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[Effectiveness of EGFR-TKIs versus chemotherapy as first-line treatment for advanced non-small cell lung cancer: a meta-analysis].

ABSTRACT: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been used for the first-line treatment of non-small cell lung cancer (NSCLC) and has shown good clinical effects. However, some patients fail to benefit from this treatment. The aim of this study is to analyze whether or not clinical-selected patients (Asian, adenocarcinoma histology, non-smoking) and EGFR mutation-selected patients benefit from EGFR-TKIs or chemotherapy. Our results could be used as basis to guide clinical therapy.Randomized controlled trials evaluating the efficacy of EGFR-TKIs versus chemotherapy as first-line treatments of NSCLC were obtained from electronic databases, namely, PubMed, Embase, American Society of Clinical Oncology (ASCO), European Society for Medical Oncology, and China Biology Medicine disc. Assessment, data collection, and statistical analysis were performed according to Cochrane Handbook 5.1.0.A total of 14 randomized controlled trials with 5,000 patients were included in this study. Compared with the chemotherapy group, EGFR-TKI therapy group in EGFR mutation-selected NSCLC patients showed a higher response rate (RR=2.31; 95%CI: 1.88-2.84) and more significant improvement in progression free survival (PFS; HR=0.39; 95%CI: 0.30-0.49); by contrast, no significant difference was observed in overall survival (OS; HR=0.99; 95%CI: 0.84-1.16). The response rate of clinical-selected patients treated with EGFR-TKI significantly increased (RR=1.30; 95%CI: 1.15-1.47) compared with that of the patients treated with chemotherapy; PFS (HR=0.93; 95%CI: 0.58-1.49) and OS (HR=0.91; 95%CI: 0.81-1.02) of the two groups did not significantly differ. Likewise, the PFS and the OS of the unselected patients in the EGFR-TKI treatment group and the chemotherapy group did not significantly differ, although the OS of the former was shorter than that of the latter.EGFR mutation-selected patients received more benefits from EGFR-TKI first-line treatment than other treatments. First-line EGFR-TKI treatment was recommended for clinically selected patients who were unsuitable for themotherapy. By comparison, first-line EGFR-TKI treatment was not a suitable choice for unselected patients.

SUBMITTER: Cao F

PROVIDER: S-EPMC6000008 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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[Effectiveness of EGFR-TKIs versus chemotherapy as first-line treatment for advanced non-small cell lung cancer: a meta-analysis].

Cao Feifei F Zhang Linlin L Wang Shuang S Zhong Diansheng D Wang Yan Y

Zhongguo fei ai za zhi = Chinese journal of lung cancer 20150301 3

<h4>Background and objective</h4>Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been used for the first-line treatment of non-small cell lung cancer (NSCLC) and has shown good clinical effects. However, some patients fail to benefit from this treatment. The aim of this study is to analyze whether or not clinical-selected patients (Asian, adenocarcinoma histology, non-smoking) and EGFR mutation-selected patients benefit from EGFR-TKIs or chemotherapy. Our results could ...[more]

PMID: 25800570

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Project description:The impact of combining epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) remains controversial. Therefore, randomized trials that compared this combined regimen with chemotherapy or EGFR-TKIs monotherapy were included for this meta-analysis. We used published hazard ratios (HRs), if available, or derived treatment estimates from other survival data. Pooled estimates of treatment efficacy of the combined regimen in the entire unselected population and selected patients by EGFR-mutation status and smoking history were calculated. Eight trials eventually entered into this meta-analysis, including 4585 patients. Overall, the combined regimen significantly delayed disease progression (HR?=?0.81, 95% CI 0.69-0.95, P?=?0.01); subgroup analysis showed significantly higher progression free survival advantages in Asian patients (P<0.001), with sequential combination of TKIs and chemotherapy (P?=?0.02). In selected patients by EGFR-mutation, both mutation positive (HR?=?0.48, 95% CI 0.28-0.83, P?=?0.009) and negative (HR?=?0.84, 95% CI 0.72-0.98, P?=?0.02) patients gained progression free survival benefit from the combined regimen, albeit the magnitude of benefit was marginally larger in mutation positive patients (P?=?0.05). In selected patients by smoking history, never/light smokers achieved a great progression free survival benefit from the combined regimen (HR?=?0.51, 95% CI 0.35-0.74, P?=?0.0004). Unfortunately, the combined regimen had no significant impact on overall survival, irrespective of ethnicity, dose schedules or EGFR-mutation status. Severe anorexia (RR?=?2.01, 95% CI 1.11-3.63; P?=?0.02) and diarrhea (RR?=?2.70, 95% CI 1.94-3.76; P<0.001) were more frequent in the combined regimen arm. This strategy of combining EGFR-TKIs and chemotherapy deserved to be considered in the future, although it is not approved for advanced NSCLC at the moment.

Project description:BackgroundActivated epidermal growth factor receptor (EGFR) mutation is the main pathogenic cause of non-small cell lung cancer (NSCLC) in Asia. However, the impact of plasma EGFR mutation abundance, especially of the ultra-low abundance of EGFR mutation detected by highly sensitive techniques on clinical outcomes of first-line EGFR tyrosine kinase inhibitors (TKIs) for advanced NSCLC patients remains unclear.MethodsWe qualitatively detected baseline EGFR status of NSCLC tissues using amplification-refractory mutation system and quantified the plasma abundance of EGFR mutations through next-generation sequencing (NGS). Every 8-12 weeks, we performed dynamic detection of plasma mutation abundance and imaging evaluation. We analyzed the association between plasma abundance of EGFR sensitizing mutations, tumor size, tumor shrinkage percentage, concomitant TP53 mutations, and clinical response to TKIs.ResultsThis prospective study enrolled 135 patients with advanced NSCLC. The objective response rate (ORR) and disease control rate (DCR) for EGFR mutation-positive patients were 50.0% and 87.0%, respectively. When the cutoff value of plasma EGFR mutation abundance was 0.1%, the ORRs of TKI-treated patients were significantly different (60.0% for the >0.1% group vs. 21.4% for the ≤0.1% group, P=0.028). Median progression-free survival (PFS) was significantly longer for participants with a mutation abundance above 0.1% compared to those with a 0.01-0.1% abundance (log rank, P=0.0115). There was no significant association between plasma abundance of EGFR sensitizing mutations and tumor size, tumor shrinkage percentage, or concomitant TP53 mutations. Cox multivariate analysis demonstrated that plasma mutation abundance was an independent predictive factor for PFS [hazard ratio (HR) 2.41, 95% confidence interval (CI): 1.12-5.20; P=0.025]. We identified 11 participants with the acquired T790M resistance mutation according to serial dynamic plasma samples.ConclusionsLiquid biopsy screening based on highly sensitive NGS is reliable for detecting drug resistance and actionable somatic mutations. The plasma abundance of the EGFR driver mutation affected clinical response to EGFR-TKIs in advanced NSCLC patients; prolongation of PFS was also observed in patients with an ultra-low abundance of EGFR sensitizing mutations.

Project description:PurposeA meta-analysis of randomized controlled trials (RCTs) was conducted to compare the difference in efficacy and safety between epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) with antiangiogenic inhibitors (A + T) and EGFR-TKI monotherapy in patients with treatment-naïve advanced EGFR-mutant non-small-cell lung cancer (NSCLC).MethodsPubMed, Embase, Web of Science, and Cochrane electronic databases were searched for relevant RCTs. Meeting abstracts were also reviewed to identify appropriate studies. The endpoints included progression-free survival (PFS), overall survival (OS), 1- and 2-year OS rates, objective response rate (ORR), and grade ≥ 3 adverse events. All pooled outcomes were expressed using hazard ratios (HRs) or relative risk ratios (RRs).ResultsData were collected from six eligible RCTs, which included 1,244 participants (619 in the A + T group and 625 in the TKI alone group). PFS was significantly improved with A + T compared to TKI alone (HR = 0.60; P < 0.01) regardless of EGFR mutation types (exon 19 deletion or L858R) and brain metastasis status (with or without brain metastases). There was no significant difference in median OS between the A + T and TKI alone groups (HR = 0.933; P = 0.551) regardless of EGFR mutation type. The ORR for A + T combination therapy was significantly increased compared to TKI monotherapy in exon 19 deletion subgroups (RR = 0.774; P = 0.008). There was no difference in the positive rates of acquired T790M mutation between the two groups (RR = 0.967; P = 0.846). More patients in the TKI alone group received a variety of subsequent systemic treatments than those in the A + T group (RR = 0.881; P = 0.002).ConclusionAddition of antiangiogenic inhibitors to first-line EGFR-TKI therapy significantly reduced the risk of disease progression for patients with advanced EGFR-mutant NSCLC regardless of EGFR mutation type and brain metastasis status. The lack of OS benefit may be explained by differences in subsequent treatments rather than drug resistance mechanisms.

Project description:ObjectivesFood and Drug Administration (FDA) approved crizotinib for advanced ROS1-rearranged (ROS1+) non-small-cell lung cancer (NSCLC) patients due to a single-arm study PROFILE 1001. However, there is no direct comparison between crizotinib and platinum-pemetrexed chemotherapy.Materials and methodsClinical data of advanced ROS1+NSCLC patients treated with first-line crizotinib or platinum-pemetrexed chemotherapy between August 2010 and December 2017 were analyzed.ResultsSeventy-seven patients were eligible, including 30 (39.0%) in the crizotinib group and 47 (61.0%) in the platinum-pemetrexed chemotherapy group. The median follow-up was 28.1 months (95% confidence interval [CI]: 19.2-39.0). The objective response rate (ORR) of crizotinib (86.7%, 95% CI: 73.3-96.7) was higher than that of platinum-pemetrexed chemotherapy (44.7%, 95% CI: 29.8-57.4, P < .001). The disease control rate (DCR) was 96.7% (95% CI: 90.0-100) in the crizotinib group and 85.1% (95% CI: 74.5-95.7) in the chemotherapy group (P = .140). Significantly longer progression-free survival (PFS) was observed in the patients treated with crizotinib (18.4 months, 95% CI: 6.4-30.3) versus platinum-pemetrexed chemotherapy (8.6 months, 95% CI: 6.9-10.3, P < .001). Overall survival (OS) was also compared between the two groups and no significant difference was seen (Not reach vs 28.4 months [95% CI: 20.7-36.0], P = .176). Notably, a total of 37 patients have treatment crossover after the failure of first-line treatment. Among those patients, difference in OS was not statistically significant between seven patients who have given first-line crizotinib (38.6 months, 95% CI: 0-81.0) and 30 patients who have given platinum-pemetrexed chemotherapy initially (32.8 months, 95% CI: 11.9-53.8, P = .805).ConclusionsOur results suggested that first-line crizotinib had higher ORR and longer PFS than platinum-pemetrexed chemotherapy in patients with advanced ROS1+NSCLC, but the differences were not observed for OS.

Project description:BackgroundRecent studies have demonstrated benefits from adjuvant tyrosine-kinase inhibitors (TKIs) compared with chemotherapy in non-small cell lung cancer. We launched a multi-center retrospective study to evaluate the efficacy and toxicity of adjuvant TKIs with or without chemotherapy in epidermal growth factor receptor (EGFR)-mutant stage III-pN2 lung adenocarcinoma.MethodsTwo hundred and seventy-four consecutive cases with stage III-pN2 lung adenocarcinoma and complete resection have been investigated. Clinic-pathologic characteristics, adjuvant treatments, long-term survivals, and toxicities were documented. Risk factors of distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) were evaluated.ResultsThere were 52 (19.0%) patients treated with adjuvant TKIs alone, 199 (72.6%) with adjuvant chemotherapy alone, and 23 (8.4%) with both. After a median follow-up time of 29 months, the two-year DMFS, DFS, and OS was 61.2%, 54.1%, and 91.2%, respectively. According to univariable analyses, the risk factors were lymphovascular invasion (p < 0.001), extranodal extension (p = 0.005), and adjuvant systemic therapy (p = 0.006) for DMFS, EGFR mutation type (p = 0.025), lymphovascular invasion (p = 0.013), extranodal extension (p = 0.004), and adjuvant systemic therapy (p < 0.001) for DFS, and EGFR mutation type (p < 0.001) for OS. Multivariable analyses indicated that the independent prognostic factors were adjuvant systemic therapy (TKIs vs. TKIs+chemotherapy, Harzard ratio (HR) = 0.40; p = 0.036; TKIs vs. chemotherapy, HR = 0.38; p = 0.004), lymphovascular invasion (yes vs. no, HR = 2.22; p = 0.001) for DMFS, and adjuvant systemic therapy (TKIs vs. TKIs+chemotherapy, HR = 0.42; p = 0.034; TKIs vs. chemotherapy, HR = 0.33; p < 0.001) for DFS. No significant difference was found in the incidence of Grade 3-4 toxicities between groups (p = 0.445).ConclusionsAdjuvant TKIs might be a beneficial choice compared with adjuvant chemotherapy or combination systemic treatments.

Project description:Importance:The survival of patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) gene mutations has improved substantially in the last decade with the development of targeted tyrosine kinase inhibitors (TKIs). Osimertinib, a third-generation TKI that is approved by the US Food and Drug Administration for the treatment of patients who develop EGFR T790M mutations, has recently shown improved clinical outcomes compared with gefitinib and erlotinib for treatment-naive patients. Objective:The aim of this study was to assess the cost-effectiveness of osimertinib for the first-line treatment of patients with EGFR-mutated NSCLC. Design, Setting, and Participants:For this cost-effectiveness analysis, we extracted individual patient data from the FLAURA randomized clinical trial and used findings of our earlier meta-analysis to develop a decision-analytic model and determine the cost-effectiveness of osimertinib (AZD9291) compared with first- and second-generation EGFR-TKIs over a 10-year time horizon. All direct costs were based on US and Brazilian payer perspectives. Main Outcomes and Measures:The main outcome of this study was the incremental cost-effectiveness ratio (ICER) expressed as cost per quality-adjusted life-year (QALY) gained by using osimertinib compared with first- or second-generation EGFR-TKIs in previously untreated EGFR-mutated NSCLC. Results:In the base case using the data as reported in the FLAURA trial, the incremental QALY for osimertinib was 0.594 compared with the first- and second-generation EGFR-TKIs. In the United States, the osimertinib ICERs were $226?527 vs erlotinib, $231?123 vs gefitinib, and $219?874 vs afatinib. In Brazil, the ICERs were $162?329, $180?804, and $175?432, respectively. The overall survival (95% CI) reported in the FLAURA trial (hazard ratio, 0.63; 95% CI, 0.45-0.88) had the strongest association with the ICER (ranging from $84?342 to $859?771). Osimertinib price adjustments to the FLAURA trial data improved cost-effectiveness. For example, a discount of 10% on osimertinib acquisition cost was associated with a 20% decreased ICER compared with the base case ICER, and a discount of 20% on osimertinib acquisition cost was associated with a 40% decreased ICER compared with the base case ICER. Conclusions and Relevance:At current costs, by World Health Organization cost-effectiveness threshold criteria, osimertinib is not cost-effective for first-line therapy of EGFR-mutated NSCLC in either the United States or Brazil.

Dataset Information

[Effectiveness of EGFR-TKIs versus chemotherapy as first-line treatment for advanced non-small cell lung cancer: a meta-analysis].

Publications

[Effectiveness of EGFR-TKIs versus chemotherapy as first-line treatment for advanced non-small cell lung cancer: a meta-analysis].

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