山东大学耳鼻喉眼学报 ›› 2019, Vol. 33 ›› Issue (3): 42-48.doi: 10.6040/j.issn.1673-3770.1.2019.001

• 研究进展 • 上一篇    下一篇

免疫检查点抑制剂在复发或转移性头颈鳞癌的治疗进展

陈曦(),乔明哲   

  1. 南京医科大学第一附属医院 江苏省人民医院耳鼻咽喉科,江苏 南京 210029
  • 收稿日期:2019-01-01 修回日期:2019-05-10 出版日期:2019-05-20 发布日期:2019-08-07
  • 通讯作者: 陈曦 E-mail:jsxycx@sina.com
  • 作者简介:陈曦,临床医学博士,主任医师、副教授,硕士研究生导师。现任南京医科大学第一附属医院(江苏省人民医院)耳鼻咽喉科副主任,咽喉与头颈组组长。主要学术任职:中国抗癌协会康复会学术指导委员会常务委员,江苏省头颈肿瘤专家委员会主任委员;中国医疗保健国际交流促进会咽喉嗓音言语分会常务委员;中国医师协会耳鼻咽喉科医师分会头颈学组委员; 江苏省医学会耳鼻咽喉头颈外科学分会头颈外科学组副组长;江苏省医师协会耳鼻咽喉科医师分会副会长兼总干事。专业特长为咽喉嗓音疾病和头颈肿瘤的临床诊治,擅长咽喉微创手术、头颈恶性肿瘤切除术及功能重建术。

Progress of immune checkpoint inhibitors in the treatment of recurrent or metastatic head and neck squamous cell carcinoma

Xi CHEN(),Mingzhe QIAO   

  1. Department of Otorhinolaryngology, The First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, Jiangsu, China
  • Received:2019-01-01 Revised:2019-05-10 Online:2019-05-20 Published:2019-08-07
  • Contact: Xi CHEN E-mail:jsxycx@sina.com

摘要:

以铂类为基础的化疗联合西妥昔单抗是复发或转移性头颈鳞状细胞癌(R/M HNSCC)的标准治疗方式,然而治疗后有易复发、中位生存期短等问题。以PD-1/PDL-1单抗为主的免疫检查点抑制剂(ICIs)开始成为R/M HNSCC新的临床治疗方案,且pembrolizumab和nivolumab都已被FDA批准用于经铂类治疗失败的R/M HNSCC。现就ICIs在R/M HNSCC的临床试验进行系统汇总,并对药物的不良反应及生物标志物进行阐述,为未来在R/M HNSCC中使用ICIs提供理论基础。

关键词: 头颈部肿瘤, 肿瘤,鳞状细胞, 免疫疗法, 免疫检查点抑制剂

Abstract:

Platinum-based chemotherapy combined with cetuximab is the standard treatment for recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC), but facing easy recurrence with a short survival time. Immune checkpoint inhibitors (ICIs), that mainly meant PD-1/PDL-1 monoclonal antibodies, have become a new clinical therapy program for R/M HNSCC, and both pembrolizumab and nivolumab have been approved by the FDA for R/M HNSCC patients with previous platinum-based treatment failure. This review systematically summarizes the clinical trials of ICIs in R/M HNSCC and describes the toxic side effects and biomarkers of the drugs, in order to provide theoretical basis for clinical usage of ICIs in future.

Key words: Head and neck neoplasms, Neoplasms, squamous cell, Immunotherapy, Immune checkpoint inhibitors

中图分类号: 

  • R739

表 1

Nivolumab和pembrolizumab在头颈部肿瘤的临床疗效对比"

试验临床阶段样本量患者群体药物客观应答率中位PFS/中位OS
Checkmate 141III期361铂类药物治疗失败的复发或转移性HNSCC

nivolumab 3 mg/kg,每2周一次;

标准的单药治疗(甲氨喋呤、多西他赛或西妥昔单抗)

nivolumab治疗组 ORR 为 13.3%;

标准治疗组ORR 为5.8%

nivolumab治疗组中位OS为7.5个月,标准治疗组为5.1个月 (P=0.01);nivolumab治疗组中位PFS为2个月,标准治疗组为2.3个月(P=0.32)
KEYTEN-012Ib期60铂类药物治疗失败的复发或转移性HNSCC

pembrolizumab

10 mg/kg,每2周一次

ORR为18%

中位PFS和中位OS分别为

2个月和13个月

KEYTEN-012-EXPExp. Ib期132铂类药物治疗失败的复发或转移性HNSCC

pembrolizumab

200 mg,每3周一次

ORR为18%6个月的PFS和OS率分别为23%和59%
KEYTEN-055II期171铂类联合西妥昔治疗失败的复发或转移性HNSCCpembrolizumab 200 mg,每3周一次ORR为16%中位PFS和中位OS分别为2.1个月和8个月

KEY

NOTE-040

III期495铂类药物治疗失败的复发或转移性HNSCC

pembrolizumab

200 mg,每3周一次;标准的单药治疗(甲氨蝶呤、多西他赛 或西妥昔单抗)

pembrolizumab治疗组ORR为14.6%;标准治疗组ORR为10.1%pembrolizumab治疗组中位OS为8.4个月;标准治疗组为7.1个月(P=0.204)

表 2

Nivolumab和pembrolizumab在头颈部肿瘤的临床不良反应比较"

试验n不良事件任何级别不良事件3~4级不良事件
CheckMate 141361疲劳、恶心、皮疹、食欲减退和瘙痒nivolumab治疗组58.9% 的患者出现不良事件,标准治疗组77.5%出现不良事件nivolumab治疗组13.1% 的患者,标准治疗组35.1%的患者发生3~4级不良事件
KEYTEN-01260

天冬氨酸氨基转移酶增加、低钠血症、疲劳、皮疹、心房颤动、充血性心力衰竭、腹泻、淋巴细胞减少、

肌肉骨骼疼痛和颈部脓肿

63%的患者出现不良事件

17%的患者发生3~4级

不良事件

KEYTEN-012 EXP132天冬氨酸氨基转移酶增加、低钠血症、疲劳、皮疹、心房颤动、充血性心力衰竭、腹泻、淋巴细胞减少、 肌肉骨骼疼痛和颈部脓肿62%的患者出现不良事件

9%的患者发生大于3级

不良事件

KEYTEN-055171疲劳、甲状腺功能减退、恶心、腹泻、食欲减退、皮疹、瘙痒、天冬氨酸氨基转移酶增加、丙氨酸氨基转移酶增加64%的患者出现不良事件

26例(15%)发生大于3级

不良事件

表 3

Nivolumab和pembrolizumab在头颈部肿瘤的生物标志物比较(PD-L1)"

试验PD-L1阈值样本量客观缓解率PFSOS
CheckMate 141

PD-L1≥1%

PD-L1<1%

88 (54%)

73 (46%)

NANA+
KEYTEN-012PD-L1≥1%60 (100%)++NA
KEYTEN-012 EXP

PD-L1≥1%

PD-L1<1%

107 (81%)

25 (19%)

+++
KEYTEN-055

PD-L1≥1%

PD-L1<1%

140(82%)

26 (15%)

---
KEYNOTE-040

PD-L1≥50%

PD-L1<50%

NA+++

表 4

Nivolumab和pembrolizumab在头颈部肿瘤的生物标志物比较(HPV)"

试验HPV状态样本量客观缓解率PFSOS
CheckMate 141

HPV 阳性

HPV 阴性

63 (26.2%)

50 (20.8%)

N/AN/A+
KEYTEN-012

HPV 阳性

HPV 阴性

23 (38%)

37 (62%)

+++
KEYTEN-055

HPV 阳性

HPV 阴性

37 (22%)

131 (77%)

--+
KEYNOTE-040

HPV 阳性

HPV 阴性

NA---

表 5

Nivolumab和pembrolizumab在头颈部肿瘤的联合试验"

状态药物试验阶段临床终点NCT Number
招募中nivolumab 对比nivolumab + cisplatin,联合放疗III期

? 无事件生存 (EFS) ;

局部控制时(DLRC);OS

NCT03349710
招募中? nivolumab联合 ipilimumab 对比标准治疗III期? OS;PFSNCT02741570
招募中? nivolumab 联合西妥昔单抗I/II期

? I期:Phase 2推荐剂量;

? II期:OS; ORR

NCT03370276
招募中? 多西他赛联合pembrolizumabI/II期? ORRNCT02718820
招募中? 乐伐替尼联合pembrolizumabI/II期? MTD; DLT;ORRNCT02501096
招募中? pembrolizumab联合放疗II期? ORRNCT03386357
招募中

durvalumab和tremelimumab

联合放疗对比 durvalumab 联合放疗

II期?? PFS;OS?NCT03624231
招募中

? nivolumab 联合ipilimumab

? 对比多西他赛

II期?? ORR;PFS;OSNCT03620123
1 SiegelRL, MillerKD, JemalA. Cancer statistics, 2015[J]. CA Cancer J Clin, 2015, 65(1): 5-29. doi:10.3322/caac.21254.
doi: 10.3322/caac.21254
2 ChenWQ, ZhengRS, BaadePD, et al. Cancer statistics in China, 2015[J]. CA Cancer J Clin, 2016, 66(2): 115-132. doi:10.3322/caac.21338.
doi: 10.3322/caac.21338
3 SaccoAG, CohenEE. Current treatment options for recurrent or metastatic head and neck squamous cell carcinoma[J]. JCO, 2015, 33(29): 3305-3313. doi:10.1200/jco.2015.62.0963.
doi: 10.1200/jco.2015.62.0963
4 SeiwertTY, BurtnessB, MehraR, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial[J]. Lancet Oncol, 2016, 17(7): 956-965. doi:10.1016/S1470-2045(16)30066-3.
doi: 10.1016/S1470-2045(16)30066-3
5 FerrisRL, BlumenscheinG Jr, FayetteJ, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck[J]. N Engl J Med, 2016, 375(19): 1856-1867. doi:10.1056/nejmoa1602252.
doi: 10.1056/nejmoa1602252
6 MeleroI, GaudernackG, GerritsenW, et al. Therapeutic vaccines for cancer: an overview of clinical trials[J]. Nat Rev Clin Oncol, 2014, 11(9): 509-524. doi:10.1038/nrclinonc.2014.111.
doi: 10.1038/nrclinonc.2014.111
7 MahoneyKM, RennertPD, FreemanGJ. Combination cancer immunotherapy and new immunomodulatory targets[J]. Nat Rev Drug Discov, 2015, 14(8): 561-584. doi:10.1038/nrd4591.
doi: 10.1038/nrd4591
8 BrahmerJR, TykodiSS, ChowLQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer[J]. N Engl J Med, 2012, 366(26): 2455-2465. doi:10.1056/NEJMoa1200694.
doi: 10.1056/NEJMoa1200694
9 MoyJD, MoskovitzJM, FerrisRL. Biological mechanisms of immune escape and implications for immunotherapy in head and neck squamous cell carcinoma[J]. Eur J Cancer, 2017, 76: 152-166. doi:10.1016/j.ejca. 2016.12.035.
doi: 10.1016/j.ejca. 2016.12.035
10 HannaGJ, LiuHY, JonesRE, et al. Defining an inflamed tumor immunophenotype in recurrent, metastatic squamous cell carcinoma of the head and neck[J]. Oral Oncol, 2017, 67: 61-69. doi:10.1016/j.oraloncology. 2017.02.005.
doi: 10.1016/j.oraloncology. 2017.02.005
11 TongCC, KaoJ, SikoraAG. Recognizing and reversing the immunosuppressive tumor microenvironment of head and neck cancer[J]. Immunol Res, 2012, 54(1/2/3): 266-274. doi:10.1007/s12026-012-8306-6.
doi: 10.1007/s12026-012-8306-6
12 MattoxAK, LeeJ, WestraWH, et al. PD-1 expression in head and neck squamous cell carcinomas derives primarily from functionally anergic CD4+ TILs in the presence of PD-l1+ TAMs[J]. Cancer Res, 2017, 77(22): 6365-6374. doi:10.1158/0008-5472.CAN-16-3453.
doi: 10.1158/0008-5472.CAN-16-3453
13 ZhaoMY, LiY, WeiX, et al. Negative immune factors might predominate local tumor immune status and promote carcinogenesis in cervical carcinoma[J]. Virol J, 2017, 14(1): 5. doi:10.1186/s12985-016-0670-8.
doi: 10.1186/s12985-016-0670-8
14 MandalR, ŞenbabaoğluY, DesrichardA, et al. The head and neck cancer immune landscape and its immunotherapeutic implications[J]. JCI Insight, 2016, 1(17): e89829. doi:10.1172/jci.insight.89829.
doi: 10.1172/jci.insight.89829
15 OoftML, van IpenburgJA, SandersME, et al. Prognostic role of tumour-associated macrophages and regulatory T cells in EBV-positive and EBV-negative nasopharyngeal carcinoma[J]. J Clin Pathol, 2018, 71(3): 267-274. doi:10.1136/jclinpath-2017-204664.
doi: 10.1136/jclinpath-2017-204664
16 ChowLQM, HaddadR, GuptaS, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase ib KEYNOTE-012 expansion cohort[J]. JCO, 2016, 34(32): 3838-3845. doi:10.1200/jco.2016.68.1478.
doi: 10.1200/jco.2016.68.1478
17 BaumlJ, SeiwertTY, PfisterDG, et al. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study[J]. J Clin Oncol, 2017, 35(14): 1542-1549. doi:10.1200/JCO.2016.70.1524.
doi: 10.1200/JCO.2016.70.1524
18 CohenEE, HarringtonKJ, Le TourneauC, et al. LBA45PRPembrolizumab (pembro) vs standard of care (SOC) for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): Phase 3 KEYNOTE-040 trial[J]. Annals of Oncology, 2017, 28(suppl_5):v605-v649. doi:10.1093/annonc/mdx440.040.
doi: 10.1093/annonc/mdx440.040
19 SzturzP, VermorkenJB. Immunotherapy in head and neck cancer: aiming at EXTREME precision[J]. BMC Med, 2017, 15(1): 110. doi:10.1186/s12916-017-0879-4.
doi: 10.1186/s12916-017-0879-4
20 WolchokJD, RollinL, LarkinJ. Nivolumab and ipilimumab in advanced melanoma[J]. N Engl J Med, 2017, 377(25): 2503-2504. doi:10.1056/NEJMc1714339.
doi: 10.1056/NEJMc1714339
21 MotzerRJ, TannirNM, McDermottDF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma[J]. N Engl J Med, 2018, 378(14): 1277-1290. doi:10.1056/NEJMoa1712126.
doi: 10.1056/NEJMoa1712126
22 JiangT, ZhouCC. The past, present and future of immunotherapy against tumor[J]. Transl Lung Cancer Res, 2015, 4(3): 253-264. doi:10.3978/j.issn.2218-6751.2015.01.06.
doi: 10.3978/j.issn.2218-6751.2015.01.06
23 LeDT, DurhamJN, SmithKN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade[J]. Science, 2017, 357(6349): 409-413. doi:10.1126/science.aan6733.
doi: 10.1126/science.aan6733
24 AguiarPN Jr, De MelloRA, HallP, et al. PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: updated survival data[J]. Immunotherapy, 2017, 9(6): 499-506. doi:10.2217/imt-2016- 0150.
doi: 10.2217/imt-2016- 0150
25 KaramouzisMV, PapavassiliouAG. Combination of checkpoint inhibitors with other agents as a strategy to improve anti-cancer effect-a glimpse to the future[J]. Expert Opin Investig Drugs, 2018, 27(7): 569-572. doi: 10.1080/13543784.2018.1494724.
doi: 10.1080/13543784.2018.1494724
26 GandhiL, Rodríguez-AbreuD, GadgeelS, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer[J]. N Engl J Med, 2018, 378(22): 2078-2092. doi:10.1056/NEJMoa1801005.
doi: 10.1056/NEJMoa1801005
27 WolchokJD, Chiarion-SileniV, GonzalezR, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma[J]. N Engl J Med, 2017, 377(14): 1345-1356. doi:10.1056/NEJMoa1709684.
doi: 10.1056/NEJMoa1709684
28 OvermanMJ, LonardiS, WongKYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-Deficient/Microsatellite instability-high metastatic colorectal cancer[J]. J Clin Oncol, 2018, 36(8): 773-779. doi:10.1200/JCO.2017.76.9901.
doi: 10.1200/JCO.2017.76.9901
29 BuruguS, DancsokAR, NielsenTO. Emerging targets in cancer immunotherapy[J]. Semin Cancer Biol, 2018, 52(Pt 2): 39-52. doi:10.1016/j.semcancer. 2017.10.001.
doi: 10.1016/j.semcancer. 2017.10.001
30 BeattyGL, LiY, LongKB. Cancer immunotherapy: activating innate and adaptive immunity through CD40 agonists[J]. Expert Rev Anticancer Ther, 2017, 17(2): 175-186. doi:10.1080/14737140.2017.1270208.
doi: 10.1080/14737140.2017.1270208
31 HowardA. Burris, Jeffrey R. Infante, Stephen Maxted Ansell,et al. Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, in patients with advanced solid tumors [J]. JCO, 2017, 35(18): 2028-2036.doi: 10.1200/JCO.2016.70.1508.
doi: 10.1200/JCO.2016.70.1508
32 邱春燕,张火俊. 新兴免疫检查点靶点的研究进展[J]. 中国肿瘤生物治疗杂志, 2018, 25(7):733-736.doi:10.3872/j.issn.1007-385x.2018.07.013.
doi: 10.3872/j.issn.1007-385x.2018.07.013
[1] 刘坤, 张欣欣. 循环肿瘤细胞在头颈部鳞癌中的富集及检测[J]. 山东大学耳鼻喉眼学报, 2019, 33(4): 18-24.
[2] 沈宇杰,张立庆,周涵,赵青,冯剑,宋圣花,董伟达. 颈部脂肪瘤34例临床分析[J]. 山东大学耳鼻喉眼学报, 2019, 33(3): 111-115.
[3] 陈慧君,宋圣花,周涵,董伟达,乔明哲,陈曦,徐进,林子萍,邢光前. 血小板与淋巴细胞比值对喉癌复发的预测价值[J]. 山东大学耳鼻喉眼学报, 2019, 33(3): 106-110.
[4] 胡娟娟, 洪育明. 咽旁间隙肿瘤的诊断和治疗[J]. 山东大学耳鼻喉眼学报, 2014, 28(5): 85-90.
[5] 叶萍,孙睿杰,金童,钱晔,魏东敏,潘新良. Caveolin-1在下咽鳞癌中的表达及其临床意义[J]. 山东大学耳鼻喉眼学报, 2012, 26(5): 22-24.
[6] 甘卫刚1综述, 洪育明2审校. 整合素β1与头颈部肿瘤关系的研究进展[J]. 山东大学耳鼻喉眼学报, 2011, 25(1): 31-34.
[7] 吕佳宝综述,邱连升审校. p27kip1、Skp2与头颈部肿瘤关系的研究进展[J]. 山东大学耳鼻喉眼学报, 2009, 23(5): 17-20.
[8] 黄 方,朱从月 . p21、p73及PTEN在头颈部多原发癌中的表达及意义[J]. 山东大学耳鼻喉眼学报, 2007, 21(5): 388-392 .
[9] 鞠秀婷,夏 明 综述, 解 光 审校 . CD4+CD25+调节性T细胞与头颈部肿瘤局部免疫抑制的关系[J]. 山东大学耳鼻喉眼学报, 2007, 21(2): 177-180 .
[10] 宋西成,张华,张庆泉 . 血循环DNA的检测与头颈部肿瘤的诊断[J]. 山东大学耳鼻喉眼学报, 2006, 20(5): 385-387 .
[11] 朱从月,黄方 . p21、p73和PTEN蛋白表达联合检测在头颈部多原发癌诊断中的价值[J]. 山东大学耳鼻喉眼学报, 2006, 20(4): 352-354 .
[12] 朱从月,杨劲松,黄方 . G1细胞周期调控与头颈部多原发癌的关系[J]. 山东大学耳鼻喉眼学报, 2006, 20(3): 268-271 .
[13] 林海,甄泽年,赵敏,袁友文,杨甫文 . 咽旁间隙肿瘤手术路径探讨(附46例分析)[J]. 山东大学耳鼻喉眼学报, 2006, 20(1): 63-64 .
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
[1] 林彬,王挥戈 . 功能性内镜鼻窦手术后鼻黏膜纤毛转归的研究[J]. 山东大学耳鼻喉眼学报, 2006, 20(6): 481 -487 .
[2] 张晗,黄一飞 . 抗角膜移植排斥的研究进展[J]. 山东大学耳鼻喉眼学报, 2006, 20(1): 84 -87 .
[3] 邓基波,孙奉乾,许安廷 . 大前庭导水管综合征[J]. 山东大学耳鼻喉眼学报, 2006, 20(2): 116 -118 .
[4] 陈文文 . 1例T/NK淋巴瘤17年演进[J]. 山东大学耳鼻喉眼学报, 2006, 20(5): 472 -472 .
[5] 周斌,李滨 . 鼻内窥镜下鼻窦鼻息肉手术75例疗效观察[J]. 山东大学耳鼻喉眼学报, 2006, 20(1): 24 -26 .
[6] 杨长亮,黄治物,姚行齐,诸勇,孙艺 . 正常气骨导听性脑干反应及其应用[J]. 山东大学耳鼻喉眼学报, 2006, 20(1): 9 -13 .
[7] 曹忠良 . 颌面复合伤155例临床分析[J]. 山东大学耳鼻喉眼学报, 2006, 20(1): 89 -89 .
[8] 牛善利,柴茂文,李振秀 . 鼻内镜下鼻甲成形术治疗慢性肥厚性鼻炎60例[J]. 山东大学耳鼻喉眼学报, 2006, 20(1): 16 -18 .
[9] 毕景云 . 鼻中隔矫正术后血肿的处理[J]. 山东大学耳鼻喉眼学报, 2006, 20(1): 90 -91 .
[10] 刘大昱,潘新良,雷大鹏,许风雷,张立强,栾信庸 . 梨状窝内侧壁癌的手术治疗[J]. 山东大学耳鼻喉眼学报, 2007, 21(1): 8 -11 .