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

Abstract

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

CLC Number:

R739

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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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

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

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