提示: 手机请竖屏浏览!

帕博利珠单抗治疗微卫星高度不稳定型晚期结直肠癌
Pembrolizumab in Microsatellite-Instability–High Advanced Colorectal Cancer


Thierry André ... 肿瘤 • 2020.12.03
相关阅读
• 帕博利珠单抗治疗微卫星高度不稳定型晚期结直肠癌 • 纳武利尤单抗联合伊匹单抗治疗MSI高/dMMR缺陷型结直肠癌 • FOLFOXIRI加贝伐单抗作为初始治疗和在转移性结直肠癌中的应用

KEYNOTE-177研究解析

 

袁瑛†,胡涵光,赵菁,翁姗姗

浙江大学医学院附属第二医院肿瘤内科

†通讯作者

 

在结直肠癌中,约有15%的患者表现出高度微卫星不稳定性(MSI-H)/DNA错配修复缺陷(dMMR)的分子表型,其中12%为散发性患者,3%为遗传性患者。MSI-H/dMMR患者临床病理特点是女性多见、好发于右半结肠、常为黏液腺癌类型。从2015年开始,程序性死亡受体-1(PD-1)抑制剂,无论是帕博利珠单抗还是纳武利尤单抗,均在MSI-H/dMMR晚期结直肠癌患者的后线治疗中显示出疗效。后线出色的疗效推动着PD-1抑制剂向肿瘤一线治疗进发。KEYNOTE-177研究就是在MSI-H /dMMR转移性结肠癌患者的一线治疗中,头对头比较了帕博利珠单抗单药和研究者选择的标准治疗(mFOLFOX6或FOLFIRI±贝伐珠单抗或西妥昔单抗)之间的疗效。

查看更多

摘要


背景

程序性死亡受体1(PD-1)阻滞剂对既往接受过治疗的微卫星高度不稳定型(MSI-H)或错配修复缺陷型(dMMR)肿瘤有临床益处。在MSI-H-dMMR晚期或转移性结直肠癌一线治疗中,PD-1阻滞剂和化疗的疗效比较尚未明确。

 

方法

在这项3期、开放标签试验中,我们以1∶1的比例将既往未经治疗的307例转移性MSI-H-dMMR结直肠癌患者随机分组,两组分别接受每3周1次,每次200 mg帕博利珠单抗治疗或每2周1次化疗(5-氟尿嘧啶方案,并且联用或不联用贝伐珠单抗或西妥昔单抗)。化疗组患者在疾病进展后可跨组接受帕博利珠单抗治疗。两个主要终点是无进展生存期和总生存期。

 

结果

在中位随访(从随机分组至数据截止日期)32.4个月(范围,24.0~48.3)后的第二次期中分析时,帕博利珠单抗在无进展生存期方面优于化疗(中位数,16.5 vs. 8.2个月;风险比,0.60;95%置信区间[CI];P=0.0002)。24个月随访后的估计限制平均生存期分别为13.7个月(范围,12.0~15.4)和10.8个月(范围,9.4~12.2)。截至数据截止日期,帕博利珠单抗组56例患者和化疗组69例患者已死亡。总生存期数据仍在不断累积(事件数量达到所需数量的66%),设盲将持续至最终分析。我们根据《实体瘤疗效评价标准》(Response Evaluation Criteria in Solid TumorsRECIST)1.1版判定帕博利珠单抗组和化疗组的总体缓解(完全或部分缓解)率分别为43.8%和33.1%。在达到总体缓解的患者中,帕博利珠单抗组83%的患者和化疗组35%的患者的缓解在24个月时仍持续。帕博利珠单抗组22%的患者和化疗组66%的患者(包括1例死亡)发生了与治疗相关的3级或更高级别不良事件。

 

结论

用于MSI-H-dMMR转移性结直肠癌的一线治疗时,帕博利珠单抗与化疗相比显著延长了无进展生存期,且与治疗相关的不良事件较少(由默沙东和对抗癌症基金会[Stand Up to Cancer]资助,KEYNOTE-177在ClinicalTrials.gov注册号为NCT02563002)。





作者信息

Thierry André, M.D., Kai-Keen Shiu, F.R.C.P., Ph.D., Tae Won Kim, M.D., Ph.D., Benny Vittrup Jensen, M.D., Lars Henrik Jensen, M.D., Ph.D., Cornelis Punt, M.D., Ph.D., Denis Smith, M.D., Rocio Garcia-Carbonero, M.D., Ph.D., Manuel Benavides, M.D., Ph.D., Peter Gibbs, M.D., Christelle de la Fouchardiere, M.D., Fernando Rivera, M.D., Ph.D., Elena Elez, M.D., Johanna Bendell, M.D., Dung T. Le, M.D., Takayuki Yoshino, M.D., Ph.D., Eric Van Cutsem, M.D., Ph.D., Ping Yang, Ph.D., Mohammed Z.H. Farooqui, D.O., Patricia Marinello, Pharm.D., and Luis A. Diaz, Jr., M.D. for the KEYNOTE-177 Investigators*
From Sorbonne Université and Hôpital Saint Antoine, Paris (T.A.), Bordeaux University Hospital, Bordeaux (D.S.), and Léon Bérard Center, Lyon (C.F.) — all in France; University College Hospital, NHS Foundation Trust, London (K.-K.S.); Asan Medical Center, University of Ulsan, Seoul, South Korea (T.W.K.); Herlev and Gentofte Hospital, Herlev (B.V.J.), and University Hospital of Southern Denmark, Vejle (L.H.J.) — both in Denmark; Amsterdam University Medical Center, University of Amsterdam, Amsterdam (C.P.); Hospital Universitario 12 de Octubre, Imas12, Madrid (R.G.-C.), Hospital Regional Universitario, Malaga (M.B.), Hospital Universitario Marques de Valdecilla, Santander (F.R.), and Vall d’Hebron Institute of Oncology, Barcelona (E.E.) — all in Spain; Western Health, St. Albans, VIC, Australia (P.G.); Sarah Cannon Research Institute–Tennessee Oncology, Nashville (J.B.); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (D.T.L.); National Cancer Center Hospital East, Kashiwa, Japan (T.Y.); University Hospital Gasthuisberg and KU Leuven, Leuven, Belgium (E.V.C.); MSD China, Beijing (P.Y.); Merck, Kenilworth, NJ (M.Z.H.F., P.M.); and Memorial Sloan Kettering Cancer Center, New York (L.A.D.). Address reprint requests to Dr. Diaz at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065, or at ldiaz@mskcc.org. *A complete list of investigators in the KEYNOTE-177 trial is provided in the Supplementary Appendix, available at NEJM.org.

 

参考文献

1. Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 2010;138(6):2073-2087.e3.

2. Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993;363:558-561.

3. Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology 2010;138:2059-2072.

4. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016;27:1386-1422.

5. Yoshino T, Arnold D, Taniguchi H, et al. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol 2018;29:44-70.

6. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: rectal cancer, version 3. 2020 (https://www.nccn.org/professionals/physician_gls/default.aspx. opens in new tab).

7. Koopman M, Kortman GAM, Mekenkamp L, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer 2009;100:266-273.

8. Zlobec I, Kovac M, Erzberger P, et al. Combined analysis of specific KRAS mutation, BRAF and microsatellite instability identifies prognostic subgroups of sporadic and hereditary colorectal cancer. Int J Cancer 2010;127:2569-2575.

9. Arnold CN, Goel A, Compton C, et al. Evaluation of microsatellite instability, hMLH1 expression and hMLH1 promoter hypermethylation in defining the MSI phenotype of colorectal cancer. Cancer Biol Ther 2004;3:73-78.

10. Goel A, Boland CR. Epigenetics of colorectal cancer. Gastroenterology 2012;143(6):1442-1460.e1.

11. Latham A, Srinivasan P, Kemel Y, et al. Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer. J Clin Oncol 2019;37:286-295.

12. Innocenti F, Ou F-S, Qu X, et al. Mutational analysis of patients with colorectal cancer in CALGB/SWOG 80405 identifies new roles of microsatellite instability and tumor mutational burden for patient outcome. J Clin Oncol 2019;37:1217-1227.

13. Tougeron D, Sueur B, Zaanan A, et al. Prognosis and chemosensitivity of deficient MMR phenotype in patients with metastatic colorectal cancer: an AGEO retrospective multicenter study. Int J Cancer 2020;147:285-296.

14. Venderbosch S, Nagtegaal ID, Maughan TS, et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res 2014;20:5322-5330.

15. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509-2520.

16. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-413.

17. Le DT, Kim TW, Van Cutsem E, et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability–high/mismatch repair–deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol 2020;38:11-19.

18. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol 2017;18:1182-1191.

19. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 2020;38:1-10.

20. Ludford K, Cohen R, Svrcek M, et al. Pathological tumor response following immune checkpoint blockade for deficient mismatch repair advanced colorectal cancer. J Natl Cancer Inst 2020 April 15 (Epub ahead of print).

21. Lenz H-J, Lonardi S, Zagonel V, et al. Nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/DNA mismatch repair deficient metastatic colorectal cancer: clinical update. J Clin Oncol 2020;38:4 Suppl:11-11. abstract.

22. Middha S, Yaeger R, Shia J, et al. Majority of B2M-mutant and -deficient colorectal carcinomas achieve clinical benefit from immune checkpoint inhibitor therapy and are microsatellite instability-high. JCO Precis Oncol 2019;3:PO.18.00321-PO.18.00321.

23. Cohen R, Hain E, Buhard O, et al. Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite instability or mismatch repair deficiency status. JAMA Oncol 2019;5:551-555.

24. Martin-Romano P, Castanon E, Ammari S, et al. Evidence of pseudoprogression in patients treated with PD1/PDL1 antibodies across tumor types. Cancer Med 2020;9:2643-2652.

25. 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.

26. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020;382:810-821.

27. Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med 2018;378:1789-1801.

服务条款 | 隐私政策 | 联系我们