免疫检查点抑制剂治疗胃肠胰神经内分泌肿瘤的进展

doi:10.16139/j.1007-9610.2023.03.015

摘要/Abstract

摘要：

靶向免疫检查点的免疫治疗发展迅速，近年来在胃肠胰神经内分泌肿瘤（gastroenteropancreatic neuroendocrine neoplasm, GEP-NEN）中初步探索，但能否带来临床获益尚无定论。本文系统梳理免疫检查点抑制剂（immune checkpoint inhibitor，ICI）单药或双药联合治疗GEP-NEN的临床试验现状及疗效。结果表明，ICI在GEP-NEN中仍未取得突破性进展，治疗复发或转移性GEP-NEN有一定的抗肿瘤活性和安全性，但总体客观缓解率（objective response rate，ORR）较低。ORR与肿瘤分化程度呈负相关，分化差的胃肠胰神经内分泌癌可能更易获得临床缓解。双药与单药相比，疾病控制率更高，但不良反应更严重。鉴于错配修复基因缺陷和微卫星高度不稳定极为罕见，肿瘤突变负荷高（≥10 muts/Mb）的病人能从ICI免疫治疗中改善生存。未来期望进一步探索ICI与化疗、放疗、抗血管生成药物等在GEP-NEN的联合应用，有可能提高其抗肿瘤疗效，起到“1+1>2”的效果。临床应根据病理分化分级、免疫标志物、病情进展程度、病人身体状态等综合评估ICI免疫治疗的获益人群。

关键词: 免疫检查点抑制剂, 胃肠胰神经内分泌肿瘤, 免疫治疗, 临床获益

Abstract:

Immunotherapies targeting immune checkpoints have undergone rapid evolution, and have been preliminary explored in treatment of gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) in recent years. However, their potential to deliver tangible clinical benefits remains uncertain. In this article, we systematically reviewed the current status and efficacy of clinical trials, which evaluated immune checkpoint inhibitor (ICI) as monotherapy or in dual-ICI therapy for GEP-NEN. Despite lacking substantial breakthroughs in GEP-NEN treatment, ICI demonstrated some antitumor activity and safety in treating recurrent or metastatic GEP-NEN, albeit with a generally low objective response rate (ORR). The ORR of ICI in GEP-NEN treatment exhibited a negative correlation with tumor differentiation, suggesting that poorly diffe-rentiated gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) might achieve better clinical responses. Disease control rate of dual-ICI therapy was higher than that of monotherapy. However, dual-ICI also got more severe side effects. Given the rarity of mismatch repair gene defects and high microsatellite instability (dMMR/MSI-H) in GEP-NEN, patients with high tumor mutational burden (TMB-H≥10 muts/Mb) could get potentially benefit from ICI therapy. In the future, it is expected to further explore the synergistic combined application of ICI with chemotherapy, radiotherapy, and antiangiogenic drugs in GEP-NEN, which may enhance its antitumor efficacy. Clinically, the benefit groups of ICI immunotherapy should be evaluated comprehensively according to pathological grading, immune markers, disease progression, and patient's physical condition.

Key words: Immune checkpoint inhibitor, Gastroenteropancreatic neuroendocrine neoplasm, Immunotherapy, Clinical benefit

中图分类号:

R735

韩序, 王文权, 楼文晖, 刘亮. 免疫检查点抑制剂治疗胃肠胰神经内分泌肿瘤的进展[J]. 外科理论与实践, 2023, 28(03): 267-272.

HAN Xu, WANG Wenquan, LOU Wenhui, LIU Liang. Emerging developments in immune checkpoint inhibitor therapy for gastroenteropancreatic neuroendocrine neoplasm[J]. Journal of Surgery Concepts & Practice, 2023, 28(03): 267-272.

图/表 5

表1

近期ICI治疗GEP-NEN的高质量临床试验汇总

Author(s)	Year	Country	Study type	Participants	Primary NET site	GEP-NET cases (%)	Differentiation	Prior Systemic treatment (%)	Prior systemic treatment protocol	Enrollment disease status	ICI	Target	Follow-up (months)
Yao et al.^[11]	2021	Global	Phase Ⅱ clinical trial	116	Lung, thymus, pancreas, gastrointestinal tract, gallbladder, unknown	86 (74.1%)	Well-differentiated (n=95), Poorly differentiated (n=21)	100%	Long-acting growth inhibitors (29.3%)	Progression after prior systemic treatment, distant metastases	Spartalizumab (PDR001)	PD-1 (CD279)	Median value 13.4
Patel et al.^[7]	2021	USA	Phase Ⅱ clinical trial	19	Nasopharynx, esophagus, gastrointestinal tract, cervix, vulva, unknown	8 (42.1%)	Moderate to well-differentiated (n=2), Poorly differentiated (n=11), Unknown (n=6)	100%	Not reported	Progression after prior systemic treatment, no available options, Ki-67 all >20%	Ipilimumab + nivolumab	CTLA-4 +PD-1	Until 31.0
Patel et al.^[6]	2020	USA	Phase Ⅱ clinical trial	32	Lung, thymus, gastrointestinal tract, cervix, prostate, unknown	15 (46.9%)	Moderate to well-differentiated (n=8), Poorly differentiated (n=4)	100%	Sunitinib (7%)	Progression after prior systemic treatment, no available options	Ipilimumab + nivolumab	CTLA-4 +PD-1	Until 15.0
Strosberg et al.^[5]	2020	Global	Phase Ⅱ clinical trial	107	Lung, pancreas, gastrointestinal tract, liver, ovaries, unknown	83 (77.6%)	All well-diffe-rentiated	97.2%	Chemotherapy (65.9%)	Majority with distant metastases (106/107), progression after prior systemic treatment	Pembrolizumab	PD-1	Median value 24.2
Klein et al.^[9]	2020	Australia	Phase Ⅱ clinical trial	29	Lung, thymus, gastrointestinal tract, prostate, unknown	10 (34.5%)	Moderate to well-differentiated (n=26), poorly differentiated (n=3)	89.7%	Chemotherapy (86% EP or CAPTEM protocol)	Local advanced stage or distant metastases	Ipilimumab + nivolumab	CTLA-4 +PD-1	Until 26.0
Lu et al.^[8]	2020	China	Phase Ⅰb clinical trial	40	Pancreas, gastrointestinal tract, others	32 (80.0%)	Well-differentiated (n=8), poorly-differentiated (n=32)	100%	PRRT (21%)	Metastasis, disease progression after prior systemic treatment, Ki-67 >20%	Toripalimab (JS 001)	PD-1	Until 24.0
Mehnert et al.^[10]	2020	Global	Phase Ⅰb clinical trial	41	Lung, pancreas, gastrointestinal tract, others	16 (39.0%)	All well-diffe-rentiated	70.7%	Everolimus (7%)	Local advanced stage or distant metastases, progression after prior systemic treatment	Pembrolizumab	PD-1	Until 24.0
Vijayvergia et al.^[4]	2020	USA	Phase II clinical trial	29	Thymus, pancreas, gastrointestinal tract, kidney	24 (82.8%)	G3	100%	Everolimus (31.7%)	Local advanced stage or distant metastases, progression after prior systemic treatment, G3	Pembrolizumab	PD-1	Until 36.0

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参考文献 18

[1]	POLEÉ I N, HERMANS B C M, VAN DER ZWAN J M, et al. Long-term survival in patients with gastroenteropancreatic neuroendocrine neoplasms: a population-based study[J]. Eur J Cancer, 2022, 172:252-263. doi: 10.1016/j.ejca.2022.06.003 URL
[2]	OTT P A, ELEZ E, HIRET S, et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ⅰb KEYNOTE-028 study[J]. J Clin Oncol, 2017, 35(34):3823-3829. doi: 10.1200/JCO.2017.72.5069 URL
[3]	WEBER M M, FOTTNER C. Immune checkpoint inhibitors in the treatment of patients with neuroendocrine neoplasia[J]. Oncol Res Treat, 2018, 41(5):306-312. doi: 10.1159/000488996 URL
[4]	VIJAYVERGIA N, DASARI A, DENG M, et al. Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials[J]. Br J Cancer, 2020, 122(9):1309-1314. doi: 10.1038/s41416-020-0775-0
[5]	STROSBERG J, MIZUNO N, DOI T, et al. Efficacy and safety of pembrolizumab in previously treated advanced neuroendocrine tumors: results from the phase Ⅱ KEYNOTE-158 study[J]. Clin Cancer Res,2020,26(9):2124-2130.
[6]	PATEL S P, OTHUS M, CHAE Y K, et al. A phase Ⅱ basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART SWOG 1609) in patients with nonpancreatic neuroendocrine tumors[J]. Clin Cancer Res, 2020, 26(10):2290-2296. doi: 10.1158/1078-0432.CCR-19-3356 URL
[7]	PATEL S P, MAYERSON E, CHAE Y K, et al. A phase Ⅱ basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: high-grade neuroendocrine neoplasm cohort[J]. Cancer, 2021, 127(17):3194-3201. doi: 10.1002/cncr.v127.17 URL
[8]	LU M, ZHANG P, ZHANG Y, et al. Efficacy, safety, and biomarkers of toripalimab in patients with recurrent or metastatic neuroendocrine neoplasms: a multiple-center phase Ⅰb trial[J]. Clin Cancer Res, 2020, 26(10):2337-2345. doi: 10.1158/1078-0432.CCR-19-4000 URL
[9]	KLEIN O, KEE D, MARKMAN B, et al. Immunotherapy of ipilimumab and nivolumab in patients with advanced neuroendocrine tumors: a subgroup analysis of the CA209-538 clinical trial for rare cancers[J]. Clin Cancer Res, 2020, 26(17):4454-4459. doi: 10.1158/1078-0432.CCR-20-0621 URL
[10]	MEHNERT J M, BERGSLAND E, O'NEIL B H, et al. Pembrolizumab for the treatment of programmed death-ligand 1-positive advanced carcinoid or pancreatic neuroendocrine tumors: results from the KEYNOTE-028 study[J]. Cancer, 2020, 126(13):3021-3030. doi: 10.1002/cncr.32883 URL
[11]	YAO J C, STROSBERG J, FAZIO N, et al. Spartalizumab in metastatic, well/poorly-differentiated neuroendocrine neoplasms[J]. Endocr Relat Cancer, 2021:ERC-20-0382.R1.
[12]	BÖSCH F, BRÜWER K, ALTENDORF-HOFMANN A, et al. Immune checkpoint markers in gastroenteropancreatic neuroendocrine neoplasia[J]. Endocr Relat Cancer, 2019, 26(3):293-301. doi: 10.1530/ERC-18-0494 URL
[13]	O'DONNELL J S, TENG M W L, SMYTH M J. Cancer immunoediting and resistance to T cell-based immunotherapy[J]. Nat Rev Clin Oncol, 2019, 16(3):151-167. doi: 10.1038/s41571-018-0142-8
[14]	楼文晖, 韩序. 胃肠胰神经内分泌肿瘤新辅助治疗及转化治疗的策略[J]. 中华消化外科杂志, 2022, 21(4):465-469.
	LOU W H, HAN X. Strategies of neoadjuvant and conversion therapy for gastroenteropancreatic neuroendocrine neoplasms[J]. Chin J Dig Surg, 2022, 21(4):465-469.
[15]	OVCINNIKOVS V, ROSS E M, PETERSONE L, et al. CTLA-4-mediated transendocytosis of costimulatory molecules primarily targets migratory dendritic cells[J]. Sci Immunol, 2019, 4(35):eaaw0902. doi: 10.1126/sciimmunol.aaw0902 URL
[16]	TEKGUC M, WING J B, OSAKI M, et al. Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells[J]. Proc Natl Acad Sci U S A, 2021, 118(30):e2023739118.
[17]	ARNASON T, SAPP H L, RAYSON D, et al. Loss of expression of DNA mismatch repair proteins is rare in pancreatic and small intestinal neuroendocrine tumors[J]. Arch Pathol Lab Med, 2011, 135(12):1539-1544. doi: 10.5858/arpa.2010-0560-OA URL
[18]	YOUNG K, LAWLOR R T, RAGULAN C, et al. Immune landscape, evolution, hypoxia-mediated viral mimicry pathways and therapeutic potential in molecular subtypes of pancreatic neuroendocrine tumours[J]. Gut, 2021, 70(10):1904-1913. doi: 10.1136/gutjnl-2020-321016 URL