Responses to different therapies and the predictive markers of advancedEGFR-mutated non-small cell lung cancer after TKI resistance
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摘要:
目的 评估TKI耐药后晚期EGFR突变型非小细胞肺癌(non-small cell lung cancer,NSCLC)在真实世界中化疗、化疗联合抗血管和免疫治疗的临床疗效以及最佳免疫治疗联合方案和探讨优势人群临床病理特征。 方法 回顾性分析2014年1月至2022年10月于广东省人民医院肿瘤医院收治229例TKI耐药后晚期EGFR突变型NSCLC患者的临床病理资料。本研究将纳入的患者分为非ICI治疗组(化疗和化疗联合抗血管)122例,ICI治疗组(含免疫治疗)107例,分析患者临床特征与治疗疗效之间的关系。 结果 纳入患者非ICI治疗组和ICI治疗组的中位无进展生存期(progression-free survival,PFS)分别为5.2个月和5.2个月(P=0.129),中位生存期(overall survival,OS)分别为18.2个月和14.1个月(P=0.026)。进一步分析107例ICI治疗组,使用化疗联合免疫治疗、化疗联合抗血管联合免疫治疗和免疫单药或抗血管联合免疫治疗的中位PFS分别为5.6、6.7和2.3个月(P=0.074),中位OS分别为15.5、18.6和8个月(P=0.165)。PD-L1表达≥50%患者的中位PFS和中位OS较PD-L1表达<50%患者明显延长(中位PFS:5.6个月vs. 5.0个月,P=0.040;中位OS:19.2个月vs. 12.6个月,P=0.046)。 结论 晚期EGFR突变型NSCLC患者TKI耐药后四药联合免疫治疗似乎呈现出更好的生存获益趋势,PD-L1表达是预测该人群免疫治疗获益的生物标志物。 Abstract:Objective To evaluate the clinical efficacy of chemotherapy, chemotherapy combined with anti-angiogenesis therapy, and immunotherapy in advanced EGFR-mutant non-small cell lung cancer (NSCLC) after tyrosine kinase inhibitor (TKI) resistance in clinical practice and to explore the optimal immunotherapy combination and clinicopathological characteristics of the dominant population. Methods Data were collected from 229 patients with advanced EGFR-mutated NSCLC who developed resistance to EGFR-TKI treatment at the Cancer Hospital of Guangdong Provincial People's Hospital from January 2014 to October 2022. One hundred and twenty-two cases of the enrolled patients were assigned into non-ICI treatment group (chemotherapy and chemotherapy combined with anti-angiogenesis therapy) and 107 cases in the ICI treatment group (including immunotherapy). The association between clinical characteristics and treatment responses were retrospectively analyzed. Results The median progression-free survival (PFS) of the non-ICI group (n=122) and the ICI group (n=107) were 5.2 months and 5.2 months, respectively (P=0.129). The median overall survival (OS) was 18.2 months and 14.1 months, respectively (P=0.026). Additional analysis of 107 patients treated with immunotherapy showed that the median PFS of chemotherapy combined with immunotherapy, chemotherapy combined with anti-vascular plus immunotherapy, and immune monotherapy or anti-vascular therapy combined with immunotherapy were 5.6 months, 6.7 months, and 2.3 months, respectively (P=0.074). The median OS was 15.5 months, 18.6 months, and 8 months, respectively (P=0.165). The median PFS and OS of patients with PD-L1 expression ≥50% were significantly longer than those with PD-L1 expression <50% (median PFS: 5.6 months vs. 5.0 months, P=0.040; median OS: 19.2 months vs. 12.6 months, P=0.046). Conclusions The four-drug combination immunotherapy provided a better survival benefit trend in patients with advanced EGFR-mutant NSCLC after TKI resistance. Furthermore, PD-L1 expression may be used as a biomarker for predicting the benefit of immunotherapy in this population. -
表 1 患者的基线情况
特征 总体(n=229) 非ICI治疗组(n=122) ICI治疗组(n=107) 性别 男性 108(47.2) 58(47.5) 50(46.7) 女性 121(52.8) 64(52.5) 57(53.3) 是否吸烟 是 56(24.5) 32(26.2) 24(22.4) 否 173(75.5) 90(73.8) 83(77.6) 免疫或化疗前分期(期) ⅣA 41(17.9) 24(19.7) 17(15.9) ⅣB 188(82.1) 98(80.3) 90(84.1) 免疫或化疗前病理类型 腺癌 226(98.7) 122(100) 104(97.2) 鳞癌 3(1.3) 0(0.0) 3(2.8) 免疫或化疗前转移病灶 胸腔转移或胸腔积液 149(65.1) 81(66.4) 68(63.6) 脑转移 101(44.1) 51(41.8) 50(46.7) 肝转移 62(27.1) 27(22.1) 35(32.7) 免疫或化疗前PS评分(分) 0~1 217(94.8) 120(98.4) 97(90.7) 2 12(5.2) 2(1.6) 10(9.3) 基因突变类型 EGFR19del 106(46.3) 56(45.9) 50(46.7) EGFR21L858R 115(50.2) 62(50.8) 53(49.5) 其他 8(3.5) 4(3.3) 4(3.8) PD-L1表达 <50% 119(52.0) 66(54.1) 53(49.5) ≥50% 57(24.9) 20(16.4) 37(34.6) 未知 53(23.1) 36(29.5) 17(15.9) 免疫或化疗前是否出现T790M突变 是 79(34.5) 44(36.1) 35(32.7) 否 150(65.5) 78(63.9) 72(67.3) 免疫或化疗前是否手术 是 53(23.1) 22(18.0) 31(29.0) 否 176(76.9) 100(82.0) 76(71.0) 免疫或化疗前是否放疗(肺部病灶) 是 20(8.7) 8(6.6) 12(11.2) 否 209(91.3) 114(93.4) 95(88.8) 是否使用过奥希替尼 是 155(67.7) 74(60.7) 81(75.7) 否 74(32.3) 48(39.3) 26(24.3) 奥希替尼使用线数(线) 0 74(32.3) 48(39.3) 26(24.3) 1 31(13.5) 13(10.7) 18(16.8) ≥2 124(54.2) 61(50.0) 63(58.9) 治疗前是否使用过化疗 是 96(41.9) 17(13.9) 79(73.8) 否 133(58.1) 105(86.1) 28(26.2) 治疗线数(线) <4 120(52.4) 87(71.3) 33(30.8) ≥4 109(47.6) 35(28.7) 74(69.2) 是否联合抗血管生成治疗 是 132(57.6) 88(72.1) 43(40.2) 否 97(42.4) 34(27.9) 64(59.8) ()内单位为%;“免疫或化疗前转移病灶”定义为患者只要出现了对应某个器官的转移就可纳入分析。患者可能会同时出现多个器官转移,例数合计非百分百 表 2 TKI耐药后晚期EGFR突变型NSCLC对不同治疗的疗效
项目 总体(n=229) ICI治疗组(n=107) 非ICI治疗组(n=122) DCR 160(69.9) 75(70.1) 85(69.7) ORR 67(29.3) 30(28.0) 37(30.3) PD 42(18.3) 20(18.7) 22(18.0) PR 67(29.3) 30(28.0) 37(30.3) SD 93(40.6) 45(42.1) 48(39.4) UK 27(11.8) 12(11.2) 15(12.3) ()内单位为% 表 3 TKI耐药后晚期EGFR突变型NSCLC接受免疫治疗的临床病理特征
特征 总体(n=107) 化疗+抗血管+免疫(n=38) 化疗+免疫(n=43) 抗血管+免疫或免疫单药(n=26) 性别 男性 50(46.7) 14(36.8) 20(46.5) 16(61.5) 女性 57(53.3) 24(63.2) 23(53.5) 10(38.5) 是否吸烟 是 24(22.4) 6(15.8) 10(23.3) 8(30.8) 否 83(77.6) 32(84.2) 33(76.7) 18(69.2) 免疫前分期(期) ⅣA 17(15.9) 3(7.9) 7(16.3) 7(26.9) ⅣB 90(84.1) 35(92.1) 36(83.7) 19(73.1) 免疫前病理类型 腺癌 104(97.2) 38(100) 41(95.3) 25(96.2) 鳞癌 3(2.8) 0(0.0) 2(4.7) 1(3.8) 免疫前转移病灶 胸腔转移或胸腔积液 68(63.6) 22(57.9) 28(65.1) 18(69.2) 脑转移 50(46.7) 20(52.6) 20(46.5) 10(38.5) 肝转移 35(32.7) 14(36.8) 10(23.3) 11(42.3) 免疫前PS评分(分) 0~1 97(90.7) 37(97.4) 38(88.4) 22(84.6) 2 10(9.3) 1(2.6) 5(11.6) 4(15.4) 基因突变类型 EGFR19del 50(46.7) 18(47.4) 19(44.2) 13(50.0) EGFR21L858R 53(49.5) 19(50.0) 21(48.8) 13(50.0) 其他 4(3.8) 1(2.6) 3(7.0) 0(0.0) PD-L1表达 <50% 53(49.5) 20(52.6) 21(48.8) 12(46.2) ≥50% 37(34.6) 9(23.7) 17(39.5) 11(42.3) 未知 17(15.9) 9(23.7) 5(11.7) 3(11.5) 免疫前是否出现T790M突变 是 35(32.7) 14(36.8) 14(32.6) 7(26.9) 否 72(67.3) 24(63.2) 29(67.4) 19(73.1) 免疫前是否手术 是 31(29.0) 14(36.8) 11(25.6) 6(23.1) 否 76(71.0) 24(63.2) 32(74.4) 20(76.9) 免疫前是否放疗(肺部病灶) 是 12(11.2) 7(18.4) 4(9.3) 1(3.8) 否 95(88.8) 31(81.6) 39(90.7) 25(96.2) 是否使用过奥希替尼 是 81(75.7) 33(86.8) 32(74.4) 16(61.5) 否 26(24.3) 5(13.2) 11(25.6) 10(38.5) 奥希替尼使用线数(线) 0 26(24.3) 5(13.2) 11(25.6) 10(38.5) 1 18(16.8) 5(13.2) 11(25.6) 2(7.7) ≥2 63(58.9) 28(73.6) 21(48.8) 14(53.8) 免疫前是否使用过化疗 是 79(73.8) 30(78.9) 28(65.1) 21(80.8) 否 28(26.2) 8(21.1) 15(34.9) 5(19.2) 治疗线数(线) ≥4 74(69.2) 31(81.6) 28(65.1) 15(57.7) <4 33(30.8) 7(18.4) 15(34.9) 11(42.3) ()内单位为% 表 4 不同免疫治疗方案对TKI耐药后晚期EGFR突变型NSCLC的疗效分析
项目 总体
(n=107)化疗+抗血管+
免疫
(n=38)化疗+免疫
(n=43)抗血管+免疫或
免疫单药
(n=26)DCR 75(70.1) 33(86.8) 31(72.1) 11(42.3) ORR 30(28.0) 13(34.2) 12(27.9) 5(19.2) PD 20(18.7) 2(5.3) 6(14.0) 12(46.2) PR 30(28.0) 13(34.2) 12(27.9) 5(19.2) SD 45(42.1) 20(52.6) 19(44.2) 6(23.1) UK 12(11.2) 3(7.9) 6(14.0) 3(11.5) ()内单位为% 表 5 影响TKI耐药后晚期EGFR突变型NSCLC免疫治疗预后的Cox多因素回归分析
临床特征 OS多因素分析 PFS多因素分析 HR(95%CI) P HR(95%CI) P 性别(女性 vs. 男性) 1.90(1.10~3.29) 0.022 1.65(1.03~2.63) 0.038 免疫前PS评分(2分 vs. 0~1分) 2.41(1.06~5.46) 0.036 — 0.491 PD-L1表达(≥50% vs. <50%) — 0.117 0.54(0.32~0.92) 0.023 治疗线数(<4线 vs. ≥4线) 2.11(1.09~4.05) 0.026 — 0.220 单药/联合(单药 vs. 联合) — 0.215 0.53(0.30~0.93) 0.028 -
[1] Li S, Li L, Zhu Y, et al. Coexistence of EGFR with KRAS, or BRAF, or PIK3CA somatic mutations in lung cancer: a comprehensive mutation profiling from 5125 Chinese cohorts[J]. Br J Cancer, 2014, 110(11):2812-2820. doi: 10.1038/bjc.2014.210 [2] Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012[J]. Int J Cancer, 2015, 136(5):E359-E386. doi: 10.1002/ijc.29210 [3] Shi YK, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER)[J]. J Thorac Oncol, 2014, 9(2):154-162. doi: 10.1097/JTO.0000000000000033 [4] Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR[J]. N Engl J Med, 2010, 362(25):2380-2388. doi: 10.1056/NEJMoa0909530 [5] Nishimura T, Okano T, Naito M, et al. Second-line therapy with first- or second-generation tyrosine kinase inhibitors in EGFR-mutated non-small cell lung cancer patients with T790M-negative or unidentified mutation[J]. Thorac Cancer, 2021, 12(7):1067-1073. doi: 10.1111/1759-7714.13870 [6] Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer[J]. N Engl J Med, 2017, 376(7):629-640. doi: 10.1056/NEJMoa1612674 [7] Lisberg A, Cummings A, Goldman JW, et al. A phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor Naïve patients with advanced NSCLC[J]. J Thorac Oncol, 2018, 13(8):1138-1145. doi: 10.1016/j.jtho.2018.03.035 [8] Gettinger S, Rizvi NA, Chow LQ, et al. Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer[J]. J Clin Oncol, 2016, 34(25):2980-2987. doi: 10.1200/JCO.2016.66.9929 [9] Gainor JF, Shaw AT, Sequist LV, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: aretrospective analysis[J]. Clin Cancer Res, 2016, 22(18):4585-4593. doi: 10.1158/1078-0432.CCR-15-3101 [10] Dong ZY, Zhang JT, Liu SY, et al. EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer[J]. Oncoimmunology, 2017, 6(11):e1356145. doi: 10.1080/2162402X.2017.1356145 [11] Jia YJ, Li XF, Jiang T, et al. EGFR-targeted therapy alters the tumor microenvironment in EGFR-driven lung tumors: implications for combination therapies[J]. Int J Cancer, 2019, 145(5):1432-1444. doi: 10.1002/ijc.32191 [12] Garassino MC, Cho BC, Kim JH, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study[J]. Lancet Oncol, 2018, 19(4):521-536. doi: 10.1016/S1470-2045(18)30144-X [13] Lu S, Wu L, Jian H, et al. Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial[J]. Lancet Oncol, 2022, 23(9):1167-1179. doi: 10.1016/S1470-2045(22)00382-5 [14] Hu J, Huang D, Wang YR, et al. The efficacy of immune checkpoint inhibitors in advanced EGFR-Mutated non-small cell lung cancer after resistance to EGFR-TKIs: real-World evidence from a multicenter retrospective study[J]. Front Immunol, 2022, 13:975246. doi: 10.3389/fimmu.2022.975246 [15] Cheng YJ, Yang B, Ouyang W, et al. Is ICI-based therapy better than chemotherapy for metastatic NSCLC patients who develop EGFR-TKI resistance? A real-world investigation[J]. Front Oncol, 2022, 12:920047. doi: 10.3389/fonc.2022.920047 [16] Reck M, Mok TSK, Nishio M, et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial[J]. Lancet Respir Med, 2019, 7(5):387-401. doi: 10.1016/S2213-2600(19)30084-0 [17] Mok TSK, Nakagawa K, Park K, et al. LBA8 Nivolumab (NIVO) + chemotherapy (chemo) vs chemo in patients (pts) with EGFR-mutated metastatic non-small cell lung cancer (mNSCLC) with disease progression after EGFR tyrosine kinase inhibitors (TKIs) in CheckMate 722[J]. Ann Oncol, 2022, 33:S1561-S1562. [18] Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma[J]. Nat Commun, 2016, 7:12624. doi: 10.1038/ncomms12624 [19] Heinhuis KM, Ros W, Kok M, et al. Enhancing antitumor response by combining immune checkpoint inhibitors with chemotherapy in solid tumors[J]. Ann Oncol, 2019, 30(2):219-235. doi: 10.1093/annonc/mdy551 [20] Li JY, Chen YP, Li YQ, et al. Chemotherapeutic and targeted agents can modulate the tumor microenvironment and increase the efficacy of immune checkpoint blockades[J]. Mol Cancer, 2021, 20(1):27. doi: 10.1186/s12943-021-01317-7 [21] Hung MS, Chen IC, Lin PY, et al. Epidermal growth factor receptor mutation enhances expression of vascular endothelial growth factor in lung cancer[J]. Oncol Lett, 2016, 12(6):4598-4604. doi: 10.3892/ol.2016.5287 [22] Teixidó C, Vilariño N, Reyes R, et al. PD-L1 expression testing in non-small cell lung cancer[J]. Ther Adv Med Oncol, 2018, 10: 1758835918763493. [23] Bodor JN, Boumber Y, Borghaei H. Biomarkers for immune checkpoint inhibition in non-small cell lung cancer (NSCLC)[J]. Cancer, 2020, 126(2):260-270. doi: 10.1002/cncr.32468 [24] Ichihara E, Harada D, Inoue K, et al. Characteristics of patients with EGFR-mutant non-small-cell lung cancer who benefited from immune checkpoint inhibitors[J]. Cancer Immunol Immunother, 2021,70(1):101-106. [25] Masuda K, Horinouchi H, Tanaka M, et al. Efficacy of anti-PD-1 antibodies in NSCLC patients with an EGFR mutation and high PD-L1 expression[J]. J Cancer Res Clin Oncol, 2021, 147(1):245-251. doi: 10.1007/s00432-020-03329-0 [26] Liu SY, Dong ZY, Wu SP, et al. Clinical relevance of PD-L1 expression and CD8+ T cells infiltration in patients with EGFR-mutated and ALK-rearranged lung cancer[J]. Lung Cancer, 2018, 125:86-92. [27] Ishii H, Azuma K, Kinoshita T, et al. Predictive value of CD73 expression in EGFR-mutation positive non-small-cell lung cancer patients received immune checkpoint inhibitors[J]. J Clin Oncol, 2018, 36(15_Suppl):9065. [28] Jiang T, Wang PY, Zhang J, et al. Toripalimab plus chemotherapy as second-line treatment in previously EGFR-TKI treated patients with EGFR-mutant-advanced NSCLC: a multicenter phase-II trial[J]. Signal Transduct Target Ther, 2021, 6(1):355. doi: 10.1038/s41392-021-00751-9