Dataset Information

Pemetrexed/carboplatin plus gefitinib as a first-line treatment for EGFR-mutant advanced nonsmall cell lung cancer: a Bayesian network meta-analysis.

ABSTRACT: Background:First-line treatments for nonsmall cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations have been evaluated in various clinical trials. However, it remains unclear which is the optimal treatment. Methods:A Bayesian network meta-analysis was used to assess the efficacy and safety profile of gefitinib, erlotinib, afatinib, dacomitinib, osimertinib, erlotinib plus bevacizumab and pemetrexed/carboplatin, or pemetrexed alone plus gefitinib. Literature was sourced from electronic databases. Data regarding objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), treatment-related adverse events (TRAEs), treatment-related adverse event grades 3-5 (TRAE 3-5), specific TRAEs [diarrhea, rash, and elevated aspartate aminotransferase/alanine aminotransferase (AST/ALT)] were extracted. The regimens were then ranked using the surface under the cumulative ranking curve (SUCRA). Results:A total of 19 studies involving 4607 EGFR-mutant NSCLC patients were analyzed. In regards to efficacy, pemetrexed/carboplatin (PC) plus gefitinib was superior in ORR and OS to chemotherapy and first-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). All the TKI-based regimens had equivalent DCR and PFS. Patients with the L858R mutation treated with PC plus gefitinib achieved a better outcome than most EGFR TKI-related groups (except osimertinib) in the PFS subgroup. In regards to safety, no statistical significance for TRAEs was observed among the eight treatments. In regards to SUCRA, PC plus gefitinib ranked first in terms of PFS, OS, and TRAE grades 3-5. Conclusions:Pemetrexed/carboplatin plus gefitinib is a promising treatment option for EGFR-mutant NSCLC patients in the first-line setting.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC6937538 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Pemetrexed/carboplatin plus gefitinib as a first-line treatment for EGFR-mutant advanced nonsmall cell lung cancer: a Bayesian network meta-analysis.

Zhang Zhonghan Z Zeng Kangmei K Zhao Shen S Zhao Yuanyuan Y Hou Xue X Luo Fan F Lu Feiteng F Zhang Yaxiong Y Zhou Ting T Ma Yuxiang Y Yang Yunpeng Y Fang Wenfeng W Huang Yan Y Zhang Li L Zhao Hongyun H

Therapeutic advances in medical oncology 20191230

<h4>Background</h4>First-line treatments for nonsmall cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations have been evaluated in various clinical trials. However, it remains unclear which is the optimal treatment.<h4>Methods</h4>A Bayesian network meta-analysis was used to assess the efficacy and safety profile of gefitinib, erlotinib, afatinib, dacomitinib, osimertinib, erlotinib plus bevacizumab and pemetrexed/carboplatin, or pemetrexed alone plus gefitinib. Li ...[more]

PMID: 31908655

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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: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.

Project description:BackgroundMany physicians consider platinum-doublet chemotherapy inappropriate for elderly patients, regardless of their medical fitness.ObjectiveThis was a retrospective subgroup analysis of data from a multicenter, randomized, phase III clinical trial evaluating pemetrexed + carboplatin versus docetaxel + carboplatin in elderly chemo-naive patients with advanced, nonsquamous non-small cell lung cancer (NSCLC).MethodsData from elderly patients (aged ≥65 years and ≥70 years) were evaluated using the same statistical methods as those used in patients aged <70 years and qualified intent-to-treat (Q-ITT) populations. The primary objective of the clinical trial was comparison of pemetrexed + carboplatin with docetaxel + carboplatin in terms of survival without grade 3 or 4 toxicity in chemo-naive NSCLC patients.ResultsThe ≥65- and ≥70-year age groups had 68 and 37 patients, respectively. Among patients aged ≥65 years, the adjusted hazard ratio (HR) for survival without grade 3-4 toxicity (HR 0.40, 95 % confidence interval [CI] 0.23-0.70) favored pemetrexed + carboplatin; this was similar to the HRs in patients aged ≥70 years (HR 0.43, 95 % CI 0.20-0.92), patients aged <70 years (HR 0.44, 95 % CI 0.32-0.62), and the Q-ITT population (HR 0.45, 95 % CI 0.34-0.61). The median values for overall survival (OS) and progression-free survival (PFS) were similar across all age-group subsets and the Q-ITT population. The HRs for OS and PFS were similar for all age-group subsets, except for the ≥70-year age group, which favored pemetrexed + carboplatin to a greater extent. The toxicity profile was similar across age groups, with the exception of diarrhea, mucosal inflammation, and grade 3-4 neutropenia and leukopenia, which were slightly more common in elderly patients in both treatment arms. Between-arm differences in the toxicity profiles for the ≥65-, ≥70- and <70-year age subgroups were similar to those in the Q-ITT population. There were no on-study deaths or unexpected toxicities.ConclusionThe benefits of pemetrexed + carboplatin were maintained, and toxicity was manageable in both elderly subgroups. The favorable risk-benefit profile of pemetrexed + carboplatin makes it an appropriate first-line treatment option for elderly patients with advanced nonsquamous NSCLC.

Dataset Information

Pemetrexed/carboplatin plus gefitinib as a first-line treatment for EGFR-mutant advanced nonsmall cell lung cancer: a Bayesian network meta-analysis.

Publications

Pemetrexed/carboplatin plus gefitinib as a first-line treatment for EGFR-mutant advanced nonsmall cell lung cancer: a Bayesian network meta-analysis.

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