Journal of Otolaryngology and Ophthalmology of Shandong University ›› 2019, Vol. 33 ›› Issue (3): 42-48.doi: 10.6040/j.issn.1673-3770.1.2019.001

• Research Progress • Previous Articles     Next Articles

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

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

Table 1

Clinical effects of nivolumab and pembrolizumab in head and neck neoplasms"

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)

Table 2

Clinical adverse reactions of nivolumab and pembrolizumab in head and neck neoplasms"

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

Table 3

Biomarker of PDL1 of nivolumab and pembrolizumab in head and neck neoplasms"

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+++

Table 4

Biomarker of HPV of nivolumab and pembrolizumab in head and neck neoplasms"

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---

Table 5

Joint application of HPV of nivolumab and pembrolizumab in head and neck neoplasms"

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
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