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Dual blockade of EGFR and VEGFR pathways: Results from a pilot study evaluating apatinib plus gefitinib as a first-line treatment for advanced EGFR-mutant non-small cell lung cancer.

ABSTRACT: BACKGROUND:Dual blockade of both EGFR and VEGFR pathways in EGFR-mutant NSCLC have shown enhanced antitumor efficacy versus EGFR-TKIs alone. Apatinib is an orally effective VEGFR-2 tyrosine kinase inhibitor (TKI). This pilot study aims to evaluate the tolerability, pharmacokinetic profile, and antitumor activity of apatinib plus gefitinib as a therapy for EGFR-mutant advanced NSCLC. METHODS:Advanced non-squamous NSCLC participants harbored with the EGFR 19 deletion or the 21 L858R point mutation were included. There were two cohorts: Cohort A: apatinib 500 mg + gefitinib 250 mg. Cohort B: apatinib 250 mg + gefitinib 250 mg. The primary endpoint was safety profile. Other endpoints consisted of PK analysis, objective response rate (ORR), and progression-free survival (PFS). Exploratory analysis was conducted using next-generation sequencing of plasma circulating-tumor DNA. RESULTS:Between July 2016 and April 2017, 13 of NSCLC patients were recruited. Six patients were pooled in Cohort A, while seven patients were in Cohort B. Adverse events (AEs) were tolerable (mostly grade 1-2) and the treatment-related AEs were similar in both cohorts: rash (100% vs 71.4%), diarrhea (66.7% vs 71.4%), hypertension (66.7% vs 71.4%), proteinuria (66.7% vs 42.9%), and hand-foot skin reaction (33.3% vs 28.6%). The area under plasma concentration-time curve for the steady state of apatinib was 2864.73 ± 2605.54 ng mL-1 h-1 in Cohort A and 2445.09 ± 1550.89 ng mL-1 h-1 in Cohort B. Of the 11 patients evaluable for efficacy, Cohort A achieved an ORR of 80.0% and reached a median PFS of 19.2 months, while it was 83.3% and 13.4 months in Cohort B. Patients without a concomitant mutation at baseline had a prolonged PFS tendency (20.99 months v 13.21 months, P = .0624). The EGFR-T790M mutation remained the dominant resistance mechanism. CONCLUSION:Apatinib (500 mg) plus gefitinib (250 mg) showed a tolerable safety profile and encouraging antitumor activity for advanced EGFR-mutant NSCLC in the first-line setting. Phase III trials of apatinib (500 mg) plus gefitinib (250 mg) are warranted. TRIAL REGISTRATION:Clinicaltrials.gov, NCT02824458, date of registration June 23, 2016.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC7403827 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Dual blockade of EGFR and VEGFR pathways: Results from a pilot study evaluating apatinib plus gefitinib as a first-line treatment for advanced EGFR-mutant non-small cell lung cancer.

Zhang Zhonghan Z Zhang Yang Y Luo Fan F Ma Yuxiang Y Fang Wenfeng W Zhan Jing J Li Su S Yang Yunpeng Y Zhao Yuanyuan Y Hong Shaodong S Zhou Ting T Zhang Yaxiong Y Zhao Shen S Huang Yan Y Zhao Hongyun H Zhang Li L

Clinical and translational medicine 20200604 2

<h4>Background</h4>Dual blockade of both EGFR and VEGFR pathways in EGFR-mutant NSCLC have shown enhanced antitumor efficacy versus EGFR-TKIs alone. Apatinib is an orally effective VEGFR-2 tyrosine kinase inhibitor (TKI). This pilot study aims to evaluate the tolerability, pharmacokinetic profile, and antitumor activity of apatinib plus gefitinib as a therapy for EGFR-mutant advanced NSCLC.<h4>Methods</h4>Advanced non-squamous NSCLC participants harbored with the EGFR 19 deletion or the 21 L858R ...[more]

PMID: 32508029

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Project description:BACKGROUND:Gefitinib, 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. METHODS:This 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 SIGNIFICANCE:The 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.

Project description:BackgroundLung cancer is one of the most common and deadly tumors around the world. Targeted therapy for patients with certain mutations, especially by use of tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR), has provided significant benefit to patients. However, gradually developed resistance to the therapy becomes a major challenge in clinical practice and an alternative to treat such patients is needed. Herein, we report that apatinib, a novel anti-angiogenic drug, effectively inhibits obtained gefitinib-resistant cancer cells but has no much effect on their parental sensitive cells.MethodsGefitinib-resistant lung cancer cell line (PC9GR) was established from its parental sensitive line (PC9) with a traditional EGFR mutation after long time exposure to gefitinib. Different concentrations of apatinib were used to treat PC9, PC9GR, and other two lung cancer cell lines for its anti-growth effects. RNA sequencing was performed on PC9, PC9GR, and both after apatinib treatment to detect differentially expressed genes and involved pathways. Protein expression of key cycle regulators p57, p27, CDK2, cyclin E2, and pRb was detected using Western blot. Xenograft mouse model was used to assess the anti-tumor activity of apatinib in vivo.ResultsThe established PC9GR cells had over 250-fold increased resistance to gefitinib than its sensitive parental PC9 cells (IC50 5.311 ± 0.455 μM vs. 0.020 ± 0.003 μM). The PC9GR resistance cells obtained the well-known T790M mutation. Apatinib demonstrated much stronger ( ~ fivefold) growth inhibition on PC9GR cells than on PC9 and other two lung cancer cell lines, A549 and H460. This inhibition was mostly achieved through cell cycle arrest of PC9GR cells in G1 phase. RNA-seq revealed multiple changed pathways in PC9GR cells compared to the PC9 cells and after apatinib treatment the most changed pathways were cell cycle and DNA replication where most of gene activities were repressed. Consistently, protein expression of p57, CDK2, cyclin E2, and pRb was significantly impacted by apatinib in PC9GR cells. Oral intake of apatinib in mouse model significantly inhibited establishment and growth of PC9GR implanted tumors compared to PC9 established tumors. VEGFR2 phosphorylation in PC9GR tumors after apatinib treatment was significantly reduced along with micro-vessel formation.ConclusionsApatinib demonstrated strong anti-proliferation and anti-growth effects on gefitinib resistant lung cancer cells but not its parental sensitive cells. The anti-tumor effect was mostly due to apatinib induced cell cycle arrest and VEGFR signaling pathway inhibition. These data suggested that apatinib may provide a benefit to patients with acquired resistance to EGFR-TKI treatment.

Dataset Information

Dual blockade of EGFR and VEGFR pathways: Results from a pilot study evaluating apatinib plus gefitinib as a first-line treatment for advanced EGFR-mutant non-small cell lung cancer.

Publications

Dual blockade of EGFR and VEGFR pathways: Results from a pilot study evaluating apatinib plus gefitinib as a first-line treatment for advanced EGFR-mutant non-small cell lung cancer.

Similar Datasets

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