Combination Of Apatinib Research Articles

Apatinib plus Chemotherapy as a Second-Line Treatment in Unresectable Non-Small Cell Lung Carcinoma: A Randomized, Controlled, Multicenter Clinical Trial.

The efficacy of second-line treatment for advanced non-small cell lung carcinoma (NSCLC) without a sensitizing driver gene mutation is still unsatisfactory. The combination of apatinib and chemotherapy improved progression-free survival in the second-line therapy of advanced NSCLC without a sensitizing mutation. This study offers a new treatment strategy for second-line treatment of such patients but requires confirmation in a larger multi-institutional trial. This study explored the efficacy and safety of apatinib combined with single-agent chemotherapy versus single-agent chemotherapy in the second-line treatment of advanced non-small-cell lung carcinoma (NSCLC) without driver mutations. In this double-arm, open label, exploratory clinical study, we enrolled patients with unresectable locally advanced or advanced NSCLC without driver mutations that had progressed following first-line chemotherapy. The subjects were allocated into an experimental group and a control group by 2:1. The experimental group received apatinib combined with four cycles of docetaxel or pemetrexed until disease progression, intolerable toxicity, or discontinuation at the patient' request. The control group only received four cycles of docetaxel or pemetrexed. The primary endpoints were progression-free survival (PFS), and the secondary endpoints were overall survival (OS), disease control rate (DCR), and safety. Thirty-seven patients were enrolled. The efficacy of 33 patients was evaluated. The median PFS was 5.47 versus 2.97 months, the DCR was 95% versus 73%, and the objective response rate (ORR) was 27% versus 9% in the experimental versus control group. The OS was still under follow-up. The most common adverse effects included hypertension, hand-foot skin reaction (HFSR), and fatigue. Apatinib combined with single-agent chemotherapy may be a novel option for second-line treatment of advanced NSCLC.

Apatinib in combination with pemetrexed-platinum chemotherapy for chemo-naive non-squamous non-small cell lung cancer: a phase II clinical study

ObjectivesApatinib showed efficacy in non-small cell lung cancer (NSCLC). We conducted this phase II clinical study to assess the efficacy and safety of apatinib in combination with pemetrexed-platinum chemotherapy in non-squamous NSCLC (Clinical Trial Registration: ChiCTR1800015920). Materials and methodsPatients received oral apatinib (250 mg/d) with intravenous pemetrexed (500 mg/m2)-platinum (carboplatin AUC = 5 or cisplatin 75 mg/m2) chemotherapy every 21 days for 6 treatment cycles, and then maintained with apatinib 250 mg/d until progressive disease or intolerable toxicity. The primary endpoint was the objective response rate (ORR). The secondary endpoints included the progression-free survival (PFS), disease control rate (DCR), overall survival (OS) and safety. ResultsTwenty advanced and chemo-naive non-squamous NSCLC patients were enrolled and evaluated. The ORR and DCR was 80% and 100%, respectively. The median PFS (mPFS) and median OS (mOS) for total patients was 7.7 (95%CI: 3.1-12.3) and 20.1 (95%CI: not available, NA) months. In the TKI-pretreated and treatment-naive subgroup, the ORR was 90% vs.70%, and the mPFS was 8.9 (95%CI: 5.5-12.3) vs.5.7 (95%CI: 0.1-11.3) months, respectively (P = 0.433). The mPFS in the responders without central nervous system (CNS) metastasis at baseline was 10.0 (95%CI: 6.1-13.9) months, and it was 3.8 (95%CI: 0.9-6.7) months in those with presence of CNS metastasis at baseline (P = 0.041, HR = 0.283, 95%CI: 0.084-0.948). Toxicities mainly included grade I-II hand-foot syndrome, hypertension, proteinuria and myelosuppression. ConclusionApatinib in combination with pemetrexed-platinum chemotherapy showed good efficacy and tolerable toxicity in advanced non-squamous NSCLC, especially for those who failed to prior TKI targeted therapies.

P-128 A novel combination of GEMOX and apatinib in treatment of unresectable or metastatic cholangiocellular carcinoma

The treatment of unresectable/metastatic cholangiocellular carcinoma (CCC) is limited and the response rate of chemotherapy is unsatisfactory. Apatinib, a novel antiangiogenic agent targeting vascular endothelial growth factor receptor (VEGFR2), is currently being studied in different tumors. This study was performed to assess the response rate and safety of apatinib in patients with unresectable/metastatic CCC.

Clinical efficacy and safety of apatinib combined with oral VP-16 for the treatment of advanced ovarian cancer: Preliminary evaluation of a clinical drug regimen

To investigate the clinical efficacy and safety of apatinib in combination with oral VP-16 for the treatment of chemotherapy-resistant advanced ovarian carcinoma. Twenty-seven advanced ovarian carcinoma patients were treated with oral VP-16 chemotherapy combined with oral apatinib mesylate (500 mg/d). CA125, VEGF, and CEA were examined every 3-4 weeks, and tumour changes were monitored by CT every 8-12 weeks. PFS was obtained by follow-up after discharge. For all patients, the ORR (including CR and PR) was 25.0%, and the DCR (including CR, PR and SD) was 75.0%. CEA and CA199 significantly decreased (p<0.05), but the decrease in VEGF was not significant. The average PFS was 5.13 months. The ECOG score had a significant effect on PFS (p<0.05), while there were no significant differences in PFS based on age (p=0.394). The main side effects of this regimen were hypertension, proteinuria, hand-foot syndrome and myelosuppression, which were tolerated by patients after active symptomatic treatment. Apatinib combined with oral VP-16 is an effective regimen for the treatment of chemotherapy-resistant advanced ovarian cancer. This combination therapy should be widely used in clinical practice.

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

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

Phase II study of apatinib combined with temozolomide in advanced melanoma patients after failure of anti-PD-1 therapy.

e22043 Background: Immunotherapy is first-line therapy in advanced melanoma. Because of different subtypes and gene alterations, the efficacy of immunotherapy in Asians, mostly comprised of acral and mucosal melanoma, is lower than Caucasians. There are no standard treatment strategies after immunotherapy failure. Chemotherapy and anti-angiogenesis combination showed emerging evidence of activity in mucosal and acral melanoma. This study was to evaluate the efficacy of apatinib combined with temozolomide in advanced immunotherapy refractory melanoma patients (pts). Methods: This prospective, single-arm, phase II study recruited unresectable or metastatic melanoma pts after failure of anti-PD-1 therapy. Other treatment including targeted therapy, chemotherapy, and clinical trials were allowed. Primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). According to the dose recommended from previous phase I study, pts were given apatinib 500 mg every day and temozolomide 300mg day 1-5, 28 days for one cycle. Results: 31 pts were enrolled between Feb 2018 and Dec 2018, with 8 males, average age 55 yrs (range 24 – 69 yrs). 13 pts (41.9%) were from mucosal primaries, 9 (29.0%) acral, 5 (16.1%) cutaneous (non-acral), and 4 (12.9%) unknown primaries. One had BRAF mutation, 1 CKIT, and 3 NRAS mutations. 9 pts (29.0%) were classified as IIIc/M1a, 9 (29.0%) M1b, and 13 (41.9%) M1c. 18 pts (58.1%) had elevated lactate dehydrogenase level. All pts progressed after anti-PD-1 therapy. In addition, 29.0% pts received dacarbazine based chemotherapy, 29.0% paclitaxel or albumin-bound paclitaxel, and 3.2% had dabrafenib with trametinib. Up to Dec 2019, 30 pts can be evaluated for efficacy. Median follow-up time was 10.2 mos (2.0-23.1 mos). There were 5 confirmed PRs and 20 SDs. ORR was 16.7%, DCR 83.3%, and median PFS was 5.0 mos (95%CI 1.9-8.1 mos). Median overall survival was 10.1 mos (95%CI 4.7-15.5 mos). Common AEs were hypertension (51.6%), proteinuria (41.9%), elevated transaminase (25.8%), thrombocytopenia (16.1%), and hand-foot syndrome (16.1%). Most were grade 1-2. Grade 3-4 AEs included proteinuria (12.9%), hypertension (6.4%), and thrombocytopenia (6.4%); 10 pts required a dose reduction, and 1 had to discontinue. No treatment-related deaths were observed. Conclusions: In pts progressed after anti-PD-1 therapy, apatinib in combination with temozolomide demonstrated promising efficacy and favorable safety profile. Clinical trial information: NCT03422445.

Efficacy and safety of SHR-1210 combined with apatinib in first-line treatment for advanced lung squamous cell carcinoma: A phase II study.

e21587 Background: PD-1 inhibitors plus chemotherapy is a standard of first-line therapy in advanced lung squamous cell carcinoma (LUSC). Previous preclinical and clinical studies suggested that the combination of anti-PD-1 antibody SHR-1210 and VEGFR-2 inhibitor apatinib significantly improved anti-tumor effects. The aim of this study was to evaluate the efficacy and safety of SHR-1210 in combination with apatinib for advanced LUSC patients as a first-line treatment. Methods: In this phase II study, patients diagnosed with stage IIIB or IV advanced LUSC were enrolled. All patients received SHR-1210 (200mg q2w) and apatinib (250mg po qd) until disease progression or unacceptable toxicity. Treatment efficacy was assessed every 3 cycles (6 weeks). The primary endpoint is progression-free survival (PFS). Secondary endpoints are objective response rate (ORR), disease control rate (DCR), and overall survival (OS), which according to RECIST 1.1. Results: At the primary analysis (data cutoff Feb 10, 2020), 26 advanced LUSC patients had enrolled, and 17 patients of which were evaluable. Baseline characteristics were shown that median age was 67 years, male percentage was 92.3% (24/26), and clinical stage IV percentage was for 57.7% (15/26). The median follow-up time was 3.1 months (range 0.4-13.7 months) in all included patients. No complete response (CR) was reported. Partial response (PR) was achieved in 13 (76.5%) and stable disease (SD) in 4 (23.5%). The ORR and DCR in 17 evaluable patients were 76.5% and 100%, respectively. The most common treatment-related adverse events were hypertension (42.3%), rash (38.5%), hand-foot skin reaction (26.9%), and reactive cutaneous capillary endothelial proliferation (RCCEP) (15.4%). Of 26 patients, 5 experienced a grade ≥3 treatment-related adverse events, including one interstitial pneumonia, one hypertension, one thrombocytopenia, one RCCEP, and one aminotransferase elevation. Three patients (3/26) were reported dead, of which one died due to interstitial pneumonia and the others died of tumor progression. Twelve patients (46.2%) ever suspended treatment or adjusted the dosage of apatinib due to interstitial pneumonia, pyelonephritis, rash, thrombocytopenia, or aminotransferase elevation. Conclusions: The combination of SHR-1210 and apatinib for advanced LUSC patients was well tolerated and effective. This treatment may be a promising method for advanced LUSC as a first-line treatment. Fund Project (No: 2017FC-CXYY-3007) & Project (No: 2017MBD-013). Clinical trial information: ChiCTR1800019329.

Apatinib, a Novel Tyrosine Kinase Inhibitor, Promotes ROS-Dependent Apoptosis and Autophagy via the Nrf2/HO-1 Pathway in Ovarian Cancer Cells.

Apatinib, a new-generation oral tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathway, shows favorable therapeutic effects in various malignant tumors. However, its effect on ovarian cancer has not yet been characterized. Here, we demonstrated that apatinib inhibited ovarian cancer cell growth and migration in a concentration-dependent manner. Further, we found that apatinib could directly act on tumor cells and promote ROS-dependent apoptosis and autophagy. Mechanistically, we showed that apatinib suppressed glutathione to generate ROS via the downregulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway and maintained an antitumor effect at a low level of VEGFR2 in ovarian cancer, suggesting that combination of apatinib with Nrf2 inhibitor may be a promising therapy strategy for patients with ovarian cancer.

Combination of apatinib and docetaxel in treating advanced non-squamous non-small cell lung cancer patients with wild-type EGFR: a multi-center, phase II trial.

BackgroundThis trial aimed to investigate the treatment response, survival profiles and treatment-related adverse events (AEs) of apatinib plus docetaxel in advanced non-squamous non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor (EGFR).MethodsThirty advanced non-squamous NSCLC patients with wild-type EGFR were recruited in this multi-center, phase II trial. All patients received apatinib (orally 500 mg, once daily until disease progression, intolerable toxicity, or death) plus docetaxel (intravenously 60 mg/m2 at day 1 every 3 weeks for 4–6 cycles). The treatment response, progression-free survival (PFS), overall survival (OS) and treatment-related AEs were evaluated.ResultsOne patient lacked response and survival assessment due to early lost follow-up, therefore, 29 patients were included in response and survival analysis. There was no (0.0%) patient achieved complete remission, 8 (27.6%) patients achieved partial remission, 20 (69%) patients with stable disease, and 1 (3.4%) patient with progressive disease, resulting in objective response rate and disease control rate of 27.6% and 96.6%, respectively. According to the survival data, median PFS was 5.3 months (95% CI: 3.6–6.9 months) and median OS was 9.6 months (95% CI: 6.33–12.9 months). For safety, totally 30 patients were included in the analysis. Common non-hematologic AEs included hypertension (66.7%), hand-foot syndrome (40.0%), proteinuria (36.7%); common hematologic AEs included leukopenia (26.7%), thrombocytopenia (23.3%), neutropenia (16.7%). Notably, majority of AEs were at grade 1–2, and the overall AEs were tolerable.ConclusionsApatinib plus docetaxel is an effective and tolerable treatment option for advanced non-squamous NSCLC with wild-type EGFR.

Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: a single-arm, open-label, phase 2 trial

BackgroundResults of our previous study showed high objective response but short-term activity of apatinib in advanced osteosarcoma. We aimed to investigate the activity of apatinib in combination with camrelizumab in...

Addition of docosahexaenoic acid synergistically enhances the efficacy of apatinib for triple-negative breast cancer therapy.

The current study aimed to investigate the antitumor and antiangiogenesis effects of apatinib in triple-negative breast cancer in vitro and also whether the combination of docosahexaenoic acid (DHA) and apatinib is more effective than apatinib monotherapy. The cell counting kit-8 assay was used to measure cell proliferation. Flow cytometry was utilized to determine the cell apoptosis rate. A wound healing assay was utilized to assess cell migration. Western blot analysis was carried out to determine the effects of apatinib and DHA on Bcl-2, BAX, cleaved caspase-3, caspase-3, phosphorylated protein kinase B (p-Akt), and Akt expression. DHA in combination with apatinib showed enhanced inhibitory effects on cell proliferation and migration compared with apatinib or DHA monotherapy. Meanwhile, DHA combined with apatinib strongly increased the cell apoptosis percentage. DHA was observed to enhance the antitumor and antiangiogenesis effects of apatinib via further downregulation of p-Akt expression.Abbreviations: FITC: fluorescein isothiocyanate; PI: propidium iodide.

A comparison of transcatheter arterial chemoembolization used with and without apatinib for intermediate- to advanced-stage hepatocellular carcinoma: a systematic review and meta-analysis.

BackgroundHepatocellular carcinoma (HCC) is a common cancer worldwide and prognosis for patients with the disease remains poor. Most patients are diagnosed at an advanced stage and are only eligible for palliative therapy. As a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor (VEGFR2-TKI), apatinib has a certain antitumor effect for a variety of solid tumors. In clinical practice, clinicians have attempted to treat intermediate- to advanced-stage HCC patients with a combination of transcatheter arterial chemoembolization (TACE) and apatinib. However, a consensus on the therapeutic effects of this treatment is yet to be reached. This meta-analysis was conducted to compare the therapeutic efficacy and clinical safety of the combination therapy of TACE plus apatinib with that of TACE alone in patients with intermediate- to advanced-stage HCC.MethodsRelevant studies were identified by searching PubMed, Embase, Web of Science, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Biomedical Literature Database (CBM), Chinese Science and Technology Periodical Database (VIP) and the reference lists of retrieved articles up to July 31, 2019. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to express the therapeutic effects of TACE plus apatinib versus TACE on survival, objective response rate, disease control rate, progressive disease rate and adverse events using a mixed-effect model. Subgroup analyses of study type, dosage of apatinib, TACE regimen, study sample size between treatment groups and control groups were performed. Publication bias was assessed using fail-safe N, Begg-Mazumdar test and Egger’s test.ResultsFrom 23 eligible studies, a total of 1,342 patients were included in this review and meta-analysis. Among these studies, 18 were randomized clinical trials and 5 were case-control studies. Compared with those being treated with TACE alone, patients receiving TACE plus apatinib showed significantly better half-year survival (OR, 2.741, 95% CI, 1.745–4.306) and 1-year survival (OR, 2.284, 95% CI, 1.442–3.620). The superiority of TACE and apatinib over TACE monotherapy was evident in the disease control rate (OR, 2.919, 95% CI, 2.184–3.903), objective response rate (OR, 2.683, 95% CI, 2.099–3.429) and progressive disease rate (OR, 0.341, 95% CI, 0.255–0.456), respectively.ConclusionsThe combination treatment of apatinib and TACE provides better survival benefits for intermediate- to advanced-stage HCC patients when compared to TACE monotherapy and should be recommended for suitable patients with unresectable HCC. However, further investigation into future prospective clinical studies is warranted.

Apatinib Monotherapy or Combination Therapy for Non-Small Cell Lung Cancer Patients With Brain Metastases.

Apatinib, an oral small molecular receptor tyrosine kinase inhibitor (TKI) developed first in China, exerts antiangiogenic and antineoplastic function through selectively binding and inhibiting vascular endothelial growth factor receptor 2 (VEGFR-2). In this study, we aimed to explore the efficacy and safety profile of apatinib monotherapy, or combined with chemotherapy or endothelial growth factor receptor (EGFR)-TKI in heavily pretreated non-small cell lung cancer (NSCLC) patients with brain metastases. We performed a retrospective analysis for relapsed NSCLC patients with brain metastases from our institute, who received apatinib (250 mg or 500 mg p.o. qd) monotherapy, or combination with EGFR-TKI or chemotherapy as second or more line systemic therapy until disease progression or unacceptable toxicity occurred. The objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and safety were analyzed. A total of 26 eligible patients were included: 24 patients diagnosed with adenocarcinoma, 2 with squamous carcinoma, and 14 patients harboring EGFR sensitizing mutations. The mPFS and mOS were 4.93 (range, 0.27–32.91; 95% CI 3.64–6.22) and 14.70 (range, 0.27–32.91; 95% CI 0.27–43.60) months for the whole group. The ORR and DCR were 7.7% (2/26) and 69.2% (18/26) for the entire lesions, and 7.7% (2/26) and 79.6% (20/26) for brain metastases, respectively. Compared with patients who received apatinib monotherapy, patients who received apatinib combination treatment had more favorable mPFS (11.77 vs. 2.27 months, p < 0.05) and mOS (24.03 vs. 6.07 months, p < 0.05). Treatment-related toxicities were tolerable including grade 1/2 hypertension, hand-and-foot syndrome, fatigue, nausea, liver dysfunction, myelosuppression, skin rash, and palpitation. In conclusion, apatinib exhibited high activity and good tolerance for NSCLC patients with brain metastasis, and it might become a potential choice for metastatic brain tumors in NSCLC patients.

Transarterial chemoembolization combined with microwave ablation and apatinib in patients with Barcelona clinic liver cancer Stage C hepatocellular carcinoma

Apatinib combined with transarterial chemoembolization (TACE) has shown promising results in cases of Barcelona clinic liver cancer Stage C (BCLC C) hepatocellular carcinoma (HCC). This study aimed to investigate the efficacy and safety of TACE in combination with microwave ablation (MWA) and apatinib. A retrospective, single.center study was undertaken using a one.to.one propensity score matching (PSM) analysis design and involved BCLC C HCC patients who underwent treatment with TACE.MWA.apatinib or TACE alone between January 2013 and June 2018. The patients were recommended to administer 500mg apatinib per day, combined with MWA and TACE. The adverse effects of apatinib, MWA. and TACE.related complications, progression.free survival (PFS), and overall survival (OS) were assessed. Of the 149 patients with BCLC C HCC who underwent TACE.MWA.apatinib or TACE alone, 131 were included in our study. Among them, 21 (16.0%) received TACE.MWA.apatinib and 110 (84.0%) underwent TACE alone. After PSM, twenty pairs were enrolled into different treatment groups. Patients in the TACE.MWA.apatinib group had a significantly longer median PFS than patients in the TACE.alone group on both before (median, 8.9 vs. 1.7 months, P = 0.0002) and after PSM (median, 5.4 vs. 2.1 months, P = 0.001). They also had a significantly longer median OS than patients in the TACE.alone group on before (median, 24.4 vs. 5.8 months, P = 0.000007) and after PSM (median, 24.4 vs. 5.4 months, P = 0.00005). The combination of apatinib, TACE, and MWA in BCLC C HCC patients is safe and effective. Toxicity is manageable by adjusting the apatinib dosage.

Chemotherapy combined with apatinib for the treatment of desmoplastic small round cell tumors: A case report

Desmoplastic small round cell tumor (DSRCT) is a type of soft-tissue sarcoma with poor prognosis. Current treatments include multidisciplinary treatment options such as surgery, chemotherapy, and radiotherapy. Apatinib is an oral, small-molecule, anti-tumor, angiogenesis-targeted drug, which acts mainly on the intracellular binding site of vascular endothelial growth factor receptor-2. In this study, we administered apatinib in combination with chemotherapy to achieve good disease control. This is a 31-year-old male who presented with upper abdominal pain, nausea, and anorexia for over a month. Imaging revealed multiple solid masses and ascites in the liver and abdominal cavity. He was diagnosed as having cholangiocarcinoma with metastasis to the liver, both lungs, bone, and multiple lymph nodes in the neck, abdominal and pelvic cavity, retroperitoneum, and palpitate angle, based on a percutaneous biopsy of the liver and an abdominal mass, and other examinations. Computed tomography revealed disease progression after two cycles of gemcitabine combined with nedaplatin chemotherapy. Next-generation sequencing detection based on the Illumina high-throughput sequencing platform suggested EWSR1 exon7- Wilms tumor 1 exon8 fusion. The pathology was verified and diagnosed as DSRCT. The chemotherapy regimen was changed to cyclophosphamide, epirubicin, vincristine, and oral apatinib for two cycles. The lesions were mostly reduced, and partial response was evaluated. This case is the first report of the efficacy of apatinib combined with systemic chemotherapy in the treatment of DSRCT, which can become an alternative treatment for this disease.

The ACTIVE study protocol: apatinib or placebo plus gefitinib as first-line treatment for patients with EGFR-mutant advanced non-small cell lung cancer (CTONG1706)

BackgroundGefitinib, as the first epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC), has been proved to significantly improve the progression-free survival (PFS) in the first-line setting but suffers from resistance 7–10 months after treatment initiation. Apatinib (YN968D1), a potent vascular endothelial growth factor receptor (VEGFR) 2-TKI, specifically binds to VEGFR2 and leads to anti-angiogenetic and anti-neoplastic effect. Concurrent inhibition of VEGFR and EGFR pathways represents a rational approach to improve treatment responses and delay the onset of treatment resistance in EGFR-mutant NSCLC. This ACTIVE study aims to assess the combination of apatinib and gefitinib as a new treatment approach for EGFR-mutant NSCLC as a first-line setting.MethodsThis multicenter, randomized, double-blind, placebo-controlled phase III study (NCT02824458) has been designed to assess the efficacy and safety of apatinib or placebo combined with gefitinib as a first-line treatment for patients with EGFR-mutant advanced NSCLC. A total of 310 patients with EGFR-mutation (19del or 21L858R), pathological stage IIIB to IV non-squamous NSCLC were to be enrolled. The primary endpoint is investigator assessment of PFS, and the secondary endpoints include independent radiological central (IRC)-confirmed PFS, overall survival (OS), objective response rate (ORR), disease control rate (DCR), time to progressive disease (TTPD), duration of response (DoR), quality of life (QoL) and safety. The patients are randomized in a 1:1 ratio to receive gefitinib (250 mg, p.o. q.d.) plus apatinib (500 mg, p.o. q.d.) or gefitinib plus placebo, given until disease progression or intolerable adverse events. Exploratory biomarker analysis will be performed. This study is being conducted across China and comprises of 30 participating centers. Enrollment commenced in August 2017 and finished in December 2018, most of the patients are in the follow-up period.Anticipated outcomes and significanceThe present study will be the first to evaluate the efficacy and safety profile of the combination of apatinib plus gefitinib as a first-line therapy for patients with EGFR-positive advanced non-squamous NSCLC. Importantly, this trial will provide comprehensive evidence on the treatment of EGFR-TKIs combined with antiangiogenic therapy.Trial registration Clinicaltrials.gov NCT02824458. Registered 23 June 2016

508P - Efficacy and safety of anti-PD-1 antibody SHR-1210 combined with apatinib in first-line treatment for advanced lung squamous carcinoma: A phase II study

BackgroundPD-1 antibody plus chemotherapy is a standard first-line therapy in patients with advanced lung squamous carcinoma. Previous study suggested that the combination of anti-PD-1 antibody SHR-1210 and VEGFR 2 inhibitor apatinib significantly improved antitumor effects. The aim of this study was to evaluate the efficacy and safety of SHR-1210 in combination with apatinib for advanced lung squamous carcinoma patients as a first-line treatment. MethodsStage IIIB or IV advanced lung squamous carcinoma patients were enrolled in this open-label, single-center, single-arm phase II study. Patients received SHR-1210 (200mg q2w) and apatinib (250mg po qd) until progression or unacceptable toxicity. Treatment efficacy was assessed every 3 cycles (6 weeks). The primary end point is progression-free survival (PFS). Secondary end points are objective response rate (ORR), disease control rate (DCR) and overall survival (OS), which according to RECIST 1.1. ResultsAt data cut-off (July 8, 2019), 12 advanced lung squamous carcinoma patients were enrolled in the study, of which 7 patients were evaluable. Median age was 67 years, male accounts for 91.7% (11/12), clinical stage IV for 83.3% (10/12). All included patients at a median follow-up of 2.3 months (range 0.4-6.5 months). No patient achieved complete response (CR). Partial response (PR) was achieved by 6 (85.7%) patients and stable disease (SD) exhibited by 1 (14.3%) patient. The ORR and DCR were 85.7% and 100%, respectively. Grade II adverse events were observed in 4 (33.3%) patients with interstitial pneumonia (1 patient), hand-foot skin reaction (2 patients) or rash (1 patient). One patient (1/12) died after 6 months treatment due to interstitial pneumonia and one patient was assessed by PD after 5.5 months treatment. Four patients ever suspended treatment due to interstitial pneumonia, pyelonephritis, rash or pneumothorax. ConclusionsThe combination of SHR-1210 and apatinib for advanced lung squamous carcinoma patients may be a promising method as a first-line treatment. Clinical trial identificationChiCTR1800019329 (Chinese Clinical Tiral Registry). Date of Registration: 2018-11-06. Legal entity responsible for the studyJinliang, Wang. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

804P - Apatinib in combination with docetaxol and S1 chemotherapy in the first-line treatment of metastatic gastric cancer

BackgroundAnti-VEGF target therapy is proven to be effective both in second and third line treatment in metastatic gastric cancer. As for Apatinib, which is the tyrosine kinase inhibitor showed highly affinity for VEGFR2, could not only reverse paclitaxel resistance but also improve the R0 resection rate in previous unresected gastric cancer in conversional settings. However, the safety and efficacy of Apatinib in combination with docetaxel plus S1 in the first line treatment of metastatic gastric cancer is unknown and worthy of investigation. MethodsThe study was expected to enroll 48 patients diagnosed with metastatic gastric cancer. Each participant was supposed to finish six cycles of chemotherapy plus apatinib (docetaxel 75mg/m2, d1, Q3W; S1 according to BSA: <1.25 40mg po bid; 1.25∼1.5 50mg po bid; >1.5 60mg po bid; d1-14, Q3W; apatinib 500mg po qd). The toxicity was determined according to CTCAE 4.0. Efficacy assessed every two cycles (6 weeks) during the study and every 2 months after finish the study. The primary endpoint was progression free survival (PFS). The secondary endpoint was OS, the objective response rate (ORR), the disease control rate (DCR). The tumor response was determined according to RECIST 1.1 criteria. ResultsFrom July 2017 to April 2019, 32 patients were enrolled. 11 female and 21 male, median age 54 years old, median matastasis organs are 3.5. 80% patients reported adverse events (AEs), most of them are 1-2 AEs. The incidence of grade 3-4 AEs was 35.7%, mainly oral mucositis (23.3%) and myelosuppression (21.5%). For ITT polulation, 24 patients were evaluable for response, 13 patients achieved PR, 4 patients achieved SD, 7 patients experienced PD. The ORR is 54.2%, the DCR is 70.8%. 8 out of 11 per protocol patients have reached primary endpoint, the median PFS is near 6.5 month. ConclusionsCombination therapy with docetaxel and S1 plus apatinib as the first line treatment could be well tolerant, the spectrum of toxicity were not exceeding expectation. This modality also exhibits promising efficacy,which might provide a new therapeutic strategy for metastatic gastric cancer. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

P1.12-14 Phase II Trial of Apatinib Plus Chemotherapy for Second-Line and Above Treatment of Advanced SCLC: Focus on Efficacy and Safety

Small-cell lung cancer (SCLC), which accounts for ∼15% of all lung cancers, is characterised by its rapid proliferation. The clinical outcomes of second-line and above treatments are unsatisfactory, resulting in a median progression-free survival (PFS) of less than 3 months. There is currently none targeted drugs or new chemotherapeutic drugs that can achieve breakthroughs in advanced SCLC. This study aims to observe whether apatinib in combination with chemotherapy can be a new choice for second-line and above treatment of advanced SCLC. This is a prospective, single-center, single-arm clinical study designed to evaluate the efficacy and safety of apatinib plus chemotherapy for second-line and above treatment of advanced SCLC (ClinicalTrials.gov NCT03547804). Patients received 500mg apatinib qd orally, if the patient has a grade 3/4 adverse reaction during the treatment, it can be reduced to apatinib 250mg qd orally. Chemotherapeutic agents are limited to irinotecan or docetaxel alone. The primary endpoint was the progression-free survival (PFS). The secondary endpoints included overall survival (OS), disease control rate (DCR), objective response rate (ORR), and adverse events (AEs). Twenty patients were enrolled from March 2018 to March 2019. Fifteen patients were available for response evaluation. The ORR and DCR were 33.33% (5/15) and 93.33% (14/15), respectively. The predicted median PFS time was 5.8 months (95% confidence interval [CI] 5.1-6.5 months) (SPSS 20.0 software). The most common treatment-related AEs were neutropenia (45.0%), leucopenia(35.0%), abnormal liver function (20%), nausea and vomiting (20%) and thrombocytopenia (20.0%), without any treatment-related deaths. It is worth noting, 12 patients underwent apatinib reduction due to grade 3/4 adverse reactions. Apatinib plus single agent chemotherapy showed promising efficacy in a patients with advanced SCLC who had failed chemotherapy. And the recommended phase II dose of apatinib as combination therapy was 250 mg qd.

EP1.14-48 Efficacy and Safety of Afatinib Plus Apatinib Combination Therapy for a Lung Adenocarcinoma Patient with Her-2 V659D Mutation

In lung cancer，several literature report the rare transmembrane domain mutations occur in V659D of Her-2 may be effective for afatinib. This is a successful case of a lung adenocarcinoma patient with a novel Her-2 V659D mutation but unsatisfactory efficacy with afatinib treated with afatinib plus apatinib. A 73-year-old Chinese man with a heavy-smoking history came to our hospital due to"Intermittent cough"in eary March 2017. He was diagnosed with stage IB(T2aN0M0)lung adenocarcinoma by pathology of left upper lobectomy in 29th Mar 2017(Fig.1). An HER-2 mutation(V659D mutation)was detected in the surgical specimen by Next-generation sequencing (mutation abundance is 44.6%). Recurrence of lung cancer occurred after 16 months on 30th July 2018. Pulmonary CT revealed multiple nodules in both lungs( Fig.2). The patient had no intention of chemotherapy. Daily oral doses of 40 mg of afatinib were given on 31st July 2018. Twenty-two days later, a CT scan revealed the bilateral pulmonary nodules were slightly smaller, however cough symptoms were worse than before(Fig.3). On 23rd Agu 2018, considering the efficacy and side effects, he started taking afatinib(reduced to 30mg)combined with apatinib(500mg/day). The chest CT scan revealed the metastases continued to shrink after 1 month, and necrotic cavities appeared in the middle of the lesions(Fig.4). Cough symptoms improved obviously. Therapeutic evaluation was stable. He had no progression of the disease for months. On 21st Feb 2019, lung CT indicated enlargement of bilateral pulmonary nodules and new lesions suggesting disease progresses. Progression-free survival is 6.1 months. As for the side effects, he had two-grade rash on the face, three-grade oral mucositis with afatinib monotherapy. And he had one-grade rash on the face, two-grade oral mucositis and two-grade hand-foot syndrome in the combined treatment of afatinib and apatinib. Afatinib combined with apatinib is a safe therapeutic method for rare mutation of HER-2 V659D that can increase the efficacy.