提示: 手机请竖屏浏览!

Ⅲ期非小细胞肺癌化放疗后的durvalumab治疗
Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer


Scott J. Antonia ... 肿瘤 呼吸系统疾病 • 2017.11.16
相关阅读
• 放化疗后使用durvalumab治疗晚期非小细胞肺癌 • 晚期非小细胞肺癌放化疗后的巩固性免疫疗法 • 晚期非小细胞肺癌的精确诊断和治疗 • ASCO 2017报告——肺癌

免疫检查点抑制剂durvalumab巩固治疗显著延长期非小细胞肺癌患者的中位无进展生存期

 

马伟杰,李天虹*

Division of Hematology & Oncology, Department of Internal Medicine, School of Medicine, University of California Davis Comprehensive Cancer Center

* 通讯作者

 

肺癌是目前全世界死亡率最高的肿瘤。近年来,肺癌人群发病率和死亡率都高居中国癌症第一1。80%~85%新诊断的肺癌为非小细胞肺癌(NSCLC)。晚期非小细胞肺癌的诊断和治疗在过去15年间取得了许多重大突破。

查看更多

摘要


背景

大多数不可切除的局部晚期非小细胞肺癌(NSCLC)患者,尽管接受确定性化放疗(化疗联合同步放疗)仍会出现疾病进展。这项3期研究在接受了至少2周期以铂类为基础的化放疗后尚未出现疾病进展的Ⅲ期NSCLC患者中,比较了抗程序性死亡配体-1抗体durvalumab和安慰剂作为巩固治疗的疗效。

 

方法

我们以2∶1的比例随机分配患者,使他们分别接受durvalumab(10 mg/kg,静脉给药)或安慰剂,每2周1次,最多持续12个月。在患者化放疗结束后的第1~42日内开始给药。研究的联合主要终点是无进展生存期(通过独立、盲法集中审核的方式进行评估)和总生存期(在中期分析时未计划对此进行分析)。次要终点包括12个月和18个月的无进展生存率、客观缓解率、缓解持续时间、至死亡或远处转移的时间以及安全性。

 

结果

在713例随机分组的患者中,709例患者接受了巩固治疗(473例患者接受了durvalumab,236例患者接受了安慰剂)。从随机分组算起,接受durvalumab和接受安慰剂患者的中位无进展生存期分别为16.8个月(95%置信区间[CI],13.0~18.1)和5.6个月(95% CI,4.6~7.8)(疾病进展或死亡的分层风险比,0.52;95% CI,0.42~0.65;P<0.001);12个月的无进展生存率分别为55.9%和35.3%,18个月的无进展生存率分别为44.2%和27.0%。durvalumab组与安慰剂组相比,缓解率较高(28.4% vs. 16.0%;P<0.001),中位缓解持续时间也较长(在18个月时仍存在缓解的比例为72.8% vs. 46.8%)。durvalumab组至死亡或远处转移的中位时间也比安慰剂组长(23.2个月vs. 14.6个月;P<0.001)。durvalumab组和安慰剂组中出现3级或4级不良事件的比例分别为29.9%和26.1%;最常见的3级或4级不良事件是感染性肺炎(分别为4.4%和3.8%)。durvalumab组和安慰剂组中分别有15.4%和9.8%的患者由于不良事件而停用研究药物。

 

结论

durvalumab组的无进展生存期显著超过安慰剂组。durvalumab组的次要终点也较优,两组的安全性相似(由阿斯利康公司资助;PACIFIC在ClinicalTrail.gov注册号为NCT02125461)。





作者信息

Scott J. Antonia, M.D., Ph.D., Augusto Villegas, M.D., Davey Daniel, M.D., David Vicente, M.D., Shuji Murakami, M.D., Rina Hui, Ph.D., Takashi Yokoi, M.D., Ph.D., Alberto Chiappori, M.D., Ki H. Lee, M.D., Ph.D., Maike de Wit, M.D., Ph.D., Byoung C. Cho, M.D., Ph.D., Maryam Bourhaba, M.D., Xavier Quantin, M.D., Ph.D., Takaaki Tokito, M.D., Ph.D., Tarek Mekhail, M.D., David Planchard, M.D., Ph.D., Young-Chul Kim, M.D., Ph.D., Christos S. Karapetis, M.D., Sandrine Hiret, M.D., Gyula Ostoros, M.D., Kaoru Kubota, M.D., Ph.D., Jhanelle E. Gray, M.D., Luis Paz-Ares, M.D., Ph.D., Javier de Castro Carpeño, M.D., Ph.D., Catherine Wadsworth, B.V.Sc., Giovanni Melillo, M.D., Haiyi Jiang, M.D., Yifan Huang, Ph.D., Phillip A. Dennis, M.D., Ph.D., and Mustafa Özgüroğlu, M.D., for the PACIFIC Investigators*
From the H. Lee Moffitt Cancer Center and Research Institute, Tampa (S.J.A., A.C., J.E.G.), Cancer Specialists of North Florida, Jacksonville (A.V.), and Florida Hospital Cancer Institute, Orlando (T.M.) — all in Florida; Tennessee Oncology, Chattanooga, and Sarah Cannon Research Institute, Nashville — both in Tennessee (D.D.); Hospital Universitario Virgen Macarena, Seville (D.V.), and Hospital Universitario 12 de Octubre, Centro de Investigación Biomédica en Red de Cáncer, Universidad Complutense and the Spanish National Cancer Research Center (L.P.-A.), and Hospital Universitario La Paz (J.C.C.), Madrid — all in Spain; Kanagawa Cancer Center, Yokohama (S.M.), Kansai Medical University Hospital, Hirakata (T.Y.), Kurume University Hospital, Kurume (T.T.), and Nippon Medical School Hospital, Tokyo (K.K.) — all in Japan; Westmead Hospital and the University of Sydney, Sydney (R.H.), and Flinders University and Flinders Medical Centre, Bedford Park, SA (C.S.K.) — all in Australia; Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju (K.H.L.), Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (B.C.C.), and Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju (Y.-C.K.) — all in South Korea; Vivantes Klinikum Neukölln, Berlin (M.W.); Centre Hospitalier Universitaire de Liège, Liège, Belgium (M.B.); Centre Hospitalier Universitaire Montpellier and Cancer Institute of Montpellier Val d’Aurelle, Montpellier (X.Q.), Institut Gustave Roussy, Villejuif (D.P.), and Institut de Cancérologie de l’Ouest–Site René Gauducheau, Saint Herblain (S.H.) — all in France; National Koranyi Institute of Pulmonology, Budapest, Hungary (G.O.); AstraZeneca, Alderley Park, United Kingdom (C.W.); AstraZeneca, Gaithersburg, MD (G.M., H.J., Y.H., P.A.D.); and Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey (M.Ö.). Address reprint requests to Dr. Antonia at the H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., MRC 3-E, Tampa, FL 33612, or at scott.antonia@moffitt.org. *A complete list of the investigators of the PACIFIC study is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Aupérin A, Le Péchoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010;28:2181-2190

2. Yoon SM, Shaikh T, Hallman M. Therapeutic management options for stage III non-small cell lung cancer. World J Clin Oncol 2017;8:1-20

3. Ahn JS, Ahn YC, Kim JH, et al. Multinational randomized phase III trial with or without consolidation chemotherapy using docetaxel and cisplatin after concurrent chemoradiation in inoperable stage III non-small-cell lung cancer: KCSG-LU05-04. J Clin Oncol 2015;33:2660-2666

4. Ettinger S, Wood DE, Aisner DL, et al. Non-small cell lung cancer, Version 5.2017. J Natl Compr Canc Netw 2017;15:504-535.

5. Vansteenkiste J, De Ruysscher D, Eberhardt WE, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24:Suppl 6:vi89-vi98

6. Hanna N, Neubauer M, Yiannoutsos C, et al. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol 2008;26:5755-5760

7. Wozniak AJ, Moon J, Thomas CR Jr, et al. A pilot trial of cisplatin/etoposide/radiotherapy followed by consolidation docetaxel and the combination of bevacizumab (NSC-704865) in patients with inoperable locally advanced stage III non-small-cell lung cancer: SWOG S0533. Clin Lung Cancer 2015;16:340-347

8. Hoang T, Dahlberg SE, Schiller JH, et al. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol 2012;30:616-622

9. Kelly K, Chansky K, Gaspar LE, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 2008;26:2450-2456

10. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015;16:187-199

11. Vokes EE, Herndon JE II, Kelley MJ, et al. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol 2007;25:1698-1704

12. Tsujino K, Kurata T, Yamamoto S, et al. Is consolidation chemotherapy after concurrent chemo-radiotherapy beneficial for patients with locally advanced non-small-cell lung cancer? A pooled analysis of the literature. J Thorac Oncol 2013;8:1181-1189

13. Butts C, Socinski MA, Mitchell PL, et al. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol 2014;15:59-68

14. Mitchell P, Thatcher N, Socinski MA, et al. Tecemotide in unresectable stage III non-small-cell lung cancer in the phase III START study: updated overall survival and biomarker analyses. Ann Oncol 2015;26:1134-1142

15. Stewart R, Morrow M, Hammond SA, et al. Identification and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer Immunol Res 2015;3:1052-1062

16. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-264

17. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol 2015;33:1974-1982

18. Antonia SJ, Brahmer JR, Khleif S, et al. Phase 1/2 study of the safety and clinical activity of durvalumab in patients with non-small cell lung cancer (NSCLC). Presented at the 41st European Society for Medical Oncology Annual Meeting, Copenhagen, October 7–11, 2016. (Poster.)

19. AstraZeneca Imfinzi (durvalumab): highlights of prescribing information. Silver Spring, MD: Food and Drug Administration, April 2017 (https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761069s000lbl.pdf).

20. Zhang P, Su DM, Liang M, Fu J. Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis. Mol Immunol 2008;45:1470-1476

21. Deng L, Liang H, Burnette B, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 2014;124:687-695

22. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res 2014;74:5458-5468

23. Goldstraw P, ed. Staging manual in thoracic oncology. 7th ed. Aurora, CO: International Association for the Study of Lung Cancer, 2010.

24. Gandara DR, Chansky K, Albain KS, et al. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504. J Clin Oncol 2003;21:2004-2010

服务条款 | 隐私政策 | 联系我们