提示: 手机请竖屏浏览!

奥希替尼在未经治疗的EGFR突变型晚期非小细胞肺癌中的应用
Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer


Jean-Charles Soria ... 肿瘤 呼吸系统疾病 • 2018.01.11
相关阅读
• 达克替尼治疗晚期非小细胞肺癌 • 使用奥希替尼治疗未经治疗的EGFR突变晚期NSCLC • 奥希替尼或铂类-培美曲塞治疗EGFR T790M阳性肺癌的研究

FLAURA试验结果对非小细胞型肺癌EGFR突变患者治疗的影响

 

张小林

迪哲医药;北京大学分子医学研究所

 

一代EGFR-TKI的安全性和有效性已经在临床上得到了很好的证明,临床医生对怎样合理使用一代EGFR-TKI和处理有关副作用也积累了很多经验。但是,约一半的一代EGFR-TKI治疗失败的患者会产生T790M突变。靶向T790M突变的第三代EGFR-TKI奥希替尼应运而生,AURA试验证明了它的良好疗效,其PFS达10.1个月,比对照组培美曲塞-铂类双药联合化疗的4.4个月有显著提高1。基于AURA结果,奥希替尼在世界多个国家被批准用于T790M阳性的非小细胞型肺癌。

查看更多

摘要


背景

奥希替尼是一种口服第三代不可逆表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI),它选择性抑制EGFR-TKI敏化和EGFR T790M耐药突变。本研究在既往未经治疗的EGFR突变阳性晚期非小细胞肺癌(NSCLC)患者中比较了奥希替尼与标准EGFR-TKI两种疗法。

 

方法

在这项双盲、3期临床试验中,我们将556例未经治疗的EGFR突变阳性(外显子19缺失或L858R)晚期NSCLC患者按1∶1的比例随机分为两组,分别接受奥希替尼(80 mg,每日1次)或标准EGFR-TKI(吉非替尼250 mg,每日1次;或厄洛替尼150 mg,每日1次)治疗。主要终点是经研究者评估的无进展生存期。

 

结果

奥希替尼组的中位无进展生存期显著超过标准EGFR-TKI组(18.9个月 vs. 10.2个月;疾病进展或死亡风险比,0.46;95%置信区间[CI],0.37~0.57;P<0.001)。客观缓解率在两组中相似:奥希替尼为80%,标准EGFR-TKI为76%(比值比,1.27;95% CI,0.85~1.90;P=0.24)。奥希替尼组的中位缓解持续时间为17.2个月(95% CI,13.8~22.0),而标准EGFR-TKI组为8.5个月(95% CI,7.3~9.8)。中期分析时总生存期数据尚不成熟(成熟度,25%)。18个月时奥希替尼组的生存率为83%(95% CI,78~87),标准EGFR-TKI组为71%(95% CI,65~76)(风险比,0.63;95% CI,0.45~0.88;P=0.007 [中期分析中无显著意义])。奥希替尼组3级或更高级不良事件的发生率低于标准EGFR-TKI组(34% vs. 45%)。

 

结论

EGFR突变阳性NSCLC患者的一线治疗中,奥希替尼的疗效优于标准EGFR-TKI,且严重不良事件发生率低于后者;在安全性方面,两者相似(由AstraZeneca资助;FLAURA在ClinicalTrials.gov注册号为NCT02296125)。





作者信息

Jean-Charles Soria, M.D., Ph.D., Yuichiro Ohe, M.D., Ph.D., Johan Vansteenkiste, M.D., Ph.D., Thanyanan Reungwetwattana, M.D., Busyamas Chewaskulyong, M.D., Ki Hyeong Lee, M.D., Ph.D., Arunee Dechaphunkul, M.D., Fumio Imamura, M.D., Ph.D., Naoyuki Nogami, M.D., Takayasu Kurata, M.D., Ph.D., Isamu Okamoto, M.D., Ph.D., Caicun Zhou, M.D., Ph.D., Byoung Chul Cho, M.D., Ph.D., Ying Cheng, M.D., Eun Kyung Cho, M.D., Ph.D., Pei Jye Voon, M.D., David Planchard, M.D., Ph.D., Wu-Chou Su, M.D., Jhanelle E. Gray, M.D., Siow-Ming Lee, M.D., Ph.D., Rachel Hodge, M.Sc., Marcelo Marotti, M.D., Ph.D., Yuri Rukazenkov, M.D., Ph.D., and Suresh S. Ramalingam, M.D., for the FLAURA Investigators*
From Gustave Roussy Cancer Campus and University Paris-Sud, Orsay, France (J.-C.S., D.P.); the Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo (Y.O.), the Department of Thoracic Oncology, Osaka International Cancer Institute (F.I.), and the Department of Thoracic Oncology, Kansai Medical University Hospital (T.K.), Osaka, the Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama (N.N.), and the Research Institute for Diseases of the Chest, Graduate School of Medical Science, Kyushu University, Fukuoka (I.O.) — all in Japan; the Respiratory Oncology Unit, University Hospital KU Leuven, Leuven, Belgium (J.V.); Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok (T.R.), the Oncology Unit, Department of Medicine, Chiang Mai University, Chiang Mai (B.C.), and the Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai (A.D.) — all in Thailand; the Division of Medical Oncology, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheong-ju (K.H.L.), the Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (B.C.C.), and the Division of Hematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon (E.K.C.) — all in South Korea; Pulmonary Hospital of Tongji University, Shanghai (C.Z.), and Jilin Provincial Cancer Hospital, Changchun (Y.C.) — both in China; Hospital Umum Sarawak, Kuching, Malaysia (P.J.V.); National Cheng Kung University, Tainan, Taiwan (W.-C.S.); the Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (J.E.G.); the Department of Oncology, University College London Hospitals Biomedical Research Centre, and the Cancer Research UK Lung Cancer Centre of Excellence, London (S.-M.L.), and AstraZeneca, Cambridge (R.H., M.M., Y.R.) — all in the United Kingdom; and Emory University School of Medicine, Winship Cancer Institute, Atlanta (S.S.R.). Address reprint requests to Dr. Ramalingam at the Winship Cancer Institute of Emory University, 1365 Clifton Rd. NE, C-4014E, Atlanta, GA 30322, or at ssramal@emory.edu. *A list of the FLAURA Investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Hanna N, Johnson D, Temin S, et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology Clinical Practice Guideline update. J Clin Oncol 2017;35:3484-3515

2. Novello S, Barlesi F, Califano R, et al. Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016;27:Suppl 5:v1-v27

3. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-246

4. Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-957

5. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013;31:3327-3334

6. Lee CK, Davies L, Wu YL, et al. Gefitinib or erlotinib vs chemotherapy for EGFR mutation-positive lung cancer: individual patient data meta-analysis of overall survival. J Natl Cancer Inst 2017;109(6).

7. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-128

8. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non–small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-2388

9. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-742

10. Wu YL, Zhou C, Liam CK, et al. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Ann Oncol 2015;26:1883-1889

11. Oxnard GR, Arcila ME, Sima CS, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res 2011;17:1616-1622

12. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 2013;19:2240-2247

13. Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014;4:1046-1061

14. Mok T, Ahn M-J, Han J-Y, et al. CNS response to osimertinib in patients (pts) with T790M-positive advanced NSCLC: data from a randomized phase III trial (AURA3). J Clin Oncol 2017;35(15):Suppl:9005-9005 abstract.

15. Mok TS, Wu Y-L, Ahn M-J, et al. Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med 2017;376:629-640

16. Goss G, Tsai CM, Shepherd FA, et al. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 2016;17:1643-1652

17. Yang JC-H, Ahn M-J, Kim D-W, et al. Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer: AURA study phase II extension component. J Clin Oncol 2017;35:1288-1296

18. Ballard P, Yates JW, Yang Z, et al. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin Cancer Res 2016;22:5130-5140

19. Goss G, Tsai C-M, Shepherd F, et al. MA16.11 CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. J Thorac Oncol 2017;12(1):Suppl:S440-S441

20. Eberlein CA, Stetson D, Markovets AA, et al. Acquired resistance to the mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling in preclinical models. Cancer Res 2015;75:2489-2500

21. Meador CB, Jin H, de Stanchina E, et al. Optimizing the sequence of anti-EGFR-targeted therapy in EGFR-mutant lung cancer. Mol Cancer Ther 2015;14:542-552

22. Ramalingam SS, Yang JC, Lee CK, et al. Osimertinib as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer. J Clin Oncol 2017 August 25 (Epub ahead of print)

23. Park K, Tan EH, O’Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol 2016;17:577-589

24. Bhatt VR, D’Souza SP, Smith LM, et al. Epidermal growth factor receptor mutational status and brain metastases in non-small-cell lung cancer. J Glob Oncol 2016;3:208-217

25. Park SJ, Kim HT, Lee DH, et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer 2012;77:556-560

26. Heon S, Yeap BY, Lindeman NI, et al. The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations. Clin Cancer Res 2012;18:4406-4414

27. Wu YL, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial. Lancet Oncol 2017 September 25 (Epub ahead of print)

28. Stewart EL, Tan SZ, Liu G, Tsao MS. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations — a review. Transl Lung Cancer Res 2015;4:67-81

29. Thress KS, Paweletz CP, Felip E, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med 2015;21:560-562

30. Chen K, Zhou F, Shen W, et al. Novel mutations on EGFR Leu792 potentially correlate to acquired resistance to osimertinib in advanced NSCLC. J Thorac Oncol 2017;12:e65-e68

31. Kim TM, Song A, Kim DW, et al. Mechanisms of acquired resistance to AZD9291: a mutation-selective, irreversible EGFR inhibitor. J Thorac Oncol 2015;10:1736-1744

32. Planchard D, Loriot Y, André F, et al. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann Oncol 2015;26:2073-2078

33. Batson S, Mitchell SA, Windisch R, Damonte E, Munk VC, Reguart N. Tyrosine kinase inhibitor combination therapy in first-line treatment of non-small-cell lung cancer: systematic review and network meta-analysis. Onco Targets Ther 2017;10:2473-2482

服务条款 | 隐私政策 | 联系我们