Emerging developments in immune checkpoint inhibitor therapy for gastroenteropancreatic neuroendocrine neoplasm

Abstract

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

CLC Number:

R735

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.

Figures/Tables5

Tab 1

Summary of recent high-quality clinical trials of ICI in GEP-NEN treatment

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

Tab 1

Fig 1

Fig 2

Fig 3

Tab 2

Survival outcomes from recent clinical trials of ICI in the treatment of gastroenteropancreatic neuroendocrine tumors

Author	Year	Country	Study type	Number of cases	ICI	Median OS (months)	Median PFS (months)
Yao et al.^{[ 11 ]}	2021	Global	Phase Ⅱ clinical trial	116	Spartalizumab (PDR001)	Not reached (NET), 6.8 (GEP-NEC)	3.8 (NET), 1.8 (GEP-NEC)
Patel et al.^{[ 7 ]}	2021	USA	Phase Ⅱ clinical trial	19	Ipilimumab + nivolumab	8.9	2.0
Patel et al.^{[ 6 ]}	2020	USA	Phase Ⅱ clinical trial	32	Ipilimumab + nivolumab	11.0	4.0
Strosberg et al.^{[ 5 ]}	2020	Global	Phase Ⅱ clinical trial	107	Pembrolizumab	24.2	4.1
Klein et al.^{[ 9 ]}	2020	Australia	Phase Ⅱ clinical trial	29	Ipilimumab + nivolumab	14.78	4.82
Lu et al.^{[ 8 ]}	2020	China	Phase Ⅰb clinical trial	40	Toripalimab (JS 001)	9.1 (PD-L1≥10%), 7.2 (PD-L1<10%)	3.8 (PD-L1≥10%), 2.2 (PD-L1<10%)
Mehnert et al.^{[ 10 ]}	2020	Global	Phase Ⅰb clinical trial	41	Pembrolizumab	21.0 (pNET)	4.5 (pNET)
Vijayvergia et al.^{[ 4 ]}	2020	USA	Phase Ⅱ clinical trial	29	Pembrolizumab	5.1	2.2

Tab 2

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