A real-world study on efficacy of different second-line treatment strategies following the progression of first-line immunotherapy and its combination therapies in driver gene-negative advanced non-small cell lung cancer

Abstract

Abstract:

ObjectiveTo explore the efficacy of different second-line treatment strategies in the real world after progression of first-line immunotherapy and its combination therapies in patients with driver gene-negative advanced non-small cell lung cancer （NSCLC）.MethodsA retrospective analysis was conducted on the clinical data of 93 driver gene-negative advanced NSCLC patients who received first-line immunotherapy and its combination therapies from January 1，2018 to December 31，2023 at the First Affiliated Hospital of Xinxiang Medical University and Xinxiang Central Hospital. Patients were categorized into immune checkpoint inhibitors （ICIs）-resistant （n=43） and ICIs-responsive （n=50） groups according to whether progression free survival （PFS） exceeded 6 months after first-line treatment. Patients were categorized into ICIs-treated （n=55） and non-ICIs-treated （n=38），anti-angiogenic-treated （n=51） and non-anti-angiogenic-treated （n=42） groups according to the different second-line treatment strategies after progression of first-line immunotherapy and its combination therapies. The median PFS2 （mPFS2） and median overall survival （mOS）2 after second-line treatment of each group were compared. The Kaplan-Meier method was used for survival analysis.ResultsThe mPFS2 and mOS2 of 93 advanced NSCLC patients who progressed after first-line ICIs treatment were 4.9 months （95%CI： 4.1-5.7 months） and 14.7 months （95%CI： 11.2-18.2 months）. The mPFS2 of patients in the first-line ICIs-responsive and ICIs-resistant groups were 6.0 and 3.8 months，respectively，with no statistically significant difference （χ²=2.00，P=0.157），and the mOS2 were 25.3 and 11.3 months，respectively，with a statistically significant difference （χ²=12.13，P<0.001）. The mPFS2 of patients in the second-line ICIs-treated group and the non-ICIs-treated group were 5.2 and 4.6 months，respectively，with no statistically significant difference （χ²=0.16，P=0.687）. The mOS2 were 15.1 and 12.7 months，respectively，with no statistically significant difference （χ²=0.01，P=0.930）. The mPFS2 of patients in the second-line anti-angiogenic-treated and non-anti-angiogenic-treated groups were 4.5 and 6.0 months，respectively，with no statistically significant difference （χ²=0.41，P=0.525），the mOS2 were 14.7 and 16.8 months，respectively，with no statistically significant difference （χ²=0.01，P=0.943）.ConclusionsAfter progression of first-line ICIs therapy in patients with driver gene-negative advanced NSCLC，first-line ICIs-responsive patients have significantly longer OS after second-line treatment compared with ICIs-resistant patients. The efficacy of second-line therapy in patients after progression of first-line ICIs therapy does not show significant differences due to the type of treatment strategies.

Key words:Carcinoma，non-small-cell lung,Immune checkpoint inhibitors,Treatment outcome

Zhang Luying, Liang Jiaxin, Zhao Kelei, Yuan Xiaohan, Liu Liangbo, Lu Ping, Zhang Guifang, Zhang Min. A real-world study on efficacy of different second-line treatment strategies following the progression of first-line immunotherapy and its combination therapies in driver gene-negative advanced non-small cell lung cancer[J]. Journal of International Oncology, 2025, 52(7): 419-425.

Figures/Tables10

临床特征	二线ICI治疗组（n=55）	二线非ICI治疗组（n=38）	χ²值	P值
性别
男	42（76.36）	25（65.79）	1.25	0.264
女	13（23.64）	13（34.21）	1.25	0.264
年龄（岁）
>65	35（63.65）	24（63.16）	0.01	0.962
≤65	20（36.35）	14（36.84）	0.01	0.962
病理类型
非腺上皮癌	20（36.36）	17（44.74）	0.66	0.417
腺上皮癌	35（63.64）	21（55.26）	0.66	0.417
发病部位
左肺	28（50.91）	14（36.84）	1.80	0.180
右肺	27（49.09）	24（63.16）	1.80	0.180
ECOG评分（分）
<2	41（74.55）	31（81.58）	0.64	0.425
≥2	14（25.45）	7（18.42）	0.64	0.425
脑转移
是	6（10.91）	3（7.89）	0.02	0.899
否	49（89.09）	35（92.11）	0.02	0.899
肝转移
是	7（12.73）	6（15.79）	0.18	0.675
否	48（87.27）	32（84.21）	0.18	0.675
PFS1（月）
<6	25（45.45）	18（47.37）	0.03	0.856
≥6	30（54.55）	20（52.63）	0.03	0.856

临床特征	二线抗血管生成治疗组（n=51）	二线非抗血管生成治疗组（n=42）	χ²值	P值
性别
男	33（74.71）	34（80.95）	3.02	0.082
女	18（35.29）	8（19.05）	3.02	0.082
年龄（岁）
>65	32（62.75）	25（59.52）	0.10	0.758
≤65	19（37.25）	17（40.48）	0.10	0.758
病理类型
非腺上皮癌	17（33.33）	20（47.62）	1.96	0.161
腺上皮癌	34（66.67）	22（52.38）	1.96	0.161
发病部位
左肺	19（37.25）	23（54.76）	2.85	0.091
右肺	32（62.75）	19（45.24）	2.85	0.091
ECOG评分（分）
<2	39（76.47）	33（78.57）	0.06	0.809
≥2	12（23.53）	9（21.43）	0.06	0.809
脑转移
是	4（7.84）	5（11.90）	0.09	0.759
否	47（92.16）	37（88.10）	0.09	0.759
肝转移
是	6（11.76）	7（16.67）	0.46	0.497
否	45（88.24）	35（83.33）	0.46	0.497
PFS1（月）
<6	26（50.98）	17（40.48）	1.02	0.312
≥6	25（49.02）	25（59.52）	1.02	0.312

References17

[1]	Ettinger DS, Wood DE, Aisner DL, et al. Non-small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology[J].J Natl Compr Canc Netw,2022,20(5): 497-530. DOI:10.6004/jnccn.2022.0025.
[2]	Li DN, Lu WQ, Yang BW, et al. Atezolizumab monotherapy or plus chemotherapy in first-line treatment for advanced non-small cell lung cancer patients: a meta-analysis[J].Front Immunol,2021,12: 666909. DOI:10.3389/fimmu.2021.666909.
[3]	Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial[J].Lancet,2019,393(10183): 1819-1830. DOI:10.1016/S0140-6736(18)32409-7. pmid:30955977
[4]	林先勇, 胡翔, 殷海涛. 免疫治疗联合放化疗治疗非小细胞肺癌的临床研究进展[J].国际肿瘤学杂志,2022,49(1): 56-60. DOI:10.3760/cma.j.cn371439-20210407-00008.
[5]	Garassino MC, Gadgeel S, Speranza G, et al. Pembrolizumab plus pemetrexed and platinum in nonsquamous non-small-cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 study[J].J Clin Oncol,2023,41(11): 1992-1998. DOI:10.1200/JCO.22.01989.
[6]	Gómez-Randulfe I, Califano R. Building on success: key takeaways from the 5-year update of the KEYNOTE-407 study[J].Transl Lung Cancer Res,2023,12(8): 1812-1815. DOI:10.21037/tlcr-23-290.
[7]	Sun Q, Wei X, Wang Z, et al. Primary and acquired resistance against immune check inhibitors in non-small cell lung cancer[J].Cancers (Basel),2022,14(14): 3294. DOI:10.3390/cancers14143294.
[8]	Cai Z, Zhan P, Song Y, et al. Safety and efficacy of retreatment with immune checkpoint inhibitors in non-small cell lung cancer: a systematic review and meta-analysis[J].Transl Lung Cancer Res,2022,11(8): 1555-1566. DOI:10.21037/tlcr-22-140.
[9]	Moliner L, Spurgeon L, Califano R. Controversies in NSCLC: which second-line strategy after chemo-immunotherapy?[J].ESMO Open,2023,8(2): 100879. DOI:10.1016/j.esmoop.2023.100879.
[10]	Watanabe H, Okada M, Kaji Y, et al. New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1)[J].Gan To Kagaku Ryoho,2009,36(13): 2495-2501.
[11]	Slowley A, Phiri K, Multani JK, et al. Real-world treatment patterns and clinical outcomes after introduction of immune checkpoint inhibitors: results from a retrospective chart review of patients with advanced/metastatic non-small cell lung cancer in the EU5[J].Thorac Cancer,2023,14(28): 2846-2858. DOI:10.1111/1759-7714.15069.
[12]	Auclin E, Benitez-Montanez J, Tagliamento M, et al. Second-line treatment outcomes after progression from first-line chemotherapy plus immunotherapy in patients with advanced non-small cell lung cancer[J].Lung Cancer,2023,178: 116-122. DOI:10.1016/j.lungcan.2023.02.002. pmid:36812760
[13]	闫相涛, 王慧娟, 李鹏, 等. 免疫治疗后进展的晚期非小细胞肺癌二线继续免疫治疗联合化疗的回顾性分析[J].肿瘤学杂志,2021,27(3): 186-190. DOI:10.11735/j.issn.1671-170X.2021.03.B006.
[14]	Yan X, Zhao L, Wu F, et al. Efficacy and safety analysis of immune checkpoint inhibitor rechallenge therapy in locally advanced and advanced non-small cell lung cancer: a retrospective study[J].J Thorac Dis,2024,16(3): 1787-1803. DOI:10.21037/jtd-23-1767. pmid:38617775
[15]	Huang H, Zhong P, Zhu X, et al. Immunotherapy combined with rhendostatin improved clinical outcomes over immunotherapy plus chemotherapy for second-line treatment of advanced NSCLC[J].Front Oncol,2023,13: 1137224. DOI:10.3389/fonc.2023.1137224.
[16]	Wang K, Fu Z, Sun G, et al. Systemic treatment options for non-small cell lung cancer after failure of previous immune checkpoint inhibitors: a bayesian network meta-analysis based on randomized controlled trials[J].BMC Immunol,2024,25(1): 37. DOI:10.1186/s12865-024-00633-z.
[17]	韩尚, 纪雅玲, 王浩, 等. 免疫跨线联合白蛋白结合型紫杉醇对比安罗替尼联合白蛋白结合型紫杉醇二线治疗晚期肺腺癌的疗效及预后分析[J].肿瘤学杂志,2024,30(4): 314-320. DOI:10.11735/j.issn.1671-170X.2024.04.B008.