Combining anti-PD-1 antibodies with surufatinib for gastrointestinal neuroendocrine carcinoma: Two cases report and review of literature

Table 1 Classification and grading criteria for neuroendocrine neoplasms of the gastrointestinal tract and hepatopancreatobiliary organs

Terminology	Differentiation	Grade	Mitotic rate (mitoses/2 mm2)	Ki-67 index
NET, G1	Well differentiated	Low	< 2	< 3%
NET, G2		Intermediate	2-20	3%-20%
NET, G3		High	> 20	> 20%
NEC, small-cell type (SCNEC)	Poorly differentiated	High	> 20	> 20%
NEC, large-cel type (LCNEC)			> 20	> 20%
MiNEN	Well or poorly differentiated	Variable	Variable	Variable

NET: Neuroendocrine tumor.

Table 2 Clinical trials in gastroenteropancreatic neuroendocrine tumors using immune checkpoint inhibitors

No.	Trial name/NCT number	Phase	Interventions	Population characteristics	ORR (%)1	mPFS (month)	mOS (month)
1	KEYNOTE-028 NCT02054806[13]	Ib	Pemprolizumab	Cohort A7: 16 patients with PD-L1-negative, well or moderately differentiated pancreatic NETs	6.3%	4.5	37.8
				Cohort A6: 25 patients with PD-L1-positive, locally advanced or metastatic carcinoids (lung, gut, and other locations)	12%	5.5	16.2
2	KEYNOTE-158 NCT02628067[14]	II	Pemprolizumab	107 patients with heavily pretreated, well-differentiated, progressive NETs	3.7% (7.5% in pancreatic NET subgroup)	4.1	24.2
3	NCT02939651[15]	II	Pemprolizumab	29 patients with advanced G3 NETs/NECs (48% patients had GI primaries) progressing on platinum-based chemotherapy	3.4% (1 patient)	8.86	20.43
4	PLANET NCT03043664[16]	Ib/II	Pemprolizumab + Lanreotide Depot	22 patients with nonresectable, recurrent or metastatic, well or moderately differentiated GEP-NETs	0.045% (39% stable disease, 52% progressive disease)	5.04	28.6
5	NCT03136055[17]	II	Pembrolizumab/Pembrolizumab + Chemotherapy (Irinotecan/ Paclitaxel)	36 patients with extrapulmonary poorly differentiated neuroendocrine carcinomas (28% in Pem-only and 73% in Pem + chemo)	7%; 5%	1.8; 2	7.8; 4.8
6	NCT02955069[18]	II	Spartalizumab	32 patients with well-differentiated GI NETs, 33 patients with pancreatic NETs, 21 patients with poorly-differentiated GEP-NECs	3.1%, 3.0%, and 4.8%, respectively	3.8 in well-differentiated NETs; 1.8 in NECs	23.4 in well-differentiated NETs; 6.8 in NECs
7	DART SWOG 1609 NCT02834013[19]	II	Ipilimumab + Nivolumab	32 patients, of whom 15 with GI-NENs and 6 with lung-NENs	Overall: 25%; 44% in nonpancreatic high-grade NEC and 0% in low-intermediate grade tumors	4	11
8	CA209-538 NCT02923934[20]	II	Ipilimumab + Nivolumab	29 patients with advanced, any grade NENs (including atypical bronchial carcinoid and high-grade pan-NENs)	43% of patients with pan-NENs achieved an objective response	4.8 (in whole cohort)	14.8 (in whole cohort)
9	NCT03074513[21]	II	Atezolizumab + Bevacizumab	40 patients with advanced, progressive grade 1 to 2 NETs (20 with pancreatic NETs and 20 with extra-pancreatic NETs)	20% in the pancreatic NET cohort; 15% in the extra-pancreatic NET cohort	19.6 and 14.9, respectively	-
10	DUNE NCT03095274[22]	I	Durvalumab + Tremelimumab	123 patients with advanced or metastatic GEP/Lung NENs or NENs of unknown primary	11.1% in lung NENs (cohort 1), 0% in G1-2 GI NETs (cohort 2), 6.3% in G1-2 pancreatic NETs (cohort 3), 9.1% in G3 GEP-NENs (cohort 4)	5.6, 5.8, 5.5 and 2.4, respectively	Not reached, 29.5, 23.8, 5.9, respectively
11	NCT03167853[23]	Ib	Toripalimab	40 patients with NENs (of whom 9 with pan-NENs)	13.0% in GI NENs, 22.2% in pan-NENs, 37.5% in nondigestive NENs	15.4 (for TMB-high subgroup), 2.1 (for TMB-low subgroup)	Not reached (for TMB-high subgroup), 227 (for TMB-low subgroup)
12	NET-001/NET-002 NCT03278405 NCT03278379[24]	II	Avelumab	27 patients with GEP NENs or from bronchial primary, (10 G2-3 NETs in NET-001, 17 NECs in NET-002)	0% (33% stable disease)	3.3	14.2
13	AVENEC NCT03352934[25]	II	Avelumab	60 patients with G3 NET (n = 22) or NEC (n = 38) of any origin	20% (9 stable disease, 3 partial response)	2.1	4.2
14	CABOAVENEC NCT05289856[25]	II	Avelumab + Cabozantinib	19 patients (12 with G3 NET, 7 with NEC)	47.4%	12.1	-

¹The objective response rate of some trials were assessed by irRECIST criteria.

NEC: Neuroendocrine carcinoma; NET: Neuroendocrine tumor; ORR: Objective response rate; mPFS: Median progression-free survival; OS: Overall survival.