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阿特珠单抗用于转移性非鳞状NSCLC的一线治疗
Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC


Mark A. Socinski ... 肿瘤 呼吸系统疾病 • 2018.06.14
相关阅读
• 阿特珠单抗一线治疗转移性非鳞状非小细胞肺癌 • ASCO 2017报告——肺癌 • 帕博利珠单抗治疗转移性非小细胞肺癌 • 晚期肺癌的新标准治疗 • 阿特珠单抗治疗晚期尿路上皮癌

摘要


背景

通过用贝伐珠单抗阻断血管内皮生长因子介导的免疫抑制,可以增强阿特珠单抗(atezolizumab)的癌细胞杀伤作用。这项开放标签、3期研究在既往未接受过化疗的转移性非鳞状非小细胞肺癌(NSCLC)患者中,对阿特珠单抗+贝伐珠单抗+化疗进行了评价。

 

方法

我们将患者随机分组,分别接受阿特珠单抗+卡铂+紫杉醇(ACP)、贝伐珠单抗+卡铂+紫杉醇(BCP)或阿特珠单抗+BCP(ABCP),每3周1次,治疗4或6个周期,随后接受阿特珠单抗、贝伐珠单抗或阿特珠单抗+贝伐珠单抗维持治疗。两个主要终点是在具有野生型基因型的意向治疗人群(WT人群;将有EGFRALK遗传改变的患者排除)患者中,以及在肿瘤内效应T细胞(Teff)基因标签高表达的WT人群(高Teff WT人群)患者中,研究者评估的无进展生存期,以及WT人群的总生存期。在将ACP组与BCP组进行比较之前,对ABCP组和BCP组进行了比较。

 

结果

在WT人群中,356例患者被分配至ABCP组,336例患者被分配至BCP组。在ABCP组的中位无进展生存期比BCP组长(8.3个月vs. 6.8个月;疾病进展或死亡的风险比,0.62;95%置信区间[CI],0.52~0.74;P<0.001);在高Teff WT人群中,相应数值分别为11.3个月和6.8个月(风险比,0.51[95% CI,0.38~0.68];P<0.001)。在整个意向治疗人群(包括有EGFRALK遗传改变的患者)、程序性死亡蛋白配体-1(PD-L1)表达低或阴性的患者、Teff基因标签表达低的患者和有肝转移的患者中,与BCP组相比,在ABCP组中,无进展生存期也较长。在WT人群患者中,ABCP组的中位总生存期也比BCP组长(19.2个月vs. 14.7个月;死亡的风险比,0.78;95% CI,0.64~0.96;P=0.02)。ABCP的安全性与之前报告的各药物的安全性风险一致。

 

结论

不论PD-L1表达和EGFRALK遗传改变状态如何,在转移性非鳞状NSCLC患者中,贝伐珠单抗+化疗加用阿特珠单抗显著改善了无进展生存期和总生存期(由罗氏制药/基因泰克资助;IMpower150在ClinicalTrials.gov注册号为NCT02366143)。





作者信息

Mark A. Socinski, M.D., Robert M. Jotte, M.D., Federico Cappuzzo, M.D., Francisco Orlandi, M.D., Daniil Stroyakovskiy, M.D., Naoyuki Nogami, M.D., Delvys Rodríguez-Abreu, M.D., Denis Moro-Sibilot, M.D., Christian A. Thomas, M.D., Fabrice Barlesi, M.D., Gene Finley, M.D., Claudia Kelsch, R.N., Anthony Lee, Pharm.D., Shelley Coleman, R.N., Yu Deng, Ph.D., Yijing Shen, Ph.D., Marcin Kowanetz, Ph.D., Ariel Lopez-Chavez, M.D., Alan Sandler, M.D., and Martin Reck, M.D. for the IMpower150 Study Group*
From the Florida Hospital Cancer Institute, Orlando (M.A.S.); Rocky Mountain Cancer Centers, Denver (R.M.J.); US Oncology, Houston (R.M.J.); Azienda Unità Sanitaria Locale della Romagna, Ravenna, Italy (F.C.); Instituto Nacional del Torax, Santiago, Chile (F.O.); Moscow City Oncology Hospital, Moscow (D.S.); National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan (N.N.); Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain (D.R.-A.); Centre Hospitalier Universitaire de Grenoble Alpes, Grenoble (D.M.-S.), and Aix Marseille University, Assistance Publique–Hôpitaux de Marseille, Marseille (F.B.) — both in France; New England Cancer Specialists, Scarborough, ME (C.A.T.); Allegheny Health Network Cancer Institute, Pittsburgh (G.F.); Genentech, South San Francisco, CA (C.K., A.L., S.C., Y.D., Y.S., M.K., A.L.-C., A.S.); and Lung Clinic Grosshansdorf, Airway Research Center North, German Center of Lung Research, Grosshansdorf, Germany (M.R.). Address reprint requests to Dr. Reck at the Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Wöhrendamm 80, Grosshansdorf 22927, Germany, or at m.reck@lungenclinic.de. *A complete list of investigators in the IMpower150 study is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Sandler A, Gray R, Perry MC, et al. Paclitaxel–carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med 2006;355:2542-2550.

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. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: non-small cell lung cancer. Vol. 2. 2018 (https://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf).

4. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med 2016;375:1823-1833.

5. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med 2018;378:2078-2092.

6. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy — inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res 2012;18:6580-6587.

7. 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.

8. 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.

9. Liu SV, Camidge DR, Gettinger SN, et al. Atezolizumab (atezo) plus platinum-based chemotherapy (chemo) in non-small cell lung cancer (NSCLC): update from a phase Ib study. J Clin Oncol 2017;35:Suppl 15:9092-9092. abstract.

10. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med 2015;373:1627-1639.

11. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 2016;387:1540-1550.

12. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAiL. J Clin Oncol 2009;27:1227-1234.

13. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 2010;21:1804-1809.

14. Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004;3:391-400.

15. Gabrilovich DI, Ciernik IF, Carbone DP. Dendritic cells in antitumor immune responses. I. Defective antigen presentation in tumor-bearing hosts. Cell Immunol 1996;170:101-110.

16. Oyama T, Ran S, Ishida T, et al. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol 1998;160:1224-1232.

17. Goel S, Duda DG, Xu L, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 2011;91:1071-1121.

18. Motz GT, Santoro SP, Wang LP, et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med 2014;20:607-615.

19. Hodi FS, Lawrence D, Lezcano C, et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res 2014;2:632-642.

20. Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun 2016;7:12624-12624.

21. Kim JM, Chen DS. Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure). Ann Oncol 2016;27:1492-1504.

22. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009;9:162-174.

23. Roland CL, Lynn KD, Toombs JE, Dineen SP, Udugamasooriya DG, Brekken RA. Cytokine levels correlate with immune cell infiltration after anti-VEGF therapy in preclinical mouse models of breast cancer. PLoS One 2009;4(11):e7669-e7669.

24. Facciabene A, Peng X, Hagemann IS, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 2011;475:226-230.

25. Voron T, Colussi O, Marcheteau E, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med 2015;212:139-148.

26. Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol 2017 December 8 (Epub ahead of print).

27. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39:1-10.

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.

29. Kowanetz M, Zou W, McCleland M, et al. Pre-existing immunity measured by Teff gene expression in tumor tissue is associated with atezolizumab efficacy in NSCLC. J Thorac Oncol 2017;12:Suppl 2:S1817-S1818. abstract.

30. Dmitrienko A, D’Agostino RB Sr, Huque MF. Key multiplicity issues in clinical drug development. Stat Med 2013;32:1079-1111.

31. Dmitrienko A, D’Agostino R Sr. Traditional multiplicity adjustment methods in clinical trials. Stat Med 2013;32:5172-5218.

32. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004;22:2184-2191.

33. Gadgeel S, Kowanetz M, Zou W, et al. Clinical efficacy of atezolizumab (atezo) in PD-L1 subgroups defined by SP142 and 22C3 IHC assays in 2L+ NSCLC: results from the randomized OAK study. Ann Oncol 2017;28:Suppl 5:460-461. abstract.

34. Pillai RN, Kamphorst AO, Owonikoko TK, et al. Liver metastases and sensitivity to checkpoint inhibition in patients with non-small cell lung cancer (NSCLC). J Clin Oncol 2016;34(15):Suppl:e20665-e20665

35. Tumeh PC, Hellmann MD, Hamid O, et al. Liver metastasis and treatment outcome with anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC. Cancer Immunol Res 2017;5:417-424.

36. Paz-Ares LG, Shen K, Higgs BW, et al. Association of liver metastases (LM) with survival in NSCLC patients treated with durvalumab (D) in two independent clinical trials. J Clin Oncol 2017;35(15):Suppl:3038-3038.

37. Peters S, Gettinger S, Johnson ML, et al. Phase II trial of atezolizumab as first-line or subsequent therapy for patients with programmed death-ligand 1-selected advanced non-small-cell lung cancer (BIRCH). J Clin Oncol 2017;35:2781-2789.

38. 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 5:468-468. abstract.

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