免疫检查点抑制剂在复发或转移性头颈鳞癌的治疗进展

doi:10.6040/j.issn.1673-3770.1.2019.001

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

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

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

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/Abstract

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

陈曦,乔明哲. 免疫检查点抑制剂在复发或转移性头颈鳞癌的治疗进展[J]. 山东大学耳鼻喉眼学报, 2019, 33(3): 42-48.

Xi CHEN,Mingzhe QIAO. Progress of immune checkpoint inhibitors in the treatment of recurrent or metastatic head and neck squamous cell carcinoma[J]. Journal of Otolaryngology and Ophthalmology of Shandong University, 2019, 33(3): 42-48.

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参考文献 32

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

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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 141	III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-012	Ib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-EXP	Exp. 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-055	II期	171	铂类联合西妥昔治疗失败的复发或转移性HNSCC	pembrolizumab 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)

试验	n	不良事件	任何级别不良事件	3~4级不良事件
CheckMate 141	361	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-012	60	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 EXP	132	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-055	171	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

试验	PD-L1阈值	样本量	客观缓解率	PFS	OS
CheckMate 141	PD-L1≥1% PD-L1<1%	88 (54%) 73 (46%)	NA	NA	+
KEYTEN-012	PD-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	+	+	+

试验	HPV状态	样本量	客观缓解率	PFS	OS
CheckMate 141	HPV 阳性 HPV 阴性	63 (26.2%) 50 (20.8%)	N/A	N/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	-	-	-

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;PFS	NCT02741570
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pembrolizumab	I/II期	? ORR	NCT02718820
招募中	? 乐伐替尼联合pembrolizumab	I/II期	? MTD; DLT;ORR	NCT02501096
招募中	? pembrolizumab联合放疗	II期	? ORR	NCT03386357
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;OS	NCT03620123

免疫检查点抑制剂在复发或转移性头颈鳞癌的治疗进展

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

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