提示: 手机请竖屏浏览!

阿特珠单抗联合化疗一线治疗广泛期小细胞肺癌
First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer


Leora Horn ... 肿瘤 呼吸系统疾病 • 2018.12.06
NEJM 动画解读

小细胞肺癌的联合治疗
相关阅读
• 阿特珠单抗用于转移性非鳞状NSCLC的一线治疗 • 阿特珠单抗一线治疗转移性非鳞状非小细胞肺癌

摘要


背景

通过抑制程序性死亡蛋白配体-1(PD-L1)-程序性死亡蛋白-1(PD-1)信号通路增强肿瘤特异性T细胞免疫有望治疗广泛期小细胞肺癌。检查点抑制联合细胞毒性化疗可能具有协同效应,并且能够提高疗效。

 

方法

我们开展了这项双盲、安慰剂对照、3期试验,在既往未经治疗的广泛期小细胞肺癌患者中,对阿特珠单抗+卡铂和依托泊苷联合疗法进行了评估。我们以1∶1的比例将患者随机分组,分别接受卡铂和依托泊苷联合阿特珠单抗或卡铂和依托泊苷联合安慰剂治疗4个周期,每个周期21日(诱导期),随后接受维持期治疗,这一期间患者接受阿特珠单抗或安慰剂治疗(根据之前的随机分组结果),直至患者出现无法接受的毒性作用、疾病进展(根据《实体瘤疗效评价标准》[Response Evaluation Criteria in Solid Tumors,RECIST] 1.1版评估),或者没有额外的临床获益。两个主要终点为研究者在意向治疗人群中判定的无进展生存期和总生存期。

 

结果

总共201例患者被随机分配至阿特珠单抗组,202例患者被分配至安慰剂组。在中位随访13.9个月时,阿特珠单抗组和安慰剂组的中位总生存期分别为12.3个月和10.3个月(死亡风险比,0.70;95%置信区间[CI],0.54~0.91;P=0.007)。中位无进展生存期分别为5.2个月和4.3个月(疾病进展或死亡风险比,0.77;95% CI,0.62~0.96;P=0.02)。阿特珠单抗联合卡铂和依托泊苷治疗的安全性符合各药既往报告的安全性,无新发现。

 

结论

在广泛期小细胞肺癌的一线治疗中,化疗加用阿特珠单抗较单独化疗获得了显著较长的总生存期和无进展生存期(由罗氏制药/基因泰克资助;IMpower133在ClinicalTrials.gov注册号为NCT02763579)。





作者信息

Leora Horn, M.D., Aaron S. Mansfield, M.D., Aleksandra Szczęsna, M.D., Libor Havel, M.D., Maciej Krzakowski, M.D., Ph.D., Maximilian J. Hochmair, M.D., Florian Huemer, M.D., György Losonczy, M.D., Ph.D., Melissa L. Johnson, M.D., Makoto Nishio, M.D., Ph.D., Martin Reck, M.D., Tony Mok, M.D., Sivuonthanh Lam, Pharm.D., David S. Shames, Ph.D., Juan Liu, Ph.D., Beiying Ding, Ph.D., Ariel Lopez-Chavez, M.D., Fairooz Kabbinavar, M.D., Wei Lin, M.D., Alan Sandler, M.D., and Stephen V. Liu, M.D. for the IMpower133 Study Group*
From Vanderbilt University Medical Center (L. Horn) and Sarah Cannon Research Institute–Tennessee Oncology (M.L.J.), Nashville; Mayo Clinic, Rochester, MN (A.S.M.); Mazowieckie Centrum Leczenia Chorób Płuc i Gruźlicy, Otwock (A. Szczęsna), and Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie, Warsaw (M.K.) — both in Poland; Thomayerova Nemocnice, Pneumologická Klinika 1.LF UK, Prague, Czech Republic (L. Havel); the Department of Respiratory and Critical Care Medicine (M.J.H.) and the 2nd Department of Respiratory and Critical Care Medicine (F.H.), Ludwig Boltzmann Institute for COPD and Respiratory Epidemiology–Sozialmedizinisches Zentrum Baumgartner Höhe, Otto-Wagner-Spital, Vienna; Semmelweis Egyetem ÁOK, Pulmonológiai Klinika, Budapest, Hungary (G.L.); the Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo (M.N.); LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany (M.R.); State Key Laboratory of South China, Chinese University of Hong Kong, Hong Kong (T.M.), and F. Hoffmann–La Roche, Shanghai (J.L.) — both in China; Genentech, South San Francisco, CA (S.L., D.S.S., B.D., A.L.-C., F.K., W.L., A. Sandler); and Georgetown University, Washington DC (S.V.L.). Address reprint requests to Dr. Horn at Vanderbilt University Medical Center, 2220 Pierce Ave., 777 PRB, Nashville, TN 37232, or at leora.horn@vumc.org. *A complete list of investigators in the IMpower133 Study Group is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. NCCN clinical practice guidelines in oncology: small cell lung cancer, version 2.2018 (https://www.nccn.org/about/news/ebulletin/ebulletindetail.aspx?ebulletinid=1318).

2. Stahel R, Thatcher N, Früh M, et al. 1st ESMO Consensus Conference in lung cancer; Lugano 2010: small-cell lung cancer. Ann Oncol 2011;22:1973-1980.

3. Farago AF, Keane FK. Current standards for clinical management of small cell lung cancer. Transl Lung Cancer Res 2018;7:69-79.

4. Socinski MA, Smit EF, Lorigan P, et al. Phase III study of pemetrexed plus carboplatin compared with etoposide plus carboplatin in chemotherapy-naive patients with extensive-stage small-cell lung cancer. J Clin Oncol 2009;27:4787-4792.

5. Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 2012;44:1111-1116.

6. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 2012;44:1104-1110.

7. Rizvi H, Sanchez-Vega F, La K, et al. Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand (PD-L)-ligand 1 blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing. J Clin Oncol 2018;36:633-641.

8. Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 2016;17:883-895.

9. Ott PA, Elez E, Hiret S, et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the Phase Ib KEYNOTE-028 study. J Clin Oncol 2017;35:3823-3829.

10. Sequist LV, Chiang A, Gilbert J, et al. Clinical activity, safety and predictive biomarkers results from a phase Ia atezolizumab (atezo) trial in extensive-stage small cell lung cancer (ES-SCLC). Ann Oncol 2016;27:Suppl 6:1425PD-1425PD. abstract.

11. Diaz LA, Marabelle A, Delord J, Shapira-Frommer R, Geva R, Peled N. Pembrolizumab therapy for microsatellite instability high (MSI-H) colorectal cancer (CRC) and non-CRC. J Clin Oncol 2017;35:Suppl:3071-3071. abstract.

12. Gadgeel SM, Pennell NA, Fidler MJ, et al. Phase II study of maintenance pembrolizumab in patients with extensive-stage small cell lung cancer (SCLC). J Thorac Oncol 2018;13:1393-1399.

13. Reck M, Luft A, Szczesna A, et al. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol 2016;34:3740-3748.

14. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515:563-567.

15. Tecentriq (atezolizumab): summary of product characteristics. Basel, Switzerland: Roche Registration GmbH(http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004143/WC500235778.pdf).

16. Micke P, Faldum A, Metz T, et al. Staging small cell lung cancer: Veterans Administration Lung Study Group versus International Association for the Study of Lung Cancer — what limits limited disease? Lung Cancer 2002;37:271-276.

17. Ishii H, Azuma K, Kawahara A, et al. Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer. J Thorac Oncol 2015;10:426-430.

18. Schultheis AM, Scheel AH, Ozretić L, et al. PD-L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer 2015;51:421-426.

19. Gandara DR, Paul SM, Kowanetz M, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med 2018;24:1441-1448.

20. Ye Y, Li A, Liu L, Yao B. A group sequential Holm procedure with multiple primary endpoints. Stat Med 2013;32:1112-1124.

21. Dmitrienko A, D’Agostino RB Sr. Multiplicity considerations in clinical trials. N Engl J Med 2018;378:2115-2122.

22. DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med 1994;13:1341-1352.

23. Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 1982;38:29-41.

24. Hellmann MD, Callahan MK, Awad MM, et al. Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer. Cancer Cell 2018;33(5):853-861.e4.

25. Hellmann MD, Nathanson T, Rizvi H, et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell 2018;33(5):843-852.e4.

26. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017;389:255-265.

27. Cortinovis D, von Pawel J, Syrigos K, et al. Immune-related adverse events (irAEs) in advanced NSCLC patients treated with atezolizumab: safety population analyses from the Ph III study OAK. Ann Oncol 2017;28:Suppl 5:1313P-1313P. abstract.

28. Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 2016;387:1837-1846.

服务条款 | 隐私政策 | 联系我们