participants of this study provided written informed consent. Between March 5, 2019, and January 20, 2020, 14 patients were enrolled and received pyrotinib with apatinib combination therapy, and all of them were stage IV at baseline. Seven (50.0%) patients had received first-line platinum-based chemotherapy or afatinib treatment, and the others had received at least 2 lines of prior therapy (range, 2-6). At the last follow-up time July 14, 2020, among these 14 evaluable patients, the ORR was 35.7% (5/14), and it showed no difference between patients with or without brain metastases (ORR, 40.0% vs 33.3%; median PFS, 6.6 vs. 8.0 months, P = 0.623). All subgroups of patients (10 with exon 20 insertions, 2 with missense mutations and 2 with amplifications) showed disease control with a DCR of 100%. The median PFS, DoR and OS were 8.0 (95%CI: 5.8-10.2), 5.3 (95%CI: 3.6-7.0) and 12.9 (95%CI: 3.8-22.0) months, respectively. The ORR in patients who administered pyrotinib with apatinib as second-line and third- or above-line treatment was 28.6% (2/7) and 42.9% (3/7), respectively; and median PFS did not differ in these two subgroups [8.8 (95%CI: 6.6-11.0) vs. 6.1 (95%CI: 4.0-8.2) months; HR=0.362; P = 0.144]. Common treatment-related adverse events included diarrhea (7.1%, grade 3; 64.3%, grade 2), hypertension (21.4%, grade 2; 50.0%, grade 1) and anorexia (57.1%, grade 1). No treatment-related deaths were reported. Patient characteristics at baseline and response for pyrotinib with apatinibTabled 1ParametersGroupsN (%)Age>602 (14.3)≤6012 (85.7)GenderMale7 (50.0)Female7 (50.0)Molecular variantA775_G776insYVMA9 (64.3)P780_Y781insGSP1 (7.1)G776V1 (7.1)R811L with Q820K1 (7.1)HER2 amplification2 (14.4)Prior lines of treatment17 (50.0)23 (21.4)≥34 (28.6)Brain metastasesPresence5 (35.7)Absence9 (64.3)Partial responseG766V HER2 amplification A775_G776insYVMA1 (7.1) 1 (7.1) 3 (21.4) Open table in a new tab Pyrotinib in combination with apatinib showed favorable antitumor activity and acceptable safety in heavily pretreated NSCLC patients with diverse HER2 mutations.

Abstract PS13-12: Apatinib combined with taxanes and platinum neoadjuvant chemotherapy for patients with triple-negative and HER2-positive breast cancer: A multicenter, randomized, open-label, phase II trial

Abstract Background: Apatinib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR2), has demonstrated a promising efficacy in patients with metastatic breast cancer. For triple-negative and HER2-positive subtypes, increasing the pathological complete response (pCR) of neoadjuvant therapy may benefit their clinical outcomes. Here, we assessed whether the combination of Apatinib with neoadjuvant chemotherapy elevate the pCR rate in locally advanced breast cancer. Method: In this multicenter, open-label trial, we randomized 53 patients into TP neoadjuvant chemotherapy (docetaxel 75 mg/m2 or nab-paclitaxel 260 mg/m2 or paclitaxel liposome 175 mg/m2 day 1, and carboplatin AUC=6 or cisplatin 75 mg/m2 or lobaplatin 30 mg/m2 day 1), or combined with apatinib (500mg day 1-21) . Trastuzumab was added to neoadjuvant therapy in HER2-positive subtype. Six cycles were repeated every 3 weeks. Results: In total patients with stage IIb-IIIc triple-negative and HER2-positive breast cancer, the addition of apatinib to TP neoadjuvant chemotherapy (Apa+TP) significantly increased the pCR rate (70.8%, 17/24), compared with TP along (41.4%, 12/29), P=0.032. When separating patients into triple-negative (Apa+TP 66.7% (8/12) vs. TP 42.9% (3/7)) and HER2-positve (Apa+TP 75% (9/12) vs. TP 40.9% (9/22)) subtypes, the effect of apatinib on pCR was also improved though no significant differences were found (P=0.377; P=0.080 separately) compared with control group. The most common Grade 3-4 adverse events (AE) included hypertension (Apa+TP 12.5% vs. TP 0%, P=0.173), hand-foot syndrome (Apa+TP 8.3% vs. TP 0%, P=0.389) and erythra (Apa+TP 4.2% vs. TP 0%, P=0.924). No significant differences of toxic effects were found between Apa+TP and control group. Conclusion: Apatinib combined with TP neoadjuvant chemotherapy significantly increased the pCR rate in patients with locally advanced triple-negative and HER2-positive breast cancer, indicating an applicable strategy in the future. EfficacyTriple-negative breast cancer efficacyHer2-positive breast cancer efficacySafety Citation Format: Yunjiang Liu, Xiangmei Zhang, Li Wang, Miao Cao, Shuo Zhang, Hui Zhang, Yarong Zhou, Jintian Wang. Apatinib combined with taxanes and platinum neoadjuvant chemotherapy for patients with triple-negative and HER2-positive breast cancer: A multicenter, randomized, open-label, phase II trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-12.

Efficacy and safety of apatinib in treatment of gastric cancer: A real-world study.

182 Background: Apatinib is a small molecule TKI inhibitor, which had been approved in China for treatment of advanced gastric cancer refractory to two or more lines of prior chemotherapy. Its efficacy and safety have been demonstrated in previous randomized controlled clinical studies. However, the efficacy and safety of apatinib in real world is lacking. This study aimed to evaluate the anti-tumor activity and toxicity of apatinib in real world. Methods: Patients older than 18 years with histologically diagnosed with gastric cancer were enrolled and treated with either apatinib alone or in combination with other drugs. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), overall response rate (ORR) and disease control rate (DCR). The adverse events were also recorded. Results: From March 2018 to March 2019, a total of 1000 patients were enrolled. Among them, 48(0.48%), 13(0.13%), 225 (22.5%), 389 (38.9%), and 325 (32.5%) patients received apatinib as postoperative auxiliary-, neoadjuvant-, first-, second-, and third- or higher line therapy, respectively. Efficacy evaluation was performed in 901 patients. Thirty-five patients achieved complete response (CR), 116 patients achieved partial response (PR), 596 patients achieved stable disease (SD), and 154 patients had progressive disease (PD), illustrating an ORR of 16.76% and a DCR of 82.91%. The mPFS was 5.32 months (95% CI, 4.93-5.75), and mOS was 9.76 months (95% CI, 8.97-10.81). In addition, the mOS of apatinib in first-line, second-line, and third-line treatments were 12.68 months, 9.49 months, and 7.62 months, respectively. Patients received apatinib in combination with other drugs had longer survival than apatinib alone, with mPFS 5.62 months vs 4.47 months and mOS 10.81 months vs 7.95 months. Such phenomenon was also observed in ORR (18.21% vs 13.04%, P&lt; 0.001) and DCR (84.88% vs 77.87%, P&lt; 0.001). The main adverse events (AE) were anemia (67.2%), thrombocytopenia (36.2%), leukopenia (34.5%)and anorexia (37.6%). The most common grade 3-4 adverse events included neutropenia, anemia and thrombocytopenia. Conclusions: In the real world, apatinib showed promising efficacy and manageable toxicities in patients with gastric cancer. Patients benefit more when received apatinib combination therapy. Clinical trial information: NCT03478943.

Prospective, multicenter study of apatinib combine with TACE in treating intermediate to advanced stage HCC patients: A real-world study from China.

282 Background: Combination of transcatheter arterial chemoembolization (TACE) with apatinib are emerging as an effective treatment for patients with intermediate to advanced stage HCC. However, the data of HCC treated by apatinib in the real-world setting are not reported. In this real-world study, we aimed to explore the efficacy and safety of HCC pts which underwent TACE combine with apatinib. Methods: This was a prospective, multicenter observational study in a real-world setting and this study was approved by our Ethics Committee. Pts aged ≥18 years with well diagnosed intermediate or advanced stage HCC were included. The pts received apatinib plus TACE treatment as the first-line therapy. TACE treatment was performed on demand, the dose of apatinib was selected by the investigator. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival rate (OS), objective response rate (ORR), disease control rate (DCR) and safety profile. All of the objective response was assessed by independent central review per mRECIST criteria. Results: From Jun 2019 to Feb 2020, a total of 98 well diagnosed HCC pts with age from 31 to 86 were enrolled in this study. As of August 2020, the median follow-up was 9.5 months. The mPFS of 98 pts was 7 months. The ORR, DCR and 6 months OS rate was 35.7%, 76.5% and 82.6%, respectively.The PFS was 7.5 months in intermediate stage and 6.4 months in advanced stage. The ORR was 46.3% in intermediate stage (41 cases) and 28% in advanced stage (57 cases) HCC. And the 6 months OS rate was 90.2% in intermediate stage and 77.1% in advanced stage HCC. Overall, 17 (17.3%) pts had grade≥3 treatment-related AEs. All of the safety adverse effects can be tolerated or reduced after symptomatic treatment and no unexpected adverse events were observed. Conclusions: In this real-world study, apatinib showed a favorable efficacy and safety profile in pts with intermediate and advanced stage cancer. Apatinib combination TACE therapy might lead to better survival benefit in first-line treatment for HCC pts. Clinical trial information: ChiCTR1900024030.

Continuous Low-Dose Apatinib Combined With WBRT Significantly Reduces Peritumoral Edema and Enhances the Efficacy of Symptomatic Multiple Brain Metastases in NSCLC.

Background:Symptomatic multiple brain metastases with peritumoral brain edema (PTBE) occur in non-small cell lung cancer patients (NSCLC) who are without driver mutations or are resistant to epidermal growth factor tyrosine kinase (EGFR-TKI) are often associated with an unfavorable prognosis. Whole brain radiation therapy (WBRT) which comes with many complications and unsatisfactory effects, is the only option for the treatment. Previous studies have shown that bevacizumab can reduce the volume of PTBE and improve efficiency of radiotherapy. This study evaluated the effects and safety of apatinib combined with WBRT in NSCLC patients with symptomatic multiple brain metastases and PTBE.Methods:We performed a retrospective review of 34 patients with symptomatic multiple brain metastases from NSCLC (number >4, and at least 1 measurable brain metastasis lesion with cerebral edema). Intracranial objective response rate (IORR), peritumoral edema and intracranial tumor volumetric measurement, Karnofsky performance status (KPS) and adverse events (AEs) were evaluated. Median intracranial progression-free survival (mIPFS) and median overall survival (mOS) were also analyzed.Results:Thirteen cases received apatinib (125 mg or 250 mg, QD, oral) combined with WBRT and 21 cases received chemotherapy combined with WBRT were inclued. Apatinib combination group can better reduce the volume of intracranial tumors and PTBE and total steroid dosage used. It was associated with a better IORR (84.6% vs 47.6%, P = 0.067), longer mIPFS (6.97 vs 4.77months; P = 0.014). There was no significant difference in mOS(7.70 vs 6.67 months; P = 0.14) between the 2 groups. The most common adverse events of apatinib combination WBRT included grade 1/2 nausea (4/13), fatigue (3/13), hypertension (2/13) and white blood cell decrease (2/13). No grade 3/4 AEs were observed.Conclusion:Apatinib plus WBRT is well tolerated and may be a potential choice for relapsed or drug-resistant advanced NSCLC patients with symptomatic multiple brain metastases and PTBE.

A Phase I Dose Escalation Study of Apatinib Combinated with Docetaxel as Second-line Therapy for Advanced Gastric Carcinoma

This study is a phase I clinical trial of 3+3 dose escalation. Three dose escalations of apatinib were employed in this study: 425 mg, 500 mg and 675 mg. Apatinib combined with fixed dose of docetaxel (60 mg/m2, d1, thrice inw). 21 d as one treatment cycle was repeated. Maximum tolerated dose, safety and efficacy were analyzed. From October 2015 to June 2017, a total of eight patients with advanced gastric or gastro-oesophageal junction adenocarcinoma who had failed in the previous first-line treatment were enrolled. One dose-limiting toxicity was observed in patients who received apatinib with the dose of 425 mg combined with docetaxel, but no dose-limiting toxicity was found in additional three patients. Two patients treated with apatinib at the dose of 500 mg combined with docetaxel experienced dose-limiting toxicity, including grade 3 oral mucositis and grade 4 neutropenia respectively. Therefore, Maximum tolerated dose of apatinib was 425 mg. No complete response and partial response were observed; five patients showed stable disease and two had progressive disease. The disease control rate was 71.43 %. The median progression free survival was 4.4 mo (95 % confidence interval, 1.48-7.03) and the median overall survival was 11.5 mo (95 % confidence interval, 3.06-16.56). All patients developed adverse events and treatment-related adverse events. Seven patients (77.78 %) showed treatment-related adverse events greater than or equal to grade 3, mostly including neutropenia and hand-foot syndrome. The combination of apatinib with the dose of 425 mg and docetaxel was well tolerated and support further evaluation for the second-line treatment of advanced gastric cancer.

Phase II study of apatinib in combination with oral vinorelbine in heavily pretreated HER2-negative metastatic breast cancer and clinical implications of monitoring ctDNA.

Objective:Apatinib is an oral TKI targeting VEGFR-2. Single-agent apatinib treatment has been shown to produce an objective response in patients with pretreated mBC. Oral vinorelbine also holds promise as a treatment of choice in patients with mBC. This study aimed to investigate the efficacy and safety of the oral vinorelbine-apatinib combination in patients with pretreated mBC. In addition, we detected gene variants in ctDNA to explore the therapeutic implications.Methods:This study enrolled patients with HER2-negative mBC who were pretreated with anthracycline/taxanes. Patients were treated with apatinib at 500 mg/425 mg daily plus oral vinorelbine 60 mg/m2 on days 1, 8, and 15 of every cycle (3 weeks). The primary endpoint was PFS. The secondary endpoints were ORR, CBR, OS, and safety. Patients eligible for ctDNA detection were evaluated before and during treatment.Results:Forty patients were enrolled. The median PFS was 5.2 months (95% CI, 3.4–7.0 months), and the median OS was 17.4 months (95% CI, 8.0–27.0 months). The ORR was 17.1% (6/35), and the CBR was 45.7% (16/35). The most common AEs included gastrointestinal reaction, myelosuppression, and hypertension. In 20 patients, ctDNA was detected at baseline and during treatment. A significant difference was found in PFS for undetected vs. detected baseline ctDNA (13.9 months vs. 3.6 months, P = 0.018).Conclusions:All-oral therapy with apatinib plus vinorelbine displayed objective efficacy in patients with heavily pretreated HER2-negative mBC, with acceptable and manageable toxicity profiles. Patients with no gene variant detected and lower variant allele frequencies in ctDNA at baseline showed longer PFS.

Raltitrexed Enhances the Antitumor Effect of Apatinib in Human Esophageal Squamous Carcinoma Cells via Akt and Erk Pathways.

ObjectiveApatinib has been proved effective in the treatment of advanced gastric cancer and a variety of solid tumors. Raltitrexed is emerging as a promising alternative for treating advanced colorectal cancer in China. This work aims to study the combinatory antitumor effect of apatinib and raltitrexed on human esophageal squamous carcinoma cells (ESCC).Materials and MethodsTwo VEGFR-2-positive human ESCC lines, KYSE-30 and TE-1, were treated with apatinib or raltitrexed, or both, then the cell proliferation rate was measured by MTS assay; cell migration and invasion were studied by transwell assays; cell apoptosis rate was determined by flow cytometry; cellular autophagy level affected was analyzed by Western blot analysis; finally, quantitative polymerase chain reaction (qPCR) was used to monitor transcription and Western blot was performed to check phosphorylation of apoptotic proteins after treatment.ResultsBoth apatinib and raltitrexed significantly inhibited KYSE-30 and TE-1 cell proliferation in a dose-dependent manner. Treatment with both drugs showed enhanced inhibitory effects on cell proliferation, migration, and invasiveness compared with apatinib monotherapy. Apoptosis percentages in both cell lines were also remarkably increased by the combined treatment. Moreover, the combination of apatinib and raltitrexed down-regulated mRNA level of the anti-apoptotic protein Bcl-2, while up-regulated pro-apoptotic protein PARP, Bax, and caspase-3 transcription. Western blot analysis showed that phosphorylation levels of Erk, Akt, and invasiveness-associated protein matrix metalloproteinases-9 (MMP-9) were decreased in the combination group.ConclusionTaken together, these results indicate that raltitrexed enhances the antitumor effects of apatinib on human ESCC cells by down-regulating phosphorylation of Akt and Erk, implying a combination of raltitrexed and apatinib might be an effective option for treating esophageal squamous cell carcinoma patients.

Safety and Efficacy of Camrelizumab Combined with Apatinib for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: A Multicenter Retrospective Study.

IntroductionPrevious trials demonstrated that anti-angiogenesis or anti-programmed death protein 1 (PD-1) monotherapy showed unsatisfied effect in advanced hepatocellular carcinoma (HCC). No study existed that focus on the effects of camrelizumab and apatinib (“C+A”) combination therapy for HCC patients with the location and extent of portal vein tumor thrombus (PVTT) as the main variable being assessed. This study was to compare the efficacy and tolerability of “C+A” for HCC patients with PVTT.MethodsWe retrospectively analyzed patients with advanced HCC and PVTT who underwent “C+A” therapy in a multicenter retrospective cohort from Jan 2019 to July 2020. Outcomes of patients who underwent “C+A” were analyzed by using the Kaplan–Meier method according to types of PVTT: PVTT in the main portal vein (type A), PVTT in the first-order portal vein branch (type B), and PVTT in second- or lower-order portal vein branches (type C).ResultsSixty-three patients were finally included and the mean duration of follow-up was 12.6 ± 4.5 months. The objective response rate (ORR) and disease control rate (DCR) for the whole cohort were 44.0% and 75.0%, respectively. The median overall survival (OS), progression-free survival (PFS) and time to progression (TTP) were 14.8 months, 11.8 months and not yet reached (NR), respectively. Patients with type B (OS, 15.9 months; PFS, 14.0 months; TTP, NR) or type C (OS, 16.0 months; PFS, 14.9 months; NR) PVTT appear to have better survival benefits compared with type A (OS, 5.8 months; PFS, 5.0 months; TTP, 7.0 months). Along with AFP, the absence of main PVTT was an independent predictive factor for survival at uni- and multivariate analysis.ConclusionCamrelizumab and apatinib yielded a promising outcome in patients with advanced HCC who developed a tumor thrombus in the first lower-order portal vein branches and was generally safe and had manageable side effects.

Case reports with durable therapeutic effects from the prospective phase 2 trial

Rationale: For advanced osteosarcoma refractory to chemotherapy, our previous phase II trial of advanced osteosarcoma progressing after chemotherapy (Apatinib Plus camrelizumab for unresectable high-grade Osteosarcoma) revealed that although the combination of apatinib and camrelizumab seemed to prolong progression-free survival in comparison to single agent apatinib in treating advanced osteosarcoma, it did not reach the prespecified target of 6-month progression-free survival of 60% or greater. Until last follow-up, 2 durable therapeutic effects were observed. Here, we present these 2 cases with detailed clinical information to gain insights into the characteristics of these clinical beneficiaries. Patient concerns: We present the clinical courses of 2 cases. Case 1 was a 44-year-old male with the primary tumor located at proximal femur. Following routine chemotherapy for osteosarcoma, the patient developed multiple pulmonary metastases and local recurrence. Case 2 was a 14-year-old female with primary tumor located at proximal tibia and fibula. Her disease progressed during chemotherapy after definitive surgery with multiple calcified pulmonary metastases. Diagnosis: High grade osteosarcoma with progression upon routine chemotherapy Interventions: Both the patients were enrolled in the advanced osteosarcoma progressing after chemotherapy trial and were treated with Apatinib 500 mg orally once daily and Camrelizumab 200 mg intravenously administered once every 2 weeks in a 4-week (28 days) cycle. Outcomes: Case 1 showed a partial response for 2 years after enrollment. The dose of apatinib was reduced due to adverse events and eventually stopped. As of February 2020, the lung lesions show a stable response and the patient is disease-free. The residual femoral lesions are planned to be treated by radiation therapy. Case 2 showed stable disease for more than 18 months after the enrollment. She is the only patient from the trial who is still using the drug combination. The last follow-up time was March 1st of 2020. Lessons: These 2 cases suggested osteosarcoma might not always be refractory to anti-PD-1/ programmed death-ligand 1 axial therapy. More prospective trials are needed to determine the biomarkers that may aid in patient selection for this combination. Trial registration: This trial is registered with ClinicalTrials.gov, number NCT03359018.

Apatinib exhibits synergistic effect with pyrotinib and reverses acquired pyrotinib resistance in HER2-positive gastric cancer via stem cell factor/c-kit signaling and its downstream pathways

BackgroundRecently, progress has been made in the development of targeted therapies for human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). However, drug resistance has severely limited the efficacy of anti-HER2 therapies. Pyrotinib is a novel pan-HER inhibitor. Although it is effective in HER2-positive GC treatment, its efficacy in combination with apatinib and associated resistance mechanisms in HER2-positive GC remains unclear.MethodsIn this study, the combination effects of pyrotinib and apatinib were examined in two pyrotinib-sensitive GC cells and xenografts. The RNA sequencing was used to determine the underlying mechanisms of acquired pyrotinib resistance. The role of imatinib and apatinib in reversing pyrotinib resistance was tested in pyrotinib-resistant cells and xenografts.ResultsHere, we reported that a combination of pyrotinib and apatinib exhibits synergistic effect in HER2-positive NCI-N87 xenografts, and showed enhanced antitumor efficacy in HER2-positive GC, both in vitro and in vivo. Moreover, up-regulation of the stem cell factor (SCF) levels, and the PI3K/AKT and MAPK pathways was associated with acquired pyrotinib resistance in HER2-positive GC. Mechanistically, we demonstrated that the activation of the SCF/c-kit signaling and its downstream PI3K/AKT and MAPK pathways mediated pyrotinib resistance by promoting cell survival and proliferation. Imatinib and apatinib augmented the sensitivity of pyrotinib-resistant cells and xenografts to pyrotinib, by blocking SCF/c-kit signaling.ConclusionThese results highlight the effectiveness of pyrotinib combined with apatinib in HER2-positive GC and acquired pyrotinib resistance, thus providing a theoretical basis for new treatment methods.

Apatinib combined with paclitaxel-based chemotherapy in patients with taxane-resistant advanced gastric cancer: a single-arm exploratory study.

BackgroundApatinib combined with chemotherapy might be effective and safe for the management of advanced gastric cancer, but the available data are limited. To investigate the efficacy and safety of apatinib in combination with paclitaxel (PTX) alone or POF (PTX, oxaliplatin, and 5-fluorouracil) in patients with taxane-resistant advanced gastric cancer.MethodsPatients with taxane-resistant advanced gastric cancer were enrolled in the single-center, open-labeled, single-arm, exploratory study (ClinicalTrials.gov #NCT02697838). Apatinib was administered at 850 mg po in combination with weekly PTX or the POF regimen. The primary endpoint was the objective response rate (ORR). The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), the time to tumor progression (TTP), and safety.ResultsTwenty participants were recruited from 08/2016 to 01/2018. The duration of the study treatment was 2.07 (0.03–16.2) months. The median follow-up was 24.8 (0.3–26.0) months. The reasons for termination of treatment were disease progression (n=6), adverse events (AEs) (n=5), and patients’ will (n=9). The ORR was 11.1% (95% CI: 1.4–34.7%) and the DCR was 77.8% (95% CI: 52.4–93.6%). The median PFS was 3.5 (95% CI: 1.9–5.1) months, the median OS was 4.7 (95% CI: 2.0–7.3) months, and the median TTP was 4.2 (95% CI: 0.562–7.838) months. All 20 (100%) patients had AEs, 17 (85%) had apatinib treatment-emergent AEs (TEAEs), and 18 (90%) had chemotherapy TEAEs. The main grade 3–4 TEAEs were neutropenia, leukopenia, hypertension, and anemia.ConclusionsThis preliminary study suggests that apatinib combined with PTX or POF might be effective and tolerable in patients with chemotherapy-refractory gastric cancer. Studies are necessary to confirm the results.Trial registrationClinicalTrials.gov #NCT02697838.

Combination of Cordycepin and Apatinib Synergistically Inhibits NSCLC Cells by Down-Regulating VEGF/PI3K/Akt Signaling Pathway.

BackgroundThe application of apatinib is immensely limited by its acquired drug resistance. This research investigates whether cordycepin, a component from Cordyceps could synergize with apatinib to improve its anticancer effect on non-small cell lung cancer (NSCLC) cells.MethodsThe NSCLC cell lines A549, PC9, and H1993, and human bronchial epithelial (HBE) cell line Bears-2B were used in this study. Cell counting kit 8, colony formation assays, wound healing assay, transwell assay, and flow cytometry analysis were performed to assess the cell viability, the migration ability, and invasion ability of the cells. Kyoto encyclopedia of genes and genomes (KEGG), western blotting and molecular docking was applied to analyze the possible pathways affected by cordycepin.ResultsThe combination of cordycepin and apatinib in a ratio of 5:1 synergistically reduced proliferation of NSCLC cells, inhibited cell migration and invasion, increased cell apoptosis by altering cell cycle in NSCLC A549 and PC9 cells. The VEGF/PI3K/Akt pathway was inhibited after treatment with cordycepin and apatinib.ConclusionOur findings demonstrated that the combination of cordycepin and apatinib has synergistically anticancer effect on NSCLC cells by down-regulating VEGF/PI3K/Akt signaling pathway. This result indicated that cordycepin and apatinib could be a promising drug combination against NSCLC.

1503TiP A prospective study of apatinib in combination with neoadjuvant concurrent chemoradiotherapy for locally advanced esophageal squamous cell carcinoma

1503TiP A prospective study of apatinib in combination with neoadjuvant concurrent chemoradiotherapy for locally advanced esophageal squamous cell carcinoma

PD-1 inhibitor combined with apatinib for advanced gastric or esophagogastric junction cancer: a retrospective study.

BackgroundNivolumab and pembrolizumab were approved as immune checkpoint inhibitors for third-line treatment of advanced gastric or esophagogastric junction cancer (GC/EGJC) in 2017. However, immunotherapy monotherapy has low efficacy. Apatinib has been proven effective in advanced GC/EGJC. Numerous studies have shown that immunotherapy has a synergistic effect when combined with targeted drug therapy. Based on these facts and to assess the efficacy and safety of programmed death 1 (PD-1) inhibitor and apatinib as combination therapy in patients (pts) with unresectable locally advanced or metastatic GC/EGJC, a retrospective clinical research study was carried out.MethodsPts (n=24) received PD-1 inhibitor and apatinib (250 mg once daily) as second- or third-line therapy in this observational, retrospective study. The primary objectives were efficacy and safety.ResultsAt data cut-off (December 31, 2019), 24 pts were enrolled. Of the 19 pts who were evaluable, the objective response rate (ORR) was 26.3% (5/19), the median progression-free survival (PFS) was 3.0 (95% CI: 1.3 to 4.7) months, and the median overall survival (OS) was not reached. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 3 (15.8%) of the 19 pts. These adverse events (AEs) included pruritus, rash, hand-foot syndrome, and increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT). No treatment-related deaths occurred.ConclusionsCombination therapy of PD-1 inhibitor and apatinib showed encouraging clinical activity and demonstrated tolerable toxicity in pts with advanced GC/EGJC. Hence, our work provide rationale for the combination of PD-1 inhibitor and apatinib in advanced GC/EGJC.

Apatinib enhanced anti-PD-1 therapy for colon cancer in mice via promoting PD-L1 expression

Increasing studies confirm that anti-angiogenesis can increase the effectiveness of immunotherapy. In this study, we found that an angiogenesis inhibitor apatinib enhanced anti-PD-1 therapy for colon cancer in mice via promoting PD-L1 expression. Apatinib treatment upregulated PD-L1 expression in various colon cancer cells both at the mRNA and protein levels. Further, apatinib-treated cancer cells hampered activation and IFN-γ secretion of T cells in the co-culture system, which was reversed by the anti-PD-1 antibody. Based on this, the combination of apatinib with anti-PD-1 on colon cancer growth in mice was examined. The combination treatment showed more significant inhibition on the growth of transplanted tumors in mice than single-drug treatment. Overall, our study here showed the enhancement of anti-PD-1 antitumor efficacy in a syngeneic mouse model (CT-26 cells in Balb/c) by the angiogenesis inhibitor apatinib via upregulating PD-L1 expression as well as angiogenesis inhibition, which may provide a rationale for the combination of apatinib and anti-PD-1 antibody for colorectal cancer treatment in the clinic.

Application of apatinib after multifaceted therapies for metastatic breast cancer.

BackgroundApatinib is a small molecule tyrosine kinase inhibitor (TKI) that is taken orally and has high specificity for vascular endothelial growth factor receptor 2 (VEGFR-2). This study explored the efficacy and toxicity of apatinib in patients with metastatic breast cancer (MBC) who failed to respond to multifaceted therapy.MethodsA total of 61 patients with MBC who were unresponsive to previous multifaceted chemotherapy were included in this study. The treatment regimens were either a combination of apatinib and chemotherapy or apatinib administered singly with a dose range of 250 mg every second day to 500 mg per day. Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicity were used as outcome measures.ResultsOf the 61 patients, partial response (PR) was observed in 14 patients (23.0%), stable disease (SD) was observed in 30 patients (49.2%), and progressive disease (PD) was observed in 17 patients (27.8%). The DCR was 44/61 (72.1%), and the ORR was 14/61 (23.0%). Of the 44 patients who achieved PR or SD, the median PFS was 4 months and 15 days. Patients with intracranial metastases were found to benefit from apatinib. Furthermore, 11 patients underwent next generation sequencing (NGS) and 5 of these had a P53 mutation. Of those 5 cases, the ORR and DCR were 0% and 20.0%, respectively. Of the 6 cases with wild-type P53, the ORR was 50.0%, and the DCR was 100.0%. Multivariate regression analysis found that hypertension was an independent prognostic factor of better DCR.ConclusionsApatinib showed good efficacy and manageable toxicity in patients with MBC that had not responded to multifaceted therapy.