Efficacy and safety comparison of EGFR-TKIs monotherapy and combination therapy as first-line treatment for advanced non-small cell lung cancer: a network meta-analysis

CHEN Guanxu; SONG Yutong; GUO Xiuqiang; ZHANG Mi; LIU Zhihong; SONG Hongtao

doi:10.12206/j.issn.2097-2024.202504044

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CHEN Guanxu, SONG Yutong, GUO Xiuqiang, ZHANG Mi, LIU Zhihong, SONG Hongtao. Efficacy and safety comparison of EGFR-TKIs monotherapy and combination therapy as first-line treatment for advanced non-small cell lung cancer: a network meta-analysis[J]. Journal of Pharmaceutical Practice and Service. doi: 10.12206/j.issn.2097-2024.202504044

Citation:

CHEN Guanxu, SONG Yutong, GUO Xiuqiang, ZHANG Mi, LIU Zhihong, SONG Hongtao. Efficacy and safety comparison of EGFR-TKIs monotherapy and combination therapy as first-line treatment for advanced non-small cell lung cancer: a network meta-analysis[J]. Journal of Pharmaceutical Practice and Service. doi: 10.12206/j.issn.2097-2024.202504044

Efficacy and safety comparison of EGFR-TKIs monotherapy and combination therapy as first-line treatment for advanced non-small cell lung cancer: a network meta-analysis

doi: 10.12206/j.issn.2097-2024.202504044

1 .
Department of Pharmacy, No. 900 Hospital of Joint Logistics Support Force of the PLA, Fuzhou 350025, China
2 .
Department of Pharmacy, West China Xiamen Hospital of Sichuan University, Xiamen 361000, China
3 .
the First School of Clinical Medicine, Nanjing Medical University, Nanjing 211166, China

Received Date: 2025-04-08
Accepted Date: 2025-07-23
Rev Recd Date: 2025-06-20

Available Online: 2025-11-17

Abstract

Objective To investigate the efficacy and safety of EGFR-TKIs monotherapy and its combination therapy in the first-line treatment of advanced non-small cell lung cancer（NSCLC）patients with EGFR mutations. Methods Databases such as PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were systematically searched to collect eligible phase II/III randomized controlled trials （RCTs）, with the time range from the establishment of the databases to June 2023. Two researchers independently screened the literature, extracted data, and assessed the risk of bias in the studies. Outcome data, including overall survival （OS）, progression-free survival （PFS）, objective response rate （ORR）, grade 3 or higher adverse events （≥3 AEs）, and serious adverse events （SAEs）, were collected. A network meta-analysis was performed using R software （version 4.2.1） under the Bayesian theoretical framework. Subgroup analyses of survival outcomes （OS, PFS） were conducted based on different clinical and pathophysiological characteristics of the patients. Results A total of t wenty-eight phase II/III RCTs were included in the study, involving a total of 7 460 patients and 18 first-line treatment regimens. The results showed that in terms of efficacy, gefitinib + pemetrexed-containing chemotherapy performed best in OS and ORR, while osimertinib + bevacizumab performed best in PFS. In terms of safety, furmonertinib had the lowest incidence of ≥3 grade AEs, and osimertinib had the lowest incidence of SAEs. Subgroup analysis results indicated that the efficacy and safety of various treatment regimens differed among patients with different clinical and pathological characteristics. Conclusion Monotherapy with third-generation EGFR-TKIs, represented by osimertinib, serves as the preferred therapeutic option considering both efficacy and safety profiles. While some combination therapies can enhance survival benefits, but need to be vigilant about increased toxicity. Clinical decision-making should be tailored based on patient' mutation subtypes, comorbidities, and tolerance.
- EGFR-TKIs,
- NSCLC,
- EGFR mutation,
- network meta-analysis,
- first-line treatment

References

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肺癌是一种全球范围内发病率和死亡率均居高不下的恶性肿瘤^[1]，根据病理类型及治疗策略的不同，可分为小细胞肺癌（SCLC）和非小细胞肺癌（NSCLC）。其中，NSCLC更为常见，约占所有肺癌病例的80%~85%^[2]。

在驱动基因阳性的NSCLC治疗领域，靶向治疗凭借其精准性和高效性，已成为不可或缺的核心治疗手段。其中，表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）作为一类靶向EGFR的小分子药物，与传统化疗相比，可显著改善EGFR突变阳性晚期NSCLC患者的生存获益，并有效延缓了耐药的发生，已被确立为一线治疗的标准策略^[3-4]。近年来，随着我国自主研发的第三代EGFR-TKIs（如阿美替尼、伏美替尼等）的相继上市，针对EGFR靶点突变的肺癌患者，临床上的治疗选择更加丰富，为患者提供了更多个性化的一线治疗方案。

与此同时，EGFR-TKIs的联合治疗方案也在不断探索与优化中。多项临床试验表明，部分联合治疗方案（如EGFR-TKIs联合抗血管生成药物或化疗）能够显著延长患者的生存获益，显示出优于单药治疗的潜力^[5-6]。然而，由于缺乏“头对头”的直接比较研究，不同治疗方案在疗效及安全性方面的差异尚未得到全面评估。基于此，本研究旨在通过网状Meta分析，系统评估EGFR-TKIs单药及其联合方案在晚期NSCLC一线治疗中的疗效与安全性，并通过概率排序为临床患者提供个体化治疗的循证医学依据。

1. 资料与方法

1.1. 文献检索

本研究系统检索了PubMed、Embase、Cochrane Library数据库以及ClinicalTrials.gov网站的相关临床试验信息，同时补充检索了美国临床肿瘤学会（ASCO）、欧洲肿瘤内科学会（ESMO）和世界肺癌大会（WCLC）等国际会议摘要，以确保文献检索的全面性。检索时间范围为数据库建库至2023年6月30日，检索文献类型限定为随机对照试验（RCT），语言类型为英文。检索策略采用主题词与自由词相结合的方式，检索词包括“NSCLC”“EGFR-TKIs”“Randomized Controlled Trial”“Furmonertinib”“Gefitinib”“Dacomitinib”“Erlotinib”“Icotinib”“Afatinib”“Osimertinib”“Almonertinib”等。

1.2. 纳入标准

①研究类型：Ⅱ期或Ⅲ期RCT。

②研究对象：年龄≥18岁，经组织学或细胞学确诊为EGFR突变阳性的晚期NSCLC患者，且既往未接受过EGFR-TKIs治疗。

③试验组：晚期EGFR突变NSCLC患者的一线治疗方案，包括EGFR-TKIs单药治疗或其联合治疗方案。

④对照组：EGFR-TKIs单药治疗或化疗。

⑤结局指标：疗效指标：总生存期（OS）、无进展生存期（PFS）、客观缓解率（ORR）；安全性指标：3级及以上不良事件（≥3AEs）、严重不良事件（SAEs）。

1.3. 排除标准

①重复发表的研究。

②仅报告临床试验亚组数据的研究。

③无法获取完整数据的临床试验。

④动物实验、回顾性研究、综述、病例报告等。

1.4. 文献筛选及数据提取

由2名研究者根据预先制定的纳入和排除标准，独立完成文献筛选及数据提取工作。若在筛选或提取过程中出现分歧，将通过协商达成一致；若协商未果，则由第三方进行裁决。数据提取内容包括以下三部分：①研究基本信息：试验名称、试验阶段、发表年份、国家、试验注册号及纳入的结局指标；②患者基本信息：性别、年龄、样本量、试验组及对照组的治疗方案、肿瘤分期及EGFR突变类型；③临床指标结局：PFS、OS、ORR、≥3 AEs、SAEs。所有数据均从文献中的图表及文本中直接提取，若文献中缺失某些关键信息，则尝试联系原作者以获取补充数据。

1.5. 偏倚评估

采用《Cochrane系统评价员手册》（5.1.0版本）推荐的偏倚风险评估工具对纳入文献进行偏倚风险评估，评估内容包括以下7个条目：随机序列生成、分配隐藏、对患者及试验人员实施盲法、对结局评估者实施盲法、结局数据的完整性、选择性报告和其他偏倚。每个条目的偏倚风险分为低偏倚风险、偏倚风险不确定和高偏倚风险三个等级^[7]。由2名研究者根据评价标准独立完成评估，若出现分歧，则通过协商达成一致；若协商未果，则由第三方进行裁决。

1.6. 统计分析方法

使用Stata 17.0软件绘制网络证据图，以直观展示不同结局指标中治疗方案之间的直接比较与间接比较关系^[8]。在贝叶斯理论框架下，基于马尔科夫链蒙特卡洛（MCMC）方法，采用R软件（版本4.2.1）的“gemtc”包进行网状Meta分析^[9]。采用I²统计量评估研究间的异质性，若I²≥50%则认为存在高异质性，选择随机效应模型；否则，采用固定效应模型^[10]。

对于二分类变量（ORR、≥3 AEs、SAEs），效应量以比值比（OR）及其95%可信区间（CrI）表示；对于生存资料（PFS、OS），效应量以风险比（HR）及其95% CrI表示。通过累积排序概率图下面积（SUCRA）对治疗方案的优劣进行排序，SUCRA值范围为0%至100%，值越大表示该治疗方案获益越大^[11]。

采用节点拆分法评估结果的局部不一致性^[12]。同时，根据患者的临床病理生理特征（如EGFR突变类型、是否为亚洲人群、是否存在脑转移、是否为吸烟人群、性别及年龄）对生存结局（OS、PFS）进行亚组分析，以探讨不同人群的疗效差异。最后，采用倒漏斗图评估发表偏倚及小样本效应^[13]。

3. 讨论

本研究通过网状Meta分析系统评估了18种EGFR-TKIs单药及联合方案的一线治疗价值。结果显示，吉非替尼联合含培美曲塞的化疗在OS和ORR方面具有显著优势，而奥希替尼联合贝伐珠单抗则在PFS方面更具优势。安全性方面，第三代EGFR-TKIs（如伏美替尼、奥希替尼）单药治疗的不良反应发生率最低，而联合治疗虽能提升疗效，但伴随更高的毒性风险。

就疗效而言，吉非替尼联合含培美曲塞化疗的OS优势可能与EGFR-TKIs和化疗药物之间的协同抗肿瘤作用相关。研究表明，T790M突变是第一、二代EGFR-TKIs获得性耐药的主要原因，而培美曲塞可能通过抑制T790M突变介导的耐药机制，从而增强吉非替尼的抗肿瘤效果^[53-54]。奥希替尼联合贝伐珠单抗与奥希替尼单药相比，显示出PFS获益的趋势，但差异并未达到统计学显著性（HR = 0.862，95%CrI：0.531～1.397）^[50]。基于此，以奥希替尼为代表的第三代EGFR-TKIs仍被视为平衡疗效与安全性的优选，其优异表现主要与其不可逆结合EGFR突变体、穿透血脑屏障能力及对T790M的活性相关。

就安全性而言，联合治疗方案在提升疗效的同时，往往伴随着更为显著的毒性反应。以吉非替尼联合含培美曲塞的化疗方案为例，尽管其在OS和ORR方面均表现优异，位列所有治疗方案之首，但其AEs发生率也显著升高，这一结果凸显了联合治疗方案在疗效与安全性之间权衡的重要性。因此，在临床实践中，治疗方案的制定需要综合考虑患者的个体化特征，包括年龄、体能状态、合并症以及对不良反应的耐受能力。

本研究结果与Zhao等人^[55]及Yang等人^[56]的结论基本一致，均支持吉非替尼联合化疗的OS优势和奥希替尼的PFS及安全性优势。但本研究创新性在于：①纳入更多治疗方案（18种），覆盖最新三代TKIs（如伏美替尼、阿美替尼）；②引入亚组分析，探索不同临床特征（如种族、脑转移）对疗效的影响，整合OS、PFS、ORR及安全性多维指标，提供更全面的方案排序。与此同时，本研究存在以下局限性：①部分RCT的OS数据成熟度不足，如伏美替尼OS数据成熟度仅29%，这可能导致结果的偏倚。②部分研究未明确疾病进展评估方式（研究者评估或第三方独立影像），可能对最终结果产生潜在影响。③SAEs网络证据图的星状结构（图4D）提示干预措施间缺乏直接比较数据，基于间接证据链的效应估计可能存在传递偏倚。

本研究为EGFR突变NSCLC一线治疗提供了循证依据，证实联合治疗在生存获益上的潜力，同时体现了第三代TKIs单药（如奥希替尼、伏美替尼、阿美替尼）在疗效-安全性平衡中的核心地位。此外，不同结局排序及亚组分析结果可为个体化治疗提供循证参考。随着临床研究数据的不断积累，未来仍需通过更长时间随访的RCT和真实世界研究进一步验证不同治疗方案间的疗效差异，并深入探索罕见靶点的精准治疗策略。

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试验名称（试验阶段，种群）	实验组（T）	对照组（C）	样本量（T/C）	中位年龄（岁）	女性占比（%）	19Del （T/C）	L858R （T/C）	报告的结局
EGFR-TKIs单药对比化疗
WJTOG3405 2019 （Ⅲ,Asian）^[14-15]	吉非替尼	PfCT	86/86	64.0/64.0	68.6/69.8	50/37	36/49	PFS/OS/ORR
NEJ002 2013 （Ⅲ,Asian）^[16-17]	吉非替尼	PfCT	114/110	63.9/62.6*	63.2/64.0	58/59	49/48	PFS/OS/ORR/ ≥3AEs
OPTIMAL 2015 （Ⅲ,Asian）^[18-19]	厄洛替尼	PfCT	82/72	57.0/59.0	58.5/59.7	43/39	39/33	PFS/OS/≥3AEs/SAEs
EURTAC 2012 （Ⅲ,non-Asian）^[20]	厄洛替尼	PfCT	86/87	65.0/65.0	67.4/78.2	57/58	29/29	PGS/OS/ORR/≥3AEs/SAEs
LUX-Lung3 2015 （Ⅲ,multiple）^[21-22]	阿法替尼	PbCT	230/115	61.5/61.0	63.9/67.0	113/57	91/47	PFS/OS/ORR/≥3AEs
LUX-Lung6 2015 （Ⅲ,Asian）^[21-23]	阿法替尼	PfCT	242/122	58.0/58.0	64.0/68.0	124/62	92/46	PFS/OS/ORR/≥3AEs
ENSURE 2015 （Ⅲ,Asian）^[24]	厄洛替尼	PfCT	110/107	57.5/56.0	61.8/60.7	57/61	52/46	PFS/OS/ORR/≥3AEs/SAEs
CONVINCE 2017 （Ⅲ,Asian）^[25]	埃克替尼	PbCT	148/137	56.0/56.0	70.9/69.3	80/74	68/63	PFS/OS/≥3AEs
LUX-Lung7 2017 （Ⅱ,multiple）^[26-27]	阿法替尼	吉非替尼	160/159	63.0/63.0	57.0/67.0	93/93	67/66	PFS/OS/ORR/≥3AEs
CTONG0901 2017 （Ⅲ,Asian）^[28]	厄洛替尼	吉非替尼	128/128	NG	53.1/53.9	74/74	54/54	PFS/OS/ORR/≥3AEs
ARCHER1050 2021 （Ⅲ,multiple）^[29-31]	达可替尼	吉非替尼	227/225	62.0/61.0	64.3/55.6	134/133	93/92	PFS/OS/ORR/≥3AEs/SAEs
FLAURA 2020 （Ⅲ,multiple）^[32-33]	奥希替尼	吉非替尼/ 厄洛替尼	279/277	64.0/64.0	63.8/62.1	175/174	104/103	PFS/OS/ORR/≥3AEs/SAEs
AENEAS 2022 （Ⅲ,Asian）^[34]	阿美替尼	吉非替尼	241/215	59.0/62.0	62.6/62.8	140/141	74/74	PFS/OS/ORR/≥3AEs/SAEs
FURLONG 2022 （Ⅲ,Asian）^[35]	伏美替尼	吉非替尼	178/179	59/60	65.2/62.0	91/92	87/87	PFS/OS/ORR/≥3AEs/SAEs
EGFR-TKIs联合化疗/免疫/靶向对比EGFR-TKIs单药
JMIT 2020 （Ⅱ,Asian）^[36-37]	吉非替尼+培美曲塞	吉非替尼	126/65	62.0/62.0	65.0/63.0	65/40	52/23	PFS/OS/ORR/≥3AEs/SAEs
Hanetal 2020 （Ⅱ,Asian）^[38-39]	吉非替尼+PbCT	吉非替尼	40/41	NG	62.5/56.1	21/21	19/20	PFS/OS/ORR
Xu et al 2019 （Ⅱ,Asian）^[40]	埃克替尼+PbCT	埃克替尼	90/89	58.6/61.0*	63.3/74.2	51/52	38/37	PFS/OS/ORR
Noronha et al 2020 （Ⅲ,Asian）^[41]	吉非替尼+培美曲塞	吉非替尼	174/176	54.0/56.0	49.2/47.2	107/109	NG	PFS/OS/ORR/≥3AEs/SAEs
NEJ009 2020 （Ⅲ,Asian）^[42-43]	吉非替尼+PbCT	吉非替尼	170/172	64.8/64.0*	67.1/62.8	93/95	69/67	PFS/OS/ORR/≥3AEs
JO25567 2014 （Ⅱ,Asian）^[44]	厄洛替尼+贝伐珠单抗	厄洛替尼	75/77	67.0/67.0	60.0/66.2	40/40	37/37	PFS/OS/ORR/≥3AEs/SAEs
NEJ026 2020 （Ⅲ,Asian）^[45]	厄洛替尼+贝伐珠单抗	厄洛替尼	112/112	67/68	63.4/65.2	56/55	56/57	PFS/OS/ORR/≥3AEs/SAEs
Stinch et al 2019 （Ⅱ,non-Asian）^[46]	厄洛替尼+贝伐珠单抗	厄洛替尼	43/45	65/63	68.9/72.1	30/29	15/14	PFS/OS/ORR
RELAY 2019 （Ⅲ,multiple）^[47]	厄洛替尼+雷莫芦单抗	厄洛替尼	224/225	65/64	62.9/63.1	123/120	99/105	PFS/OS/ORR/≥3AEs/SAEs
CTONG1706 2021 （Ⅲ,Asian）^[48]	吉非替尼+阿帕替尼	吉非替尼	157/156	57/60	58.0/6.3	81/83	74/73	PFS/OS/ORR/≥3AEs/SAEs
ARTEMIS 2021 （Ⅲ,Asian）^[49]	厄洛替尼+贝伐珠单抗	厄洛替尼	157/154	57/59	61.8/62.3	82/79	75/75	PFS/ORR/OS/≥3AEs
WJOG9717L 2022（Ⅱ,Asian）^[50]	奥希替尼+贝伐珠单抗	奥希替尼	61/61	67/66	60.7/62.3	35/36	26/25	PFS/OS/ORR/≥3AEs
BEVERLY 2022 （Ⅲ,non-Asian）^[51]	厄洛替尼+贝伐珠单抗	厄洛替尼	80/80	65.9/67.7	65.0/62.5	44/44	34/32	PFS/OS/ORR/≥3AEs/SAEs
SWOGS1403 2020 （Ⅱ,multiple）^[52]	阿法替尼+西妥昔单抗	阿法替尼	83/85	66.5/66.3	71.1/62.4	53/54	30/31	PFS/OS/ORR/≥3AEs
T/C：试验组/对照组；19Del：EGFR 19外显子缺失；L858R：EGFR 21外显子L858R突变；PfCT：不含培美曲塞的化疗；PbCT：含培美曲塞的化疗；PFS：无进展生存期；OS：总生存期；ORR：客观缓解率；≥3 AEs：3级及以上不良事件；SAEs：严重不良事件；NG：无数据；*：无中位年龄数据，使用平均年龄代替。

治疗方案	缩写	PFS	OS	ORR	≥3AEs	SAEs
奥希替尼+贝伐珠单抗	Osi+Bev	83.08（1）	56.67（8）	63.34（4）	71.77（5）	NA
伏美替尼	Fur	80.36（2）	37.09（15）	59.38（6）	83.54（1）	68.25（2）
阿美替尼	Aum	76.80（3）	53.59（10）	39.67（13）	70.64（6）	63.62（4）
奥希替尼	Osi	76.64（4）	57.30（7）	46.71（9）	82.04（2）	75.91（1）
埃克替尼+含培美曲塞的化疗	Ico+PbCT	74.49（5）	60.15（6）	NA	NA	NA
厄洛替尼+雷莫芦单抗	Erl+Ram	74.33（6）	61.87（4）	53.87（8）	34.16（12）	NA
厄洛替尼+贝伐珠单抗	Erl+Bev	71.71（7）	54.34（9）	73.78（3）	16.32（16）	NA
吉非替尼+含培美曲塞的化疗	Gef+PbCT	70.33（8）	84.38（1）	85.72（1）	34.12（13）	16.28（8）
达可替尼	Dac	53.80（9）	65.35（3）	44.92（12）	46.43（10）	47.64（5）
吉非替尼+培美曲塞	Gef+P	43.20（10）	60.21（5）	57.26（7）	38.39（11）	30.94（6）
吉非替尼+阿帕替尼	Gef+Apa	38.18（11）	21.75（18）	46.17（11）	15.24（17）	29.58（7）
阿法替尼+西妥昔单抗	Afa+Cet	36.34（12）	68.26（2）	59.66（5）	18.12（15）	NA
阿法替尼	Afa	35.75（13）	48.99（11）	82.33（2）	52.48（9）	NA
埃克替尼	Ico	34.52（14）	37.74（14）	NA	79.73（3）	NA
厄洛替尼	Erl	28.41（15）	38.37（13）	46.40（10）	57.14（7）	NA
吉非替尼	Gef	13.83（16）	23.37（17）	30.48（14）	74.37（4）	67.79（3）
含培美曲塞的化疗	PbCT	8.18（17）	32.11（16）	9.65（15）	52.71（8）	NA
不含培美曲塞的化疗	PfCT	0.05（18）	38.47（12）	0.67（16）	22.79（14）	NA
NA：无数据，未纳入排名。

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