The efficacy of combination of EGFR TKIs and chemotherapy versus EGFR TKIs monotherapy for first-line treatment of NSCLC with EGFR mutation: A Meta-analysis北大核心CSCD

Objective: To investigate the clinical value of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) combined with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation. Methods: Retrieval of PubMed, EMBASE, Web of Science and other databases from the start of the database building to 2017 was conducted to search randomized controlled trial of EGFR-TKI combined with chemotherapy vs EGFR-TKI single drug first-line treatment of EGFR mutant NSCLC. Meta-analysis was performed. The primary end point was progression-free survival (PFS), the secondary end points were objective response rate (ORR), disease control rate (DCR) and safety. Results: A total of 4 articles were included in this analysis, with a total of 353 patients. Compared with EGFR-TKI monotherapy, EGFR-TKI in combination with chemotherapy significantly prolonged PFS [hazard ratio (HR) = 0.65, 95% confidence interval (CI): 0.50-0.84, P= 0.001], as well as in subgroups of EGFR 19 deletion, L858R point mutation, age 5=65 years, performance status (PS) score was 1, female and never smoker (all P < 0.05). However, the combination group did not show significant differences in ORR and DCR compared with EGFR-TKI monotherapy group [relative risk (RR) = 1.07, 95% CI: 0.94-1.22, P = 0.282; RR = 1.02, 95% CI: 0.96-1.08; P = 0.531]. The combined regimen caused more fatigue, nausea and leukopenia (RR = 2.64, 95% CI: 1.32-5.25, P = 0.006; RR = 6.87, 95% CI: 3.06-15.45, P < 0.001; RR = 10.02, 95% CI: 3.18-31.55, P < 0.001). There were no differences in adverse reactions more than grade 3 between two groups (all P > 0.05). Conclusion: The combination of EGFR-TKI and chemotherapy can prolong the PFS compared with EGFR-TKI alone for the first-line treatment of NSCLC with EGFR mutation, and the adverse reactions were tolerable. Copyright © 2018 by TUMOR. All rights reserved.     

Meta-analysis of Seven Randomized Control Trials to Assess the Efficacy and Toxicity of Combining EGFR-TKI with Chemotherapy for Patients with Advanced NSCLC who Failed First-Line Treatment

Background: Some recent clinical trials have been conducted to evaluate a combination of EGFR- TKI withchemotherapy for advanced NSCLC patients as second-line therapy, but the results on the efficacy of such trialsare inconsistent. The aim of this meta-analysis was to evaluate the efficacy and safety of combination of EGFR-TKIand chemotherapy for patients with advanced NSCLC who failed first-line treatment. Materials and Methods:We searched relative trials from PubMed, EMBASE, ASCO Abstracts, ESMO Abstracts, Cochrane Libraryand Clinical Trials.gov. Outcomes analyzed were overall response rate (ORR), progression- free survival (PFS),overall survival (OS) and major toxicity. Results: Seven trails eventually were included in this meta-analysis,covering 1,168 patients. The results showed that the combined regimen arm had a significant higher ORR (RR1.76 [1.16, 2.66], p=0.007) and longer PFS (HR 0.75 [0.66-0.85], p<0.00001), but failed to show effects on OS (HR0.88 [0.68- 1.15], p=0.36). In terms of subgroup results, continuation of EGFR-TKI in addition to chemotherapyafter first-line EGFR-TKI resistance confered no improvement in ORR (RR 0.95 [0.68, 1.33], p=0.75) and PFS(HR 0.89[0.69, 1.15], p=0.38), and OS was even shorter (HR1.52 [1.05- 2.21], p=0.03). However, combinationtherapy with EGFR-TKI and chemotherapy after failure of first-line chemotherapy significantly improvedthe ORR (RR 2.06 [1.42, 2.99], p=0.0002), PFS (HR 0.71 [0.61, 0.82], p<0.00001) and OS (HR 0.74 [0.62- 0.88],p=0.0008), clinical benefit being restricted to combining EGFR-TKI with pemetrexed, but not docetaxel. Grade3-4 toxicity was found at significantly higher incidence in the combined regimen arm. Conclusions: Continuationof EGFR-TKI in addition to chemotherapy after first-line EGFR-TKI resistance should be avoided. Combinationtherapy of EGFR-TKI and pemetrexed for advanced NSCLC should be further investigated for prognostic andpredictive factors to find the group with the highest benefit of the combination strategy.     

Tumor-associated macrophages correlate with response to epidermal growth factor receptor-tyrosine kinase inhibitors in advanced non-small cell lung cancer

Our study investigated whether tumor-associated macrophages (TAMs) in advanced non-small cell lung cancer (NSCLC) are related to treatment response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and may be a predictor of survival. Of 206 advanced NSCLC patients treated (first-line) with an EGFR-TKI at the study hospital from 2006 to 2009, 107 with adequate specimens for assessing CD68 immunohistochemistry as a marker of TAMs were assessed. After EGFR-TKI treatment, response was observed in 55 (51%) patients, and the median follow-up period was 13.5 months. Most TAMs were located in the tumor stroma (>95%) and positively costained with the M2 marker CD163. TAM counts were significantly higher in patients with progressive disease than in those without (p < 0.0001), a trend that remained in patients with known EGFR mutation status (n = 59) and those with wild-type EGFR (n = 20). High TAM counts, among other factors (e.g., wild-type EGFR), were significantly related to poor progression-free survival (PFS) and overall survival (OS) (all p < 0.0001 for TAMs). Multivariate Cox analyses showed that high TAM counts and EGFR mutations were both independent factors associated with PFS [odds ratio (OR), 8.0; 95% confidence interval (CI), 2.87-22.4; p = 0.0001 and OR, 0.03; 95% CI, 0.003-0.31; p = 0.003, respectively] and OS (OR, 2.641; 95% CI, 1.08-6.5; p = 0.03 and OR, 0.14; 95% CI, 0.03-0.56; p = 0.006, respectively). TAMs are related to treatment response irrespective of EGFR mutation and can independently predict survival in advanced NSCLC treated with an EGFR-TKI.     

EGFR-TKI一线治疗不同EGFR突变状态晚期非小细胞肺癌疗效分析

目的：分析表皮生长因子受体酪氨酸酶抑制剂（EGFR-TKI）一线治疗不同EGFR突变状态（外显子19缺失、21突变）晚期非小细胞肺癌（NSCLC）的疗效。方法收集徐州市肿瘤医院经组织病理学证实的EGFR突变阳性晚期NSCLC患者72例,分析两种不同EGFR突变状态与一线EGFR-TKI治疗的客观缓解率（ORR）、疾病控制率（DCR）、无进展生存期（PFS）以及总生存期（OS）之间的关系。结果72例患者均进行EGFR基因检测,其中37例为EGFR19外显子缺失,35例为EGFR21外显子突变。72例患者均可评价疗效,其中EGFR19外显子缺失的患者ORR 75．7％,DCR 89．2％;EGFR21外显子突变的患者ORR 51．4％,DCR 68．6％,差异均有统计学意义（χ2＝4．583,P＝0．032;χ2＝4．636,P＝0．031）。EGFR19外显子缺失和21外显子突变的患者校正后的中位PFS分别为13．2个月、10．8个月,差异有统计学意义（χ2＝4．700,P＝0．030）;中位OS分别为30．2个月、25．6个月,差异有统计学意义（χ2＝4．686,P＝0．030）。两组间不良反应无明显差别,皮疹最为常见,两组差异无统计学意义（48．7％∶48．6％,χ2＝0．000,P＝0．995）。结论 EGFR突变状态是晚期NSCLC患者一线EGFR-TKI治疗疗效和OS的预测因素,EGFR19外显子缺失患者的疗效优于EGFR21外显子突变患者。     

Final overall survival results from a randomised,phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL,CTONG-0802)

BackgroundThe OPTIMAL study was the first study to compare efficacy and tolerability of the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) erlotinib, versus standard chemotherapy in first-line treatment of patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). Findings from final overall survival (OS) analysis and assessment of post-study treatment impact are presented.Patients and methodsOf 165 randomised patients, 82 received erlotinib and 72 gemcitabine plus carboplatin. Final OS analyses were conducted when 70% of deaths had occurred in the intent-to-treat population. Subgroup OS was analysed by Cox proportional hazards model and included randomisation stratification factors and post-study treatments.ResultsMedian OS was similar between the erlotinib (22.8 months) and chemotherapy (27.2 months) arms with no significant between-group differences in the overall population [hazard ratio (HR), 1.19; 95% confidence interval (CI) 0.83–1.71; P = 0.2663], the exon 19 deletion subpopulation (HR, 1.52; 95% CI 0.91–2.52; P = 0.1037) or the exon 21 L858 mutation subpopulation (HR, 0.92; 95% CI 0.55–1.54; P = 0.7392). More patients in the erlotinib arm versus the chemotherapy arm did not receive any post-study treatment (36.6% versus 22.2%). Patients who received sequential combination of EGFR-TKI and chemotherapy had significantly improved OS compared with those who received EGFR-TKI or chemotherapy only (29.7 versus 20.7 or 11.2 months, respectively; P < 0.0001). OS was significantly shorter in patients who did not receive post-study treatments compared with those who received subsequent treatments in both arms.ConclusionThe significant OS benefit observed in patients treated with EGFR-TKI emphasises its contribution to improving survival of EGFR mutant NSCLC patients, suggesting that erlotinib should be considered standard first-line treatment of EGFR mutant patients and EGFR-TKI treatment following first-line therapy also brings significant benefits to those patients.ClinicalTrials.gov IdentifierNCT00874419.     

表皮生长因子受体突变晚期非小细胞肺癌靶向治疗效果影响因素分析

目的:探讨表皮生长因子受体（EGFR）突变晚期非小细胞肺癌（NSCLC）EGFR-酪氨酸激酶抑制剂（EGFR-TKI）治疗效果的影响因素。方法:收集2015年1月至2019年10月南京医科大学附属无锡第二医院接受EGFR-TKI治疗的104例EGFR突变晚期NSCLC患者的临床资料。分析EGFR突变类型与患者的临床病理...     

化疗间插联合EGFR-TKIs对比单独化疗一线治疗晚期非小细胞肺癌的meta分析

背景与目的化疗与表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitors, EGFR-TKIs）联合疗法一直是许多研究的焦点,其中间插联合疗法受到了更多研究者的关注。本研究旨在系统评价化疗与EGFR-TKIs间插联合疗法对比单独化疗一线治疗晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）的有效性及安全性。方法检索hTe Cochrane Library、PubMed、EMBASE、中国生物医学文献数据库（CBM）、知网和万方等数据库关于化疗间插联合EGFR-TKIs疗法和单独化疗一线治疗晚期NSCLC的随机对照试验（randomized controlled trial, RCT）,分析如下结局指标：无进展生存期（progression-free survival, PFS）、总体生存期（overall survival, OS）、客观缓解率（objective response rate, ORR）、疾病控制率（disease control rate, DCR）以及不良反应发生率。由两名研究者根据Cochrane系统评价手册筛选文献、进行质量评价以及提取并交叉核对数据。应用Stata12.0软件进行meta分析。结果本研究共纳入6个RCT,共计933例晚期NSCLC患者。Meta分析结果表明,在晚期NSCLC患者一线治疗中,与单独化疗相比,间插联合疗法虽然延长了患者的PFS（HR=0.72,95%CI：0.53-0.98, P=0.037）,但并不能提高其OS（HR=0.85,95%CI：0.72-1.01,P=0.060）、ORR（OR=1.59,95%CI：0.86-2.95,P=0.142）和DCR（OR=1.09,95%CI：0.95-1.25,P=0.226）。进一步的亚组分析发现,间插联合疗法提高了女性、腺癌、从不吸烟和EGFR突变等患者的PFS,差异具有统计学意义。在安全性方面,间插联合疗法的主要不良反应为皮疹（OR=7.81,95%CI：3.74-16.34,P<0.001）和腹泻（OR=2.73,95%CI：1.92-3.89,P<0.001）。结论一线接受化疗间插联合EGFR-TKIs治疗的NSCLC患者的PFS明显高于接受单独化疗者,其主要不良事件是皮疹和腹泻。因此,间插联合治疗具有一定优势,但仍需要更多大样本、高质量的RCT进一步验证。     

VEGF抑制剂联合酪氨酸激酶抑制剂一线治疗EGFR突变晚期非小细胞肺癌的疗效和安全性

目的:探讨血管内皮生长因子(vascular endothelial growth factor,VEGF)抑制剂联合酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKI)一线治疗表皮生长因子受体(epidermal growth factor receptor,EGFR)突变晚期非小细胞肺癌...     

Efficacy of epidermal growth factor receptor inhibitors versus chemotherapy as second-line treatment in advanced non-small-cell lung cancer with wild-type EGFR: A meta-analysis of randomized controlled clinical trials

Background

EGFR mutation status is closely related to the efficacy of EGFR-TKIs in advanced non-small cell lung cancer (NSCLC). EGFR-TKIs have become the standard first-line treatment for advanced EGFR-mutation NSCLC, while for EGFR wild-type tumors, the preferred first-line treatment is chemotherapy. However, the efficacy of EGFR-TKIs as second-line treatment in EGFR wild-type NSCLC remains controversial. We sought to evaluate the effectiveness of EGFR-TKI as second-line treatment in EGFR wild-type NSCLC.

Methods

Randomized controlled trials that compared EGFR-TKIs with chemotherapy in previously treated advanced NSCLC with wild-type EGFR were included. We performed a meta-analysis to evaluate the effectiveness of EGFR-TKIs compared with standard chemotherapy. The endpoints were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).

Results

Six randomized controlled trials with a total of 990 patients with wild-type EGFR were included: 499 in the EGFR-TKIs group and 491 in the chemotherapy group. The results indicated that in the second-line treatment of EGFR wild-type advanced NSCLC, PFS was significantly inferior in the EGFR-TKIs group versus the chemotherapy group (HR = 1.37, 95% CI = 1.20–1.56, P < 0.00001). However, this significant difference did not translate into OS (HR = 1.02, 95% CI = 0.87–1.20, P = 0.81). ORR tended to favor chemotherapy but there was no significant difference compared with EGFR-TKI (RR = 1.77, 95% CI = 0.90–3.50, P = 0.10).

Conclusions

Chemotherapy improves PFS significantly but not OS, compared with EGFR-TKIs as a second-line treatment in advanced NSCLC with wild-type EGFR. Whether EGFR-TKIs should be used in EGFR wild-type patients should be considered carefully.     

Intercalated Chemotherapy and Epidermal Growth Factor Receptor Inhibitors for Patients With Advanced Non–Small-cell Lung Cancer: A Systematic Review and Meta-analysis

Randomized clinical trials (RCTs) of concurrent epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) plus chemotherapy for unselected patients with advanced non–small-cell lung cancer (NSCLC) produced negative results. Intercalated administration could avoid the reduction of chemotherapy activity due to G₁ cell-cycle arrest from EGFR-TKIs. A PubMed search was performed in December 2015 and updated in February 2016. The references from the selected studies were also checked to identify additional eligible trials. Furthermore, the proceedings of the main international meetings were searched from 2010 onward. We included RCTs comparing chemotherapy intercalated with an EGFR-TKI versus chemotherapy alone for patients with advanced NSCLC. Ten RCTs were eligible (6 with erlotinib, 4 with gefitinib): 39% of patients had a known EGFR mutational status, 43% of whom EGFR mutation positive. The intercalated combination was associated with a significant improvement in overall survival (OS; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.71-0.95; P = .01), progression-free survival (PFS; HR, 0.60; 95% CI, 0.53-0.68; P < .00001), and objective response rate (ORR; odds ratio [OR], 2.70; 95% CI, 2.08-3.49; P < .00001). Considering only first-line trials, similar differences were found in OS (HR, 0.85; 95% CI, 0.72-1.00; P = .05), PFS (HR, 0.63; 95% CI, 0.55-0.73; P < .00001), and ORR (OR, 2.21; 95% CI, 1.65-2.95; P < .00001). In EGFR mutation-positive patients, the addition of an intercalated EGFR-TKI produced a significant benefit in PFS (129 patients; HR, 0.24; 95% CI, 0.16-0.37; P < .00001) and ORR (168 patients; OR, 11.59; 95% CI, 5.54-24.25; P < .00001). In patients with advanced NSCLC, chemotherapy plus intercalated EGFR-TKIs was superior to chemotherapy alone, although a definitive interpretation was jeopardized by the variable proportion of patients with EGFR mutation-positive tumors included.     

Comparison of the Efficacy and Safety of EFGR TyrosineKinase Inhibitor Monotherapy with Standard Second-line Chemotherapy in Previously Treated Advanced Non-small-cell Lung Cancer: a Systematic Review and Meta-analysis

Purpose: To compare the efficacy and safety of epidermal growth factor receptor tyrosine kinaseinhibitormonotherapy (EFGR-TKIs: gefitinib or erlotinib) with standard second-line chemotherapy (single agentdocetaxel or pemetrexed) in previously treated advanced non-small-cell lung cancer (NSCLC). Methods: Wesystematically searched for randomized clinical trials that compared EGFR-TKI monotherapy with standardsecond-line chemotherapy in previously treated advanced NSCLC. The end points were overall survival (OS),progression-free survival (PFS), overall response rate (ORR), 1-year survival rate (1-year SR) and grade 3 or 4toxicities. The pooled hazard ratio (HR) or risk ratio (RR), with their corresponding 95% confidence intervals(CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the includedtrials. Results: Eight randomized controlled trials (totally 3218 patients) were eligible. Our meta-analysis resultsshowed that EGFR-TKIs were comparable to standard second-line chemotherapy for advanced NSCLC interms of overall survival (HR 1.00, 95%CI 0.92-1.10; p=0.943), progression-free survival (HR 0.90, 95%CI0.75-1.08, P=0.258) and 1-year-survival rate (RR 0.97, 95%CI 0.87-1.08, P=0.619), and the overall responserate was higher in patients who receiving EGFR-TKIs(RR 1.50, 95%CI 1.22-1.83, P=0.000). Sub-group analysisdemonstrated that EGFR-TKI monotherapy significantly improved PFS (HR 0.73, 95%CI: 0.55-0.97, p=0.03)and ORR (RR 1.96, 95%CI: 1.46-2.63, p=0.000) in East Asian patients, but it did not translate into increase in OSand 1-year SR. Furthermore, there were fewer incidences of grade 3 or 4 neutropenia, febrile neutropenia andneutrotoxicity in EGFR-TKI monotherapy group, excluding grade 3 or 4 rash. Conclusion: Both interventions hadcomparable efficacy as second-line treatments for patients with advanced NSCLC, and EGFR-TKI monotherapywas associated with less toxicity and better tolerability. Moreover, our data also demonstrated that EGFRTKImonotherapytended to be more effective in East Asian patients in terms of PFS and ORR compared withstandard second-line chemotherapy. These results should help inform decisions about patient management anddesign of future trials.     

Predictive value of K-ras and PIK3CA in non-small cell lung cancer patients treated with EGFR-TKIs: a systemic review and meta-analysis

Objective

A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment of non-small cell lung cancer (NSCLC) patients.

Methods

Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios (ORs) for objective response rate (ORR) and hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were calculated.

Results

Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval (CI), 0.13-0.35], shorter PFS (HR =1.56; 95% CI, 1.27-1.92), and shorter OS (HR =1.59; 95% CI, 1.33-1.91) in NSCLC patients treated with EGFR-TKIs. Mutant PIK3CA significantly predicted shorter OS (HR =1.83; 95% CI, 1.05-3.20), showed poor ORR (OR =0.70; 95% CI, 0.22-2.18), and shorter PFS (HR =1.79; 95% CI, 0.91-3.53) in NSCLC patients treated with EGFR-TKIs.

Conclusion

K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFR-TKIs. PIK3CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment.KEYWORDS : Non-small cell lung cancer (NSCLC), tyrosine kinase inhibitor (TKI), targeted therapy, K-ras, PIK3CA, meta-analysis     

PD-1/PD-L1抑制剂对比化疗一线治疗晚期非小细胞肺癌的Meta分析

 目的 系统评价PD-1/PD-L1抑制剂对比化疗一线治疗晚期非小细胞肺癌的疗效及安全性。方法 通过Web of science等国内外数据库，ASCO会议摘要及杂志筛选文献，进行Meta分析。结果 纳入7项RCT研究，4 101例患者，荟萃分析显示抑制剂联合化疗对比化疗可显著延长患者的PFS（HR=0.59, 95%CI: 0.50~0.70, P<0.00001）、OS（HR=0.65, 95%CI: 0.46~0.92, P=0.02）及ORR（RR=1.72, 95%CI: 1.13~2.62, P=0.01）。亚组分析显示，抑制剂联合化疗可显著延长PFS及OS，且PD-L1表达程度越高，疗效获益越显著。而单药抑制剂对比化疗在延长晚期NSCLC患者的PFS（HR=0.87, 95%CI: 0.57~1.31, P=0.50）、OS（HR=0.82, 95%CI: 0.65~1.03, P=0.09）及提高ORR（RR=1.12, 95%CI: 0.55~2.28, P=0.76）方面两组差异无统计学意义。与化疗相比，单药抑制剂一线治疗PD-L1高表达的晚期NSCLC患者可显著延长OS，但在延长PFS方面未见明显优势。与化疗组相比，抑制剂联合化疗组3~4级不良反应发生率无明显改善（HR=1.09，95%CI: 0.99~1.20, P=0.09），而单药PD-1/PD-L1抑制剂组3~4级不良反应发生率低（RR=0.43, 95%CI: 0.36~0.52, P<0.00001）。 结论 PD-1/PD-L1抑制剂联合化疗一线治疗晚期NSCLC患者疗效优于化疗方案；PD-L1高表达者单药PD-1/PD-L1抑制剂可作为一线治疗的优先选择，且具有良好的安全性。     

EGFR-TKI一线治疗EGFR基因突变的晚期非小细胞肺癌临床观察

背景与目的研究表明,一线表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptortyrosine kinase inhibitor,EGFR-TKI)治疗晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的客观缓解率及无进展生存期明显优于铂二联的化疗,且耐受性更好。本研究旨在分析EGFR-TKI一线治疗晚期EGFR突变阳性的NSCLC患者的疗效与耐受性。方法 54例晚期NSCLC患者肿瘤标本采用直接测序法证实EGFR活化突变(外显子19缺失或外显子21点突变),一线给予EGFR-TKI口服治疗直至疾病进展,观察疗效及不良反应,并进行生存随访。结果 54例患者外显子19缺失33例(61%),外显子21点突变21例(39%)。均一线接受EGFR-TKI治疗,总体缓解率为90%,中位无进展生存期(progression free survival,PFS)为8.3个月,中位生存期为19.5个月;外显子19缺失患者的中位PFS(9.0个月)较21点突变(7.0个月)时间长(P=0.002)。外显子19缺失患者的中位总生存期(overall survival,OS)(25.0个月)较21点突变(16.0个月)时间长(P=0.001);吉非替尼与厄洛替尼疗效相当,但吉非替尼组安全性更好;最常见的不良事件为皮疹和腹泻,有2例患者(4%)出现了3度皮肤毒性反应,2例患者(4%)出现了3度的转氨酶升高,1例患者(1%)出现了3度口腔炎。结论存在EGFR基因突变的晚期NSCLC患者一线接受EGFR-TKI治疗安全有效,且外显子19缺失比L858R突变疗效更优。     

Efficacy of First-line Chemotherapy Affects the Second-Line Setting Response in Patients with Advanced Non-Small Cell Lung Cancer

Background: Chemotherapy is the mainstay of treatment for the majority of patients with advanced nonsmall cell lung cancer (NSCLC) without driver mutations and many receive therapies beyond first-line. Secondline chemotherapy has been disappointing both in terms of response rate and survival and we know relatively little about the prognostic factors. Materials and Methods: One thousand and eight patients with advanced NSCLC who received second-line chemotherapy after progression were reviewed in Shanghai PulmonaryHospital, China, from September 2005 to July 2010. We analyzed the effects of potential prognostic factors on the outcomes of second-line chemotherapy (overall response rate, ORR; progression free survival, PFS; overall survival, OS). Results: The response and progression free survival of first-line chemotherapy affects the ORR, PFS and OS of second-line chemotherapy (ORR: CR/PR 15.4%, SD 10.1%, PD2.3%, p<0.001; PFS: CR/PR 3.80 months, SD 2.77 months, PD 2.03 months, p<0.001; OS: CR/PR 11.60 months, SD 10.33 months, PD 6.57 months, p=0.578, p<0.001, p<0.001, respectively). On multivariate analysis, better response to first-line therapy (CR/PR: HR=0.751, p=0.002; SD: HR=0.781, p=0.021) and progression within 3-6 months (HR=0.626, p<0.001), together with adenocarcinoma (HR=0.815, p=0.017), without liver metastasis (HR=0.541, p=0.001), never-smoker(HR=0.772, p=0.001), and ECOG PS 0-1 (HR=0.745, p=0.021) were predictors for good OS following secondline chemotherapy. Conclusions: Patients who responded to first-line chemotherapy had a better outcome after second-line therapy for advanced NSCLC, and the efficacy of first-line chemotherapy, period of progression, histology, liver metastasis, smoking status and ECOG PS were independent prognostic factors for OS.     

Efficacy and safety of osimertinib in treating EGFR-mutated advanced NSCLC: A meta-analysis

Osimertinib is the only Food and Drug Administration-approved third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI). A meta-analysis was performed to aggregate the mixed results of published clinical trials to assess the efficacy and safety of osimertinib. A systematic search of the PubMed, Web of Science, and Cochrane Library electronic databases was performed to identify eligible literature. The primary endpoints were overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and adverse events (AEs). A total of 3,086 advanced nonsmall cell lung cancer (NSCLC) patients from 11 studies have been identified. The aggregate efficacy parameters for treatment-naïve patients with EGFR-TKI-sensitizing mutations are as follows: ORR 79% (95% CI 75–84%), DCR 97% (95% CI 95–99%), 6-month PFS 83% (95% CI 80–87%), and 12-month PFS 64% (95% CI 59–69%). The aggregate efficacy parameters for advanced NSCLC harboring T790M mutations after earlier-generation EGFR-TKI therapy are as follows: ORR 58% (95% CI 46–71%), DCR 80% (95% CI 63–98%), 6-month PFS 63% (95% CI 58–69%), and 12-month PFS 32% (95% CI 17–47%). EGFR-TKI-naïve patients with EGFR-positive mutations tend to have longer median PFS than EGFR-TKI-pretreated counterparts (19.17 vs. 10.58 months). The most common AEs were diarrhea and rash, of which the pooled incidences were 44 and 42%, respectively. Generally, osimertinib is a favorable treatment option for previously treated T790M mutation-positive advanced NSCLC as well as a preferable therapy for untreated EGFR mutation-positive advanced NSCLC. Additionally, osimertinib is well tolerated by most patients.     

A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small-cell lung cancer

Imetelstat, a novel telomerase inhibitor, failed to improve significantly median PFS and OS as maintenance therapy (±bevacizumab) in advanced NSCLC. Telomere length (TL) biomarker results were consistent with the hypothesis that telomerase inhibition is of greater benefit to patients with tumors possessing shorter telomeres; the patients with shorter TL had a trend toward longer median PFS and OS.BackgroundContinuation or ‘switch’ maintenance therapy is commonly used in patients with advancd non-small-cell lung cancer (NSCLC). Here, we evaluated the efficacy of the telomerase inhibitor, imetelstat, as switch maintenance therapy in patients with advanced NSCLC.Patients and methodsThe primary end point of this open-label, randomized phase II study was progression-free survival (PFS). Patients with non-progressive, advanced NSCLC after platinum-based doublet (first-line) chemotherapy (with or without bevacizumab), any histology, with Eastern Cooperative Oncology Group performance status 0–1 were eligible. Randomization was 2 : 1 in favor of imetelstat, administered at 9.4 mg/kg on days 1 and 8 of a 21-day cycle, or observation. Telomere length (TL) biomarker exploratory analysis was carried out in tumor tissue by quantitative PCR (qPCR) and telomerase fluorescence in situ hybridization.ResultsOf 116 patients enrolled, 114 were evaluable. Grade 3/4 neutropenia and thrombocytopenia were more frequent with imetelstat. Median PFS was 2.8 and 2.6 months for imetelstat-treated versus control [hazard ratio (HR) = 0.844; 95% CI 0.54–1.31; P = 0.446]. Median survival time favored imetelstat (14.3 versus 11.5 months), although not significantly (HR = 0.68; 95% CI 0.41–1.12; P = 0.129). Exploratory analysis demonstrated a trend toward longer median PFS (HR = 0.43; 95% CI 0.14–1.3; P = 0.124) and overall survival (OS; HR = 0.41; 95% CI 0.11–1.46; P = 0.155) in imetelstat-treated patients with short TL, but no improvement in median PFS and OS in patients with long TL (HR = 0.86; 95% CI 0.39–1.88; and HR = 0.51; 95% CI 0.2–1.28; P = 0.145).ConclusionsMaintenance imetelstat failed to improve PFS in advanced NSCLC patients responding to first-line therapy. There was a trend toward a improvement in median PFS and OS in patients with short TL. Short TL as a predictive biomarker will require further investigation for the clinical development of imetelstat.     

Combination of chemotherapy and gefitinib as first‐line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A randomized controlled trial

To explore the optimal treatment strategy for patients who harbor sensitive EGFR mutations, a head‐to‐head study was performed to compare chemotherapy and gefitinib in combination or with either agent alone as first‐line therapy, in terms of efficacy and safety. A total of 121 untreated patients with advanced lung adenocarcinoma who harbored sensitive EGFR mutations were randomly assigned to receive gefitinib combined with pemetrexed and carboplatin, pemetrexed plus carboplatin or gefitinib alone. The progression‐free survival (PFS) of patients in the combination group (17.5 months, 95% CI, 15.3–19.7) was longer than that of patients in the chemotherapy group (5.7 months, 95% CI, 5.2–6.3) or gefitinib (11.9 months, 95% CI, 9.1–14.6) group. The (hazard ratios) HRs of PFS for the combination group vs. chemotherapy and gefitinib groups were 0.16 (95% CI, 0.09–0.29, p < 0.001) and 0.48 (95% CI, 0.29–0.78, p = 0.003), respectively. The overall response rate (ORR) in the combination therapy group, chemotherapy group and the gefitinib group was 82.5%, 32.5% and 65.9%, respectively. The combinational strategy resulted in longer overall survival (OS) than chemotherapy (HR = 0.46, p = 0.016) or gefitinib (HR = 0.36, p = 0.001) alone. Our finding suggested that treatment with pemetrexed plus carboplatin combined with gefitinib could provide better survival benefits for patients with lung adenocarcinoma harboring sensitive EGFR mutations.     

Efficacy and safety of anti‐EGFR agents administered concurrently with standard therapies for patients with head and neck squamous cell carcinoma: a systematic review and meta‐analysis of randomized controlled trials

Agents targeting epidermal growth factor receptor (EGFR) are used to treat head and neck squamous cell carcinoma (HNSCC); however, their efficacy and safety is poorly understood. Here we evaluated the efficacy and safety of anti‐EGFR agents administered concurrently with standard therapies for HNSCC. Randomized controlled trials that evaluated addition of EGFR targeted therapy versus standard therapy alone were included. The primary outcome was overall survival (OS). Secondary outcomes were progression‐free survival (PFS), overall response rate (ORR), locoregional control, and severe adverse events (SAEs, grade ≥ 3). Sixteen eligible trials with 4031 patients were included. Addition of anti‐EGFR regimens to standard therapy significantly improved OS of patients with HNSCC (HR = 0.89; 95% CI, 0.82–0.96), with a moderately elevated rate of SAEs (RR = 1.08; 95% CI, 1.03–1.13). Subgroup analysis indicated that the survival benefit was observed when cetuximab was administered concurrently with radiotherapy (RT) for stage III/IV patients (HR = 0.76; 95% CI, 0.61–0.94; p = 0.01), or with chemotherapy for recurrent or metastatic (R/M) HNSCC (HR = 0.86; 95% CI, 0.78–0.95; p = 0.005). Significantly increased ORR (RR = 1.51; 95% CI 1.05–2.18) and PFS (HR = 0.72; 95% CI, 0.59–0.88) were found in R/M HNSCC patients treated with anti‐EGFR plus chemotherapy, while no significant improvements were found in stage III/IV patients treated with anti‐EGFR plus standard therapy. In conclusion, addition of cetuximab to standard therapy may improve outcomes for R/M HNSCC patients, while causing a moderate increase in SAEs. For stage III/IV patients, anti‐EGFR mAb plus RT can improve OS compared with RT alone, while replacement of chemotherapy with EGFR mAb or adding EGFR mAb to combined chemotherapy and RT did not improve outcomes.     

一线用药的EGFR－TKIs与化疗治疗基因突变型NSCLC疗效比较的Meta分析

目的：系统评价表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors,EGFR－TKIs）与化疗一线治疗基因突变型非小细胞肺癌（non－small cell lung cancer,NSCLC）患者的疗效比较。方法：自PubMed、Cochrane Library、Embase中检索相关的主题词及自由词,收集EGFR－TKIs与化疗相比一线治疗基因突变型NSCLC疗效的随机对照研究（randomized controlled trials,RCT）。按纳入标准及排除标准筛选文献,采用Cochrane偏倚风险评估表对纳入文献进行质量评价,自纳入文献中提取有效数据,应用RevMan 5．3．5和STATA 12．0分析基因突变型晚期NSCLC患者在EGFR－TKIs治疗中的疗效。敏感性分析和发表偏倚分析以评价结果的稳定性和可靠性。结果：共纳入5篇RCT,共1091例患者,对于EG-FR基因变异型晚期NSCLC患者：EGFR－TKIs一线治疗与化疗相比,有较好的无进展生存期（PFS）、客观反应率（ORR）,但总体生存期（OS）两者无明显差异。结论：EGFR基因突变的晚期NSCLC患者接受一线EGFR－TKIs治疗相比化疗获益更多。