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中华肺部疾病杂志(电子版) ›› 2023, Vol. 16 ›› Issue (02) : 145 -155. doi: 10.3877/cma.j.issn.1674-6902.2023.02.001

所属专题: 指南共识

专家共识

第三代EGFR-TKI耐药后诊疗策略专家共识
李咏生1,(), 孙建国2, 李梦侠3, 重庆肺癌精准治疗协作组(CPLOG)   
  1. 1. 401120 重庆,重庆大学附属肿瘤医院
    2. 400037 重庆,陆军军医大学第二附属医院
    3. 400042 重庆,陆军军医大学第三附属医院
  • 收稿日期:2023-02-07 出版日期:2023-04-25
  • 通信作者: 李咏生
  • 基金资助:
    国家自然科学基金重点国际合作研究项目(81920108027); 重庆市杰出青年科学基金(cstc2020jcyj-jqX0030); 重庆英才-创新领军人才项目(CQYC202003006)

Expert consensus of clinical strategy on the third generation EGFR-TKI post-drug resistance

Yongsheng Li1(), Jianguo Sun2, Mengxia Li3   

  • Received:2023-02-07 Published:2023-04-25
  • Corresponding author: Yongsheng Li
引用本文:

李咏生, 孙建国, 李梦侠, 重庆肺癌精准治疗协作组(CPLOG). 第三代EGFR-TKI耐药后诊疗策略专家共识[J]. 中华肺部疾病杂志(电子版), 2023, 16(02): 145-155.

Yongsheng Li, Jianguo Sun, Mengxia Li. Expert consensus of clinical strategy on the third generation EGFR-TKI post-drug resistance[J]. Chinese Journal of Lung Diseases(Electronic Edition), 2023, 16(02): 145-155.

近年来,随着肺癌精准诊疗的快速发展,表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI)已成为EGFR突变晚期非小细胞肺癌(non-small cell lung cancer, NSCLC)患者的标准治疗选择,但EGFR-TKI耐药是难以避免的临床和科学难题,尤其以第三代EGFR-TKI治疗耐药最被临床所关注。第三代EGFR-TKI治疗后耐药机制多样化,基于不同耐药机制探索个体化治疗方案,不仅可以进一步延长患者生存,还可以提升患者整体生活质量。对于三代EGFR-TKI耐药后治疗策略,既往临床实践中以传统化疗为主,但化疗疗效有限,远不能满足临床需求。因此,重庆市肺癌精准治疗协作组(CPLOG)针对第三代EGFR-TKI治疗耐药后诊疗策略进行多次探讨,最终形成了第三代EGFR-TKI耐药后诊疗策略专家共识,旨在为临床实践中应对三代EGFR-TKI耐药提供参考及指导,规范临床诊疗实践,进一步改善EGFR突变晚期NSCLC患者的生存及生活质量。

表1 共识分级及说明
表2 第三代EGFR-TKI治疗耐药后的EGFR依赖性耐药机制
表3 第三代EGFR-TKI治疗耐药后的非EGFR依赖性耐药机制
1
Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung cancer[J]. Nat Rev Cancer, 2007, 7(3): 169-181.
2
Wang J, Gao J, He J. Diagnostic value of ProGRP and NSE for small cell lung cancer: a meta-analysis[J]. Zhongguo Fei Ai Za Zhi, 2010, 13(12): 1094-1100.
3
Qian H, Zhang Y, Xu J, et al. Progress and application of circulating tumor cells in non-small cell lung cancer[J]. Mol Ther Oncolytics, 2021, 22: 72-84.
4
Gallo M, De Luca A, Maiello MR, et al. Clinical utility of circulating tumor cells in patients with non-small-cell lung cancer[J]. Transl Lung Cancer Res, 2017, 6(4): 486-498.
5
Esposito A, Criscitiello C, Locatelli M, et al. Liquid biopsies for solid tumors: Understanding tumor heterogeneity and real time monitoring of early resistance to targeted therapies[J]. Pharmacol Ther, 2016, 157: 120-124.
6
Chabon JJ, Simmons AD, Lovejoy AF, et al. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients[J]. Nat Commun, 2016, 7: 11815.
7
Garraway LA, Janne PA. Circumventing cancer drug resistance in the era of personalized medicine[J]. Cancer Discov, 2012, 2(3): 214-226.
8
Lee JK, Shin JY, Kim S, et al. Primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer harboring TKI-sensitive EGFR mutations: an exploratory study[J]. Ann Oncol, 2013, 24(8): 2080-2087.
9
Ortiz-Cuaran S, Scheffler M, Plenker D, et al. Heterogeneous mechanisms of primary and acquired resistance to third-generation EGFR inhibitors[J]. Clin Cancer Res, 2016, 22(19): 4837-4847.
10
Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-Mutated advanced non-small-cell lung cancer[J]. N Engl J Med, 2018, 378(2): 113-125.
11
Bivona TG, Hieronymus H, Parker J, et al. FAS and NF-kappaB signalling modulate dependence of lung cancers on mutant EGFR[J]. Nature, 2011, 471(7339): 523-526.
12
Ng KP, Hillmer AM, Chuah CT, et al. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer[J]. Nat Med, 2012, 18(4): 521-528.
13
Jackman D, Pao W, Riely GJ, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer[J]. J Clin Oncol, 2010, 28(2): 357-360.
14
Leonetti A, Sharma S, Minari R, et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer[J]. Br J Cancer, 2019, 121(9): 725-737.
15
Ramalingam SS, Cheng Y, Zhou C, et al. Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase Ⅲ FLAURA study[J]. Ann Oncol, 2018, 29: viii740.
16
Papadimitrakopoulou VA, Wu YL, Han JY, et al. Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study[J]. Ann Oncol, 2018, 29: viii741.
17
Lu S, Wang Q, Zhang G, et al. 1208P Final results of APOLLO study: Overall survival (OS) of aumolertinib in patients with pretreated EGFR T790M-positive locally advanced or metastatic non-small cell lung cancer (NSCLC)[J]. Ann Oncol, 2021, 32: S962.
18
Shi Y, Hu X, Zhang S, et al. Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre, single-arm, open-label study[J]. Lancet Respir Med, 2021, 9(8): 829-839.
19
Bertoli E, De Carlo E, Del Conte A, et al. Acquired resistance to osimertinib in EGFR-mutated non-small cell lung cancer: how do we overcome It?[J] Int J Mol Sci, 2022, 23(13): 6936.
20
Schoenfeld AJ, Chan JM, Kubota D, et al. Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer[J]. Clin Cancer Res, 2020, 26(11): 2654-2663.
21
Ahn Mj, De Marinis F, Bonanno L, et al. MET biomarker-based preliminary efficacy analysis in SAVANNAH: savolitinib+osimertinib in EGFRm NSCLC post-osimertinib[J]. J Thorac Oncol, 2022, 17(9): S469-S470.
22
Hsu CC, Liao BC, Liao WY, et al. Exon 16-Skipping HER2 as a novel mechanism of osimertinib resistance in EGFR L858R/T790M-positive non-small cell lung cancer[J]. J Thorac Oncol, 2020, 15(1): 50-61.
23
Zeng L, Yang N, Zhang Y. GOPC-ROS1 Rearrangement as an acquired resistance mechanism to osimertinib and responding to crizotinib combined treatments in lung adenocarcinoma[J]. J Thorac Oncol, 2018, 13(7): e114-e116.
24
Xu C, Li D, Duan W, et al. TPD52L1-ROS1 Rearrangement as a new acquired resistance mechanism to osimertinib that responds to crizotinib in combination with osimertinib in lung adenocarcinoma[J]. JTO Clin Res Rep, 2020, 1(2): 100034.
25
Ichihara E, Westover D, Meador CB, et al. SFK/FAK signaling attenuates osimertinib efficacy in both drug-sensitive and drug-resistant models of EGFR-mutant lung cancer[J]. Cancer Res, 2017, 77(11): 2990-3000.
26
Taniguchi H, Yamada T, Wang R, et al. AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells[J]. Nat Commun, 2019, 10(1): 259.
27
Lee JK, Lee J, Kim S, et al. Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas[J]. J Clin Oncol, 2017, 35(26): 3065-3074.
28
Tanaka K, Yu HA, Yang S, et al. Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis[J]. Cancer Cell, 2021, 39(9): 1245-1261.e1246.
29
Keller L, Belloum Y, Wikman H, et al. Clinical relevance of blood-based ctDNA analysis: mutation detection and beyond[J]. Br J Cancer, 2021, 124(2): 345-358.
30
Dingemans AC, Hendriks LEL, Berghmans T, et al. Definition of synchronous oligometastatic non-small cell lung cancer-a consensus report[J]. J Thorac Oncol, 2019, 14(12): 2109-2119.
31
Rossi S, Finocchiaro G, Noia VD, et al. Survival outcome of tyrosine kinase inhibitors beyond progression in association to radiotherapy in oligoprogressive EGFR-mutant non-small-cell lung cancer[J]. Future Oncology, 2019, 15(33): 3775-3782.
32
Guo T, Ni J, Yang X, et al. Pattern of recurrence analysis in metastatic EGFR-mutant NSCLC treated with osimertinib: Implications for consolidative stereotactic body radiation therapy[J]. Int J Radiat Oncol Biol Phys, 2020, 107(1): 62-71.
33
Shi Y, Sun Y, Yu J, et al. China experts consensus on the diagnosis and treatment of brain metastases of lung cancer (2017 version)[J]. Zhongguo Fei Ai Za Zhi, 2017, 20(1): 1-13.
34
Goldstein IM, Roisman LC, Keren-Rosenberg S, et al. Dose escalation of osimertinib for intracranial progression in EGFR mutated non-small-cell lung cancer with brain metastases[J]. Neurooncol Adv, 2020, 2(1): vdaa125.
35
Park S, Lee MH, Seong M, et al. A phase Ⅱ,multicenter, two cohort study of 160 mg osimertinib in EGFR T790M-positive non-small-cell lung cancer patients with brain metastases or leptomeningeal disease who progressed on prior EGFR-TKI therapy[J]. Ann Oncol, 2020, 31(10): 1397-1404.
36
Ricordel C, Friboulet L, Facchinetti F, et al. Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer[J]. Ann Oncol, 2018, 29(suppl_1): i28-i37.
37
Wang Z, Yang JJ, Huang J, et al. Lung adenocarcinoma harboring EGFR T790M and in trans C797S responds to combination therapy of first- and third-generation EGFR-TKIs and shifts allelic configuration at resistance[J]. J Thorac Oncol, 2017, 12(11): 1723-1727.
38
Wang Y, Yang N, Zhang Y, et al. Effective treatment of lung adenocarcinoma harboring EGFR-activating mutation, T790M, and cis-C797S triple mutations by brigatinib and cetuximab combination therapy[J]. J Thorac Oncol, 2020, 15(8): 1369-1375.
39
Yu HA, Ambrose H, Baik C, et al. ORHARD osimertinib+savolitinib interim analysis: A biomarker-directed phase Ⅱ platform study in patients (pts) with advanced non-small cell lung cancer (NSCLC) whose disease has progressed on first-line (1L) osimertinib[J]. Ann Oncol, 2021, 32(suppl_5): S949-S1039.
40
Mazieres J, Kim TM, Lim BK, et al. Tepotinib + osimertinib for EGFRm NSCLC with MET amplification (METamp) after progression on first-line (1L) osimertinib: Initial results from the INSIGHT 2 study[J]. Ann Oncol, 2022, 33(suppl_7): S808-S869.
41
Goldman JW, Horinouchi H, Cho BC, et al. Phase 1/1b study of telisotuzumab vedotin (Teliso-V) + osimertinib (Osi), after failure on prior Osi, in patients with advanced, c-Met overexpressing, EGFR-mutated non-small cell lung cancer (NSCLC)[J]. J Clin Oncol, 2022, 40(16_suppl): 9013.
42
Neal JW, Hausrath D, Wakelee HA, et al. Osimertinib with chemotherapy for EGFR-mutant NSCLC at progression: Safety profile and survival analysis[J]. J Clin Oncol, 2019, 37(15_suppl): 9083.
43
Patil T, Tsui DCC, Nicklawsky A, et al. Effect of continuing osimertinib with chemotherapy in the post-progression setting on progression-free survival among patients with metastatic epidermal growth factor receptor (EGFR) positive non-small cell lung cancer[J]. J Clin Oncol, 2021, 39(15_suppl): 9124.
44
Sequist LV, Peled N, Tufman A, et al. COMPEL: Chemotherapy with/without osimertinib in patients with EGFRm advanced NSCLC and progression on first-line osimertinib[J]. J Thorac Oncol, 2021, 16(10): S1101.
45
Yang X, Xia Y, Xu L, et al. Efficacy and safety of combination treatment with apatinib and osimertinib after osimertinib resistance in epidermal growth factor receptor-mutant non-small cell lung carcinoma-a retrospective analysis of a multicenter clinical study[J]. Front Mol Biosci, 2021, 8: 639892.
46
Socinski MA, Nishio M, Jotte RM, et al. IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic no squamous NSCLC[J]. J Thorac Oncol, 2021, 16(11): 1909-1924.
47
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.
48
Lu S, Wu L, Jian H, et al. Sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated non-squamous non-small cell lung (EGFRm nsqNSCLC) who progressed on EGFR tyrosine-kinase inhibitors (TKIs) therapy: Second interim analysis of phase Ⅲ ORIENT-31 study[J]. Ann Oncol, 2022, 33(supp_7): S808-S869.
49
Furuya N, Watanabe S, Nakamura A, et al. NEJ043: A phase 2 study of atezolizumab (atezo) plus bevacizumab (bev) plus carboplatin (carbo) plus paclitaxel (pac; ABCP) for previously treated patients with NSCLC harboring EGFR mutations (EGFRm)[J]. J Clin Oncol, 2022, 40(16_suppl): 9110.
50
Mok TSK, Nakagawa K, Park K, et al. Nivolumab (NIVO) + chemotherapy vs chemotherapy 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.
51
Criscitiello C, Morganti S, Curigliano G. Antibody-drug conjugates in solid tumors: a look into novel targets[J]. J Hematol Oncol, 2021, 14(1): 20.
52
Garon EB, Johnson ML, Lisberg AE, et al. Efficacy of datopotamab deruxtecan (Dato-DXd) in patients (pts) with advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC) and actionable genomic alterations (AGAs): Preliminary results from the phase I TROPION-PanTumor01 study[J]. Ann Oncol, 2021, 32(suppl_5): S1283-S1346.
53
Janne PA, Baik C, Su WC, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated non-small cell lung cancer[J]. Cancer Discov, 2022, 12(1): 74-89.
54
Cho BC, Lee KH, Cho EK, et al. Amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in combination with lazertinib, a 3rd-generation tyrosine kinase inhibitor (TKI), in advanced EGFR NSCLC[J]. Ann Oncol, 2020, 31: S813.
55
Zhao Y, Fang W, Yang Y, et al. A phase Ⅱ study of AK112 (PD-1/VEGF bispecific) in combination with chemotherapy in patients with advanced non-small cell lung cancer[J]. J Clin Oncol, 2022, 40(16_suppl): 9019.
56
To C, Jang J, Chen T, et al. Single and dual targeting of mutant EGFR with an allosteric inhibitor[J]. Cancer Discov, 2019, 9(7): 926-943.
57
Eno MS, Brubaker JD, Campbell JE, et al. Discovery of BLU-945, a reversible, potent, and wild-type-sparing next-generation EGFR mutant inhibitor for treatment-resistant non-small-cell lung cancer[J]. J Med Chem, 2022, 65(14): 9662-9677.
58
Spira A, Spigel DR, Camidge DR, et al. A phase 1/2 study of the highly selective EGFR inhibitor, BLU-701, in patients with EGFR-mutant non-small cell lung cancer (NSCLC)[J]. J Clin Oncol, 2022, 40(16_suppl): TPS9142.
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