Immunotherapies for well-differentiated grade 3 gastroenteropancreatic neuroendocrine tumors: A new category in the World Health Organization classification

Table 1 Clinical trials related to gastroenteropancreatic neuroendocrine tumors

ClinicalTrials.gov identifier	Intervention	Study phase	Trial name	Primary outcome	Estimated/actual enrollment, n	Estimated/actual date	Trial status	Medical condition related to advanced NENs	Reported assessable n of NENs
NCT02054806[21]	Pembrolizumab	Ib	Phase Ib study of pembrolizumab (MK-3475) in subjects with select advanced solid tumors (MK-3475-028/KEYNOTE-028)	ORR	477	April 30, 2021	Completed	pNETs: PD-L1 (+), well or moderately differentiated	16 pNETs
NCT02628067[22]	Pembrolizumab	II	A clinical trial of pembrolizumab (MK-3475) evaluating predictive biomarkers in subjects with advanced solid tumors (KEYNOTE-158)	ORR	1595	June 18, 2026	Recruiting	NETs: Well or moderately differentiated	107 NETs: Lung, appendix, small intestine, colon, rectum, or pan origin
NCT02939651[23]	Pembrolizumab	II	A phase 2, open-label study of pembrolizumab monotherapy in patients with metastatic high grade neuroendocrine tumors	ORR	21	March 2020	Completed	G3 NENs: Ki-67 > 20%, poorly or well-differentiated, failed for platinum based chemotherapy, excluding MCC, large/small cell NENs of lung/thymus origin	29 G3 NENs: 19 NECs, 9 G3 NET, 14 Ki-67 ≤ 50%, 12 Ki-67 > 50%, 10 pan, 14 GI, 5 unknown origin
NCT03136055[24,48]	Part A: pembrolizumab alone; Part B: Pembrolizumab + chemotherapy	II	A pilot study of pembrolizumab-based therapy in previously treated high grade neuroendocrine carcinomas	ORR	36	May 31, 2023	Active, not recruiting	EP-PDNECs: Failed for first-line systemic therapy, excluding MCC or well differentiated G3 NET	Part A: 13 EP-PDNECs; Part B: 22 EP-PDNEC
NCT03190213	Pembrolizumab	II	Pembrolizumab for the treatment of recurrent high grade neuroendocrine carcinoma (Pembro NEC)	ORR (irRECIST)	6	March 11, 2019	Terminated	G3 NENs: Failed for platinum-based regimen or temozolomide-based regimen. exluding lung origin	6 G3 NENs
NCT02955069[25]	Spartalizumab	II	An open label phase II study to evaluate the efficacy and safety of PDR001 in patients with advanced or metastatic, well-differentiated, non-functional neuroendocrine tumors of pancreatic, gastrointestinal (GI), or thoracic origin or poorly-differentiated gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC), that have progressed on prior treatment	ORR	116	May 13, 2020	Completed	NENs: Exclude G3 NETs and include G1/2 NET (non-functional, GEP or thoracic origin, failed to prior treatment) and GEP-NEC (progressed on or after one prior chemotherapy regimen)	99 NETs: 30 thoracic, 32 GI-NET, 33 pNET; 21 GEP-NEC
NCT03167853[30]	Toripalimab	Ib	Phase Ib study of safety and efficacy of recombinant humanized anti-PD-1 monoclonal antibody for patients with advanced neuroendocrine tumors following failure of first-line	ORR	40	May 11, 2019	Completed	NENs: Ki-67 ≥ 10%, nonfunctional NENs, well- or poorly-differentiated, failed for first line therapy	40 NENs: 8 well-differentiated, 32 poorly-differentiated
NCT03352934[26]	Avelumab	II	A phase II, open-label, multicenter trial to investigate the clinical activity and safety of avelumab in patients with advanced, metastatic high grade neuroendocrine carcinomas NEC G3 (WHO 2010) progressive after chemotherapy (AveNEC)	DCR	60	January 2024	Active, not recruiting	G3 NENs: after first-line chemotherapy, excluding MCC, SCLC	29 G3 NENs: 16 NEC and 11 G3 NETs, 12 pan, 5 GI, 9 other origin)
NCT03278405[58]	Avelumab	IIa	A pilot study of avelumab in unresectable/metastatic, progressive, poorly differentiated grade 3 neuroendocrine carcinomas (NET001)	ORR	10	March 12, 2020	Completed	NECs: Poorly-differentiated, GI or lung origin, have received 0-2 prior lines of systemic therapy, excluding MANEC	10 NECs: 9 GI and 1 lung
NCT03278379[28]	Avelumab	II	A phase II study of avelumab in unresectable/metastatic, progressive grade 2-3 neuroendocrine tumors (NET-002)	ORR	17	September 20, 2021	Active, not recruiting	G2-3 NETs: GEP or lung, received 0-2 prior lines of therapy (excluding SSAs), excluding G1 NET, NEC and MANEC	17 G2-3 NETs (12 GEP, 5 lung)
NCT03147404	Avelumab	II	Phase II study of avelumab in metastatic gastronetro-pancreatic (GEP) neuroendocrine carcinoma (NEC, WHO Grade 3) as second-line treatment after failing to etoposide + cisplatin: integration of genomic analysis to identify predictive molecular subtypes (MS100070-0177)	Best response	14	July 22, 2019	Completed	G3 GEP-NECs: Second-line treatment after failing to etoposide + cisplatin	-
NCT03879057[39]	Toripalimab + surufatinib	I	Phase I trial evaluating the safety, tolerability, pharmacokinetics, and efficacy of surufatinib combined with JS001 in patients with advanced solid tumors	AEs, MTD	24	December 20, 2021	Recruiting	NENs: G1-3 NET, NEC	18 NENs:11 NECs,4 G2 NETs; 4 G3 NETs, 12 GI,4 pan, 1 lung
NCT04169672[40]	Toripalimab + surufatinib	II	A phase II, open-label, single-arm, multi-center study of the efficacy and safety of surufatinib combined with toripalimab in patients with advanced solid tumors	AEs, ORR	200	February 28, 2022	Recruiting	NECs: Refractory to first-line chemotherapy	20 NECs
NCT03475953	Avelumab + regorafenib	I/II	A phase I/II study of regorafenib plus avelumab in solid tumors (REGOMUNE)	Phase I: Recommended dose of regorafenib; Phase II: ORR, PFS	482	May 2022	Recruiting	G2/3 GEP-NETs	-
NCT03290079	Pembrolizumab + lenvatinib	II	Phase II study of pembrolizumab and lenvatinib in advanced well-differentiated neuroendocrine tumors	ORR	35	December 2023	Recruiting	NETs: Well-differentiated, lung, thymus, small bowel or colon origin, including unknown primary, excluding pNENs and poorly differentiated NECs	-
NCT04579757	Surufatinib + tislelizumab	Ib/II	An open-label phase Ib/II study of surufatinib in combination with tislelizumab in subjects with advanced solid tumors	DLT, ORR	120	April 30, 2023	Recruiting	G1/2 NETs: Thoracic or GEP origins, have progressed on at least one line of standard therapy	-
NCT04207463	AK105 + anlotinib	II	A phase II, open, single-arm, multi-cohort, multicenter study of anlotinib and AK105 (anti-PD-1) injection in subjects with gastrointestinal tumors, urinary system tumors, neuroendocrine tumors	ORR	150	May 30, 2021	Recruiting	G1/2 GEP-NETs	-
NCT03074513[41]	Atezolizumab + bevacizumab	II	A phase II, single-arm open-label study of the combination of atezolizumab and bevacizumab in rare solid tumors	ORR	164	March 31, 2021	Active, not recruiting	G1/2 NETs: pNET cohort and epNET cohort containing typical or atypical carcinoid if originating in lung	20 G1/2 pNETs, 20 G1/2 epNETs
NCT02923934[45]	Nivolumab + ipilimumab	II	A phase II clinical trial evaluating ipilimumab and nivolumab in combination for the treatment of rare gastrointestinal, neuro-endocrine and gynaecological cancers (CA209-538)	CBR	120	December 2023	Active, not recruiting	NENs: G1-3 NETs, NECs, GEP or lung origin	10 GEP-NENs: 7 pNENs (3 G3 pNETs, 2 pNECs, 2 G2 pNETs); 3 GI-NENs (1 gastro-oesophageal junction NEC, 1 colonic NECs, 1 G1 gastric NET)
NCT02834013[15,46]	Nivolumab + ipilimumab	II	A prospective, open-label, multicenter phase II basket clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts (DART)	ORR	818	August 1, 2021	Recruiting	SWOG 1609 cohort: Refractory epNENs. G3 NETs were included in G3 NECs. SWOG S1609 cohort: Dedicated cohort include G3 NENs	SWOG 1609 cohort: 32 epNENs (18 G3, 10 G2, 4 G1, 15 GI, 6 Lung). S1609 cohort: 19 G3 NENs (2 G3 NETs, 11 NEC, 6 unknown differentiation status)
NCT04969887	Nivolumab + ipilimumab	II	Ipilimumab and nivolumab combination therapy in patients with selected immunotherapy sensitive advanced rare cancers (MOST-CIRCUIT)	CBR	240	December 2024	Not yet recruiting	NECs and G3 NETs independent of primary site, excluding SCLC	-
NCT03591731	Nivolumab alone or nivolumab + ipilimumab	II	A GCO trial exploring the efficacy and safety of nivolumab monotherapy or nivolumab plus ipilimumab in pre-treated patients with advanced, refractory pulmonary or gastroenteropancreatic poorly differentiated neuroendocrine tumors (NECs) (NIPINEC)	ORR	180	September 2023	Recruiting	NECs: Poorly differentiated, refractory, pulmonary or GEP, excluding SCLC	-
NCT03095274[47]	Tremelimumab + durvalumab	II	A phase II study of durvalumab (MEDI4736) plus tremelimumab for the treatment of patients with advanced neuroendocrine neoplasms of gastroenteropancreatic or lung origin (DUNE) (GETNE 1601)	Cohort 1-3: CBR at 9 m; Cohort 4: OS at 9 mo	126	July 2021	Recruiting	G1/G2 NETs of GEP and lung, and G3 of GEP or unknown primary site (excluding lung primaries) after progression to standard therapies	123 NENs (Cohort 1: 27 typical/atypical lung carcinoid; Cohort 2: 31 G1/2 GI-NENs; Cohort 3: 32 G1/2 pNENs; Cohort 4: 33 G3 NEN of GEP or unknown primary site)
NCT04079712	Nivolumab + ipilimumab + cabozantinib	II	A phase 2 study of XL184 (Cabozantinib) in combination with nivolumab and ipilimumab for the treatment of poorly differentiated neuroendocrine carcinomas	ORR	30	October 1, 2021	Recruiting	NECs: All variations of poorly differentiated NECs (small cell, large cell and mixed cells) are eligible, excluding SCLC and MCC. Failure of only one line of prior systemic cancer treatment	-
NCT03728361[49]	Nivolumab + temozolomide	II	A phase II, multi-cohort trial of combination nivolumab and temozolomide in recurrent/refractory small-cell lung cancer and advanced neuroendocrine tumors	ORR	55	December 31, 2021	Active, not recruiting	NENs: Any grade or primary site	12 NENs: 1 G1, 8 G2, 3 G3
NCT03980925	Nivolumab + platinum-doublet chemotherapy	II	A phase II study of platinum-doublet chemotherapy in combination with nivolumab as first-line treatment in subjects with unresectable, locally advanced or metastatic G3 neuroendocrine neoplasms (NENs) of the gastroenteropancreatic (GEP) tract or of unknown (UK) origin (GETNE-T1913)	OS at 12 mo	38	December 2022	Recruiting	G3 NENs: GEP or unknown primary site	-
NCT03365791[59]	Spartalizumab + LAG525	II	Modular phase 2 study to link combination immune-therapy to patients with advanced solid and hematologic malignancies. Module 9: PDR001 plus LAG525 for patients with advanced solid and hematologic malignancies	CBR at 24 wk	76	September 17, 2020	Completed	NETs: Well-differentiated, relapsed and/or refractory to available standard of care therapies	7 NETs
NCT03043664[60]	Pembrolizumab + lanreotide depot	Ib/II	Phase Ib/II study of pembrolizumab with lanreotide depot for gastroenteropancreatic neuroendocrine tumors (PLANET)	ORR	22	September 1, 2021	Active, not recruiting	G1-2 GEP-NETs: Had progressed on a prior SSA	22 G1/2 GEP-NETs (14 GI, 8 pan)
NCT04525638	Nivolumab + 177Lu-DOTATATE	II	A phase II single arm trial evaluating the preliminary efficacy of the combination of 177Lu-DOTATATE and nivolumab in grade 3 well-differentiated neuroendocrine tumours (NET) or poorly differentiated neuroendocrine carcinomas (NEC)	ORR	30	September 30, 2024	Recruiting	G3 NENs: GEP or unknown primary site, well-differentiated or poorly-differentiated.	-
NCT04701307	Dostarlimab + niraparib	II	Niraparib (PARP Inhibitor) plus dostarlimab (Anti-PD1) for small cell lung cancer (SCLC) and other high-grade neuroendocrine carcinomas (NEC)	6 mo PFS, 3 mo ORR	48	May 30, 2025	Recruiting	G3 NECs: SCLC (Cohort 1) and other G3 NECs (Cohort 2), had at least one prior line of systemic therapy, excluding prostate origin	-
NCT03457948	Group I: Pembrolizumab + 177Lu DOTATATE; Group II: Pembrolizumab + TAE; Group III: Pembrolizumab + 90Yttrium- Microsphere Radioembolization	II	A pilot study of pembrolizumab and liver-directed therapy or peptide receptor radionuclide therapy for patients with well-differentiated neuroendocrine tumors and symptomatic and/or progressive metastases	ORR	32	March 31, 2024	Recruiting	G1-3 NETs: Well-differentiated, any primary site and unknown primary site, have liver metastases	-
NCT03879694	SVN53-67/M57-KLH peptide vaccine (SurVaxM) +Octreotide	I	A phase I study of safety and immunogenicity of Survivin Long Peptide Vaccine (SurVaxM) in patients with metastatic neuroendocrine tumors (NETs)	AEs	10	June 13, 2024	Recruiting	NETs: GEP or lung origin, positive for survivin	-
NCT04166006	Dendritic cells loaded with autologous tumour (DC vaccine) + IL-2	II	A phase II study on adjuvant vaccination with dendritic cells loaded with autologous tumor homogenate in resected stage iv rare cancers: Head & neck (H & N), neuroendocrine tumors (NET) and soft tissue sarcoma (STS)	Treatment-Emergent AEs	51	December 2026	Recruiting	NET: Stage IV	-

AE: Adverse event; CBR: Clinical benefit rate; DCR: Disease control rate; DLT: Dose-limiting toxicity; EP-PDNECs: Extrapulmonary poorly differentiated neuroendocrine carcinomas; ep: Extra-pancreatic; G1, 2, 3: Grade 1, 2, 3; GEP: Gastroenteropancreatic; GI: Gastrointestinal; irRECIST: Immune-related Response Evaluation Criteria in Solid Tumors; MANEC: Mixed adenoneuroendocrine carcinomas; MCC: Merkel cell carcinoma; MTD: Maximum tolerated dose; NECs: Neuroendocrine carcinomas; NENs: Neuroendocrine neoplasms; NETs: Neuroendocrine tumors; ORR: Objective response rate; OS: Overall survival; p: Pancreatic; pan: Pancreas origin; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; PFS: Progression-free survival; SCLC: Small cell lung cancer; WHO: World Health Organization.