P1.01-109 Phase I Study of Apatinib Plus Gefitinib as First-Line Therapy in Patients with EGFR Mutant Advanced Non-Small Cell Lung Cancer

Zhao, Hongyun; Zhang, Z.; Li, Shaozhi; Fang, Wenfeng; Ma, Yuxiang; Zhang, Y.; Yang, Yunpeng; Luo, Fan; Huang, Yan; Zhang, L.

doi:10.1016/j.jtho.2018.08.666

Cited by 2 publications

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“…In our former pilot phase I study, we have found that apatinib plus gefitinib had a tolerable safety profile and promising antitumor activity. The median PFS of the apatinib (500 mg) plus gefitinib (250 mg) group was 19.0 months, much longer than historically reported by gefitinib monotherapy [29]. This innovative design of apatinib plus gefitinib will enable patients to derive a survival benefit from the combinational regimen while convenience and comfort were taken into account.…”

Section: Discussionmentioning

confidence: 92%

“…Promisingly, in our exploratory phase I study evaluating apatinib plus gefitinib as a first-line of treatment for NSCLC, of the twelve evaluable patients, the observed objective response rate (ORR) was 83.3% (10/12), and disease control rate (DCR) was 91.7% (11/12). The observed median PFS was 19.0 months in the apatinib (500 mg) plus gefitinib group while a PFS of 13.4 months was achieved in the apatinib (250 mg) plus gefitinib group ( P = 0.657) [29]. Simultaneously targeting the EGFR and VEGR pathways might be a feasible therapeutic approach for patients with EGFR-mutant NSCLC.…”

Section: Introductionmentioning

confidence: 99%

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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)

et al. 2019

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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

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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)

et al. 2019

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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

Luo

et al. 2020

Clinical & Translational Med

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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.

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P1.01-109 Phase I Study of Apatinib Plus Gefitinib as First-Line Therapy in Patients with EGFR Mutant Advanced Non-Small Cell Lung Cancer

Cited by 2 publications

References 0 publications

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)

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)

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

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