38235757

Society for Endocrinology

Immunotherapy for endocrine tumours: a clinician’s perspective

Anna Angelousi®1, Ploutarchos Tzoulis2, Marina Tsoli3, Eleftherios Chatzellis4, Anna Koumarianou5 and Gregory Kaltsas3

11st Department of Internal Medicine, Unit of Endocrinology, Laikon Hospital, Athens, Greece

2Department of Metabolism & Experimental Therapeutics, Division of Medicine, University College London, London, UK

31st Department of Propaedeutic and Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece 4251 HAF and VA Hospital, Athens, Greece

5Fourth Department of Internal Medicine, Hematology Oncology Unit, Attikon University Hospital, National and Kapodistrian University of Athens, Greece

Correspondence should be addressed to A Angelousi: a.angelousi@gmail.com

Abstract

Immunotherapy has revolutionised the treatment of oncological patients, but its application in various endocrine tumours is rather limited and is mainly used when conventional therapies have failed. Immune checkpoint inhibitors (ICIs) have been employed in progressive adrenocortical carcinoma, primarily utilizing the anti-PD-L1 agent pembrolizumab, obtaining overall response rates ranging between 14% and 23%. In contrast, the response rate in phaeochromocytoma/paraganglioma was substantially less at 9%, considering the small number of patients treated. Similarly, the response rate in advanced differentiated thyroid carcinomas treated with pembrolizumab was also low at 9%, although the combination of ICIs with tyrosine kinase inhibitors showed higher efficacy. Low response rates to ICIs have also been observed in progressive medullary thyroid cancer, except in tumours with a high mutation burden (TMB). Pembrolizumab or spartalizumab can be utilized in patients with high TMB anaplastic thyroid cancer, obtaining better response rates, particularly in patients with high PD-L1 expression. Immunotherapy has also been used in a few cases of parathyroid carcinoma, showing limited antitumour effect. Pituitary carcinomas may exhibit a more favourable response to ICIs compared to aggressive pituitary tumours, particularly corticotroph tumours. Patients with advanced neuroendocrine tumours achieve an overall response rate of 15%, which varies according to the primary tumour site of origin, degree of differentiation, and therapeutic regimen utilised. Future research is needed to evaluate the potential role of immunohistochemical biomarkers, such as programmed death 1/programmed death ligand 1 and TMB, as predictors for the response to immunotherapy. Furthermore, randomised prospective studies could provide more robust data on the efficacy and side effects of ICIs.

Keywords: adrenal tumours; immune check point inhibitors; parathyroid carcinoma; thyroid carcinoma; neuroendocrine neoplasms; pituitary carcinoma; aggressive pituitary tumours; differential thyroid carcinoma; medullary thyroid cancer; anaplastic thyroid carcinoma

Introduction

Immunotherapy represents a promising novel cancer treatment designed to enhance the immune system of oncological patients through immunomodulatory actions (Hodi et al. 2010). Immune checkpoints are small molecules expressed on the surface of T lymphocytes that play vital roles in maintaining immune homeostasis and modulating the duration and amplitude of the immune response against tumour cells (Pardoll 2012). Programmed death-1 (PD-1) functions as a T-cell surface receptor and binds to two ligands, programmed death- ligand 1 and 2 (PD-L1 and PD-L2) (Byun et al. 2017). The binding of PD-1 to PD-L1/PD-L2 negatively regulates T-cell effector functions (Fig. 1). Cytotoxic T-lymphocyte-

associated protein 4 (CTLA-4) is also constitutively expressed on regulatory T-cells and is also induced on conventional T-cells (Byun et al. 2017). CTLA-4 competes with CD28 for binding to CD80 or CD86 on antigen- presenting cells, thereby inhibiting immune activation (Byun et al. 2017) (Fig. 1). Monoclonal antibodies blocking CTLA-4, PD-1 and PD-L1 have demonstrated durable anti- neoplastic effects in many cancer patients (Intlekofer & Thompson 2013).

Since 2011, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved several immune checkpoint inhibitors (ICIs), including the CTLA-4 inhibitor ipilimumab; PD-1 inhibitors such as nivolumab, pembrolizumab and cemiplimab; and PD-L1 inhibitors such as atezolizumab,

Figure 1 Mechanisms of action of immune checkpoint inhibitors (ICIs). A. Mechanisms of action of immune checkpoint inhibitors (ICIs): tumour-associated antigen (Ag) is presented by major histocompatibility complex (MHC) on antigen-presenting cells (APCs) and recognised by the T-cell receptor (TCR) of T cell. Binding B7 on APC cell with the CD28 receptor on T cell is the second signal required for the activation of the T cell and the initiation of the immune response against the tumour cells. CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) is a homologue of CD28 and limits the proliferative response of activated T-cells, competing with CD28 for the ligand B7. This inhibition occurs in response to the binding of B7 on APC with the CTLA-4 receptor on T-cells and interrupts the second signal. Anti-CTLA-4 antibodies block CTLA-4 and restore T-cell activation and proliferation. B. PD-1 is an immune cell-specific surface receptor, and ligands for PD-1 (PD-L1 and PD-L2) are associated proteins that are found on antigen-presenting cells and cancer cells. When bound to a ligand, PD-1 lowers the threshold for apoptosis, induces anergy via blunted T-cell receptor signalling, and generally leads to T-cell depletion. In certain tumour cells, upregulation of PD-L1 expression has been observed, which leads to increased inhibition of T-cell activity in favour of tumour cell survival. A monoclonal antibody against PD-1 can block this pathway (i.e. a PD-1-PD-L1 interaction), and result in upregulation of immune response and inhibition of tumour growth.

A

Cancer cell Antigen

83

B

Cancer cell Antigen

TCR

MHC

MHC

TCR

Cancer cell

APC

B7

CD28

T-cell

T-cell activation

T-cell

T-cell activation

Cancer cell Antigen

Cancer cell Antigen

TCR

MHC

MHC

TCR

T-cell Inhibition

T-cell

Cancer cell

PD-L1

APC

PD-1

B7

CD28

T-cell

PD-1

PD-L1

T-cell Inhibition

CTLA-4

Cancer cell Antigen

Cancer cell Antigen

TCR

MHC

MHC

TCR

T-cell activation

T-cell

PD-1

Cancer cell

PD-L1

APC

B7

CD28

T-cell

T-cell activation

CTLA-4

Anti-CTLA-4 mAbs Ipilimumab Tremelimumab

Anti-PD-1 mAbs Nivolumab Pembrolizumab Cemiplimab Dostarlimab

Anti-PD-L1 mAbs Atezolizumab Avelumab Durvalumab

avelumab and durvalumab. Depending on the tumour type, stage and resectability, ICIs may be used as first-line, second-line or third-line therapy, and even in adjuvant/ neo-adjuvant settings. Their indications are related to various tumour-specific features, including PD-1/PD-L1 expression, microsatellite instability (MSI)/mismatch repair deficiency (MMRd), BRAF proto-oncogene status, tumour mutational burden (TMB) and somatic copy number alteration (Calsina et al. 2023). The expression of PD-L1 and the density and location of cytotoxic CD8 T-lymphocytes (CTLs) within the tumour represent the best predictors for the efficacy of ICI-based monotherapy (Celada et al. 2023). However, favourable response rates may occur even in PD-L1-negative tumours (Cui et al. 2023, Song et al. 2023). This review will focus on the clinical application of ICIs in the treatment of various endocrine tumours, a field where immunotherapy seems to be less well studied and, in some cases, with inferior efficacy compared to other solid tumours such as melanoma, lung cancer or renal cell carcinoma. Our aim is to provide endocrine oncology physicians with an overview of the current status and clinical applications of these agents in a variety of endocrine tumours, particularly when conventional therapies have failed.

Methods

A comprehensive search was conducted in the databases PubMed, EMBASE and COCHRANE Library, spanning up to 3 June 2023, to identify pertinent studies. Following an initial screening of titles and abstracts, we assessed the full texts of potentially eligible studies. Additionally, we manually examined the reference lists of these studies to identify any supplementary relevant publications. The search terms encompassed the following keywords: ‘immunotherapy’, ‘immune checkpoint inhibitors’, ‘adrenocortical carcinoma’, ‘pheochromocytoma’, ‘paraganglioma’, ‘differentiated thyroid cancer’, ‘medullary thyroid cancer’, ‘anaplastic thyroid cancer’, ‘pituitary carcinoma’, ‘parathyroid carcinoma’, ‘neuroendocrine tumours and carcinomas’. These keywords were combined using Boolean operators AND/OR. The literature search was executed independently by three investigators (PT, MT and AA). The selection process for retrieved reports, including the number of records identified, excluded records and the rationale for exclusions, is illustrated in a flow diagram (Supplementary Fig. 1, see the section on supplementary materials given at the end of this article).

Adrenal tumours

Adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is an orphan endocrine malignancy with an incidence of 1/106 cases per year (Else et al. 2014) and a 5-year survival rate of 15% in the

presence of metastases (Gaujoux et al. 2017). Despite the expanding knowledge of molecular pathogenesis, chemotherapy and mitotane still remain the only available therapeutic options for advanced disease (Ribeiro et al. 2001). An objective response rate of 23% was obtained when combining mitotane with cisplatin, etoposide and doxorubicin (EDPM) vs 9% mitotane with streptozotocin (Fassnacht et al. 2012), with a progression- free survival (PFS) of 5 vs 2 months, respectively, without any difference in overall survival (OS) (14 vs 12 months). Thus, alternatively, therapy with ICIs has already been studied in a few clinical trials, and the anti-PD-L1 agent pembrolizumab has been introduced in a consensus statement and the National Comprehensive Cancer Network guidelines for patients with metastatic or progressive ACC on standard treatments (Habra et al. 2019, Naing et al. 2020).

There have been eight prospective, mainly phase II, clinical trials, including 185 patients with metastatic ACC, one retrospective multinational study including 52 patients, and eight case series/reports of 32 patients treated with ICIs (Table 1) (Supplementary Table 1). The majority (n = 175) had metastatic or locally advanced ACC despite previous treatments; 24.8% had cortisol-secreting ACC. In four phase II prospective trials, 22 patients were treated with nivolumab and ipilimumab, 33 with nivolumab and vaccination (E02401), 25 with avelumab, and 25 with avelumab and mitotane (Le Tourneau et al. 2018, Klein et al. 2021, McGregor et al. 2021, Baudin et al. 2022). In the remaining four prospective phase II trials, patients were treated with pembrolizumab (n = 54) (Carneiro et al. 2019, Habra et al. 2019, Naing et al. 2020, Raj et al. 2020) or nivolumab (n = 10) (Carneiro et al. 2019).

Overall, analysing data from prospective studies, patients treated with pembrolizumab monotherapy obtained a partial response (PR) or stable disease (SD) ranging between 14% and 23% and 18% and 50%, respectively (Habra et al. 2019, Naing et al. 2020, Raj et al. 2020) (Table 1). More specifically, in a phase II study of 16 progressive ACC patients treated with pembrolizumab, the response rate in 14 patients at 27 weeks was 35%. In particular, 2 out of 14 patients had PR (including one with cortisol- secreting ACC), 7 had SD (including three with cortisol- producing ACC) and 5 patients had PD, exhibiting an overall response rate (ORR) of 14% (Habra et al. 2019). In another phase II study of 39 patients treated with pembrolizumab, the ORR was 23%, whereas the median PFS and OS were 2.1 and 24.9 months, respectively, during a median follow-up of 17.8 months (Raj et al. 2020). In a phase II study including 15 patients with progressive ACC who had received at least one dose of pembrolizumab, the response rate at 27 weeks was 31%, demonstrating an ORR of 15% (Naing et al. 2020)

Monotherapy with nivolumab was evaluated in only a single-arm, phase II study, including ten patients with progressive ACC receiving a limited number of doses (Table 1) (Carneiro et al. 2019). One patient had PR,

Table 1 Data from clinical trials about the role of immunotherapy in adrenocortical carcinoma (ACC) and future studies.

Reference	Study (n), age in years median (range)	Previous treatment	Type of ICIs, n	ACC (histological type, stage/functionality)	PD-1, PD-L1, MSI and TMB expression	Response	Grade 3-4 AEs
Clinical trials	Retrospective		Pembrolizumab n = 32,
Remde et al.		n = 54 on mitotane		Metastatic ACC,	- n = 1/18 with	- n = 7/54(13.5%) had PR.	n = 2 colitis
(2023)	(n = 54), 46	± chemotherapy	nivolumab n = 13,	Weiss (median,	PD-1	n = 7/54 (13.5%) had SD.	n=2
	(19-70)	(EDP, n = 53),	avelumab n = 6, atezolizumab n = 1,	range = 7.5 (3-9))/	expression.	- n = 38/54 (70%) had PD.	pneumonitis
		median number of		n = 22 cortisol-	- n = 8/33 with	- Longer PFS for those
		prior therapies n = 3	ipilimumab, nivolumab	secreting, n = 6 sex	PD-L1.	with PD-L1 staining but
			n =2 (n = 13 with	hormones-	expression.	no difference for OS.
			concomitant mitotane)	secreting, n = 2	- n = 3/32 had	- Better OS and PFS with
				aldosterone-	MMR loss.	nivolumab compared to
				secreting	- n = 11/36 had TMB.	pembrolizumab.
Klein et al. (2021)	Prospective	n = 3 were naïve of	Nivolumab and	Metastatic ACC	- n = 2/6 with	- n = 2 (33%) had PR.	n = 5/6 patients
(CA209-538)	multicentre	any systematic	ipilimumab followed by	(stages II-IV)	PD-L1	- n = 2 (33%) had SD.	(83%) (the most
	clinical trial	treatment, n = 1	nivolumab and	histologically	expression.		frequent was
	(n=6), 22-1	had one line of treatment and n = 2 had two lines of treatment	continued for up to 96 weeks (no concurrent mitotane)	confirmed/n =2 cortisol-secreting	- n = 2/6 with MSI. - n = 2/6 with CTTNB1 somatic mutation. - n = 2/6 with MSH somatic mutation. - n = 2/6 with TP53 somatic mutation.		hepatitis).
Naing et al.	Phase II	Progressed on previous standard treatment the last 6 months	Monotherapy with pembrolizumab	Progressive ACC	ND	- PFS at 27 weeks: 31%.	ND
(2020)	(n=15), ND			while on standard therapies (all histologically confirmed)		- ORR:15%.
Habra et al.	Phase II	Median number of	Pembrolizumab	Metastatic ACC (all	None of the	- PFS at 27 weeks: 35%.	n = 2/16 (13%)
(2019)	(n=16), 48	prior therapies		histologically	included	- n = 2/14 (14%) had PR.	patients (n = 1
	(31-78)	(range): 2 (1-5)		confirmed)/n=10	patients	- n = 7/14 (50%) had SD.	colitis and n = 1
				cortisol secreting	expressed PD-L1	- n = 5/14 (35%) had PD. - ORR = 14% (95% CI: 2-43%).	pneumonitis)
Raj et al. (2020)	Phase II	Adrenalectomy or	Monotherapy with	Unresectable or	- n = 6/38 with	- ORR: 23% (95% CI:	n = 5/39 (13%),
	(n=39), 62	debulking	pembrolizumab (no	metastatic ACC	MSI-H/	11-39%).	most common
	(19-87)	surgeries and	concurrent mitotane)		MMR-D.	- n = 9/39 (23%) had PR.	hepatitis
		mitotane and			- n = 7/34 with	- n = 7/39 (18%) had SD.
		chemotherapy			PD-L1	- n = 15/39 (38%) had PD.
					expression >1.	- PD-L1 expression and
						MSI-H/MMRD status were not associated with objective response.

Table 1 Continued.

Reference	Study (n), age in years median (range)	Previous treatment	Type of ICIs, n	ACC (histological type, stage/functionality)	PD-1, PD-L1, MSI and TMB expression	Response	Grade 3-4 AEs
Carneiro et al.	Single-arm,	Mitotane and/or	Monotherapy with	ACC (histologically	- n = 6/10 with	- n = 1/10 (10%) had PR.	n = 7/10 (n=3
(2019)	multicentre,	EDP or other	nivolumab	confirmed)	PD-L1	- n = 2/10 (20%) had SD.	elevation of liver
	phase II	chemotherapies		metastatic or locally advanced with	expression.	- n = 7/10 (70%) had PD.	enzymes)
	(n=10), 57				- n = 5/5 with
	(31-67)			disease	negative MSI.
				progression/n = 4 secreting cortisol
Le Tourneau	Phase Ib	Progressive on	Monotherapy with	Metastatic ACC	n = 12/42 with	- n = 3/50 (2%) had PR.	n = 8/50 (16%)
et al. (2018)	(n=50), 50	platinum-based	avelumab n = 25 or		PD-L1	- n = 21/50 (42%) had SD.	(elevation of
(NCT01772004)	(21-71)	therapy, median	avelumab + mitotane		expression	- n = 23/50 (46%) had PD.	liver enzymes)
JAVELIN Solid		number of prior	n = 25			- Median PFS: 2.6 months
Tumor		therapies (range): 2 (1-6)				(95% CI: 1.4 - 4.0). - Median OS:10.6 months (95% CI: 7.4 -15.0). - 1 year OS rate: 43.4%(95% CI: 27.9- 57.9%). - ORR = 6%
Baudin et al.	Phase I/II	n = 26 with and n =7	EO2401 (EO) and	Metastatic ACC	Low level of	- n = 12% had PR.	ND
(2022)	(n=33), 47	without prior	nivolumab		TMB, MSI and	- n = 24% had SD.
(NCT04187404)		treatment			PD-L1	- n = 45% had PD.
SPENCER study					expression	- Median PFS: 1.9 (0.4-7.6) months. - Survival rate at 6 months: 63%. - Post hoc selected group (n = 14): PFS at 6.0 months: 2% and survival rate: 93%.
Future studies
NCT05036434	Phase II	Not yet recruiting	Pembrolizumab plus	lenvatinib
	(ACCOMPLISH trial)
NCT04400474	Phase II	Active, not yet recruiting	Cabozantinib plus	atezolizumab
	(CABATEN trial)
NCT00457587	Observational	Recruiting
NCT03333616	Phase II	Active, not recruiting	Nivolumab and ipilimumab
NCT02721732	Phase II	Active, not	Pembrolizumab
		recruiting

AE, adverse events; ACC, adrenocortical carcinoma; anti-PD-1, anti-programmed cell death protein 1; CR, complete response; EDP, etoposide doxorubicin cisplatin; ICIs, immune checkpoint inhibitors; IHC, immunohistochemistry; MSI, microsatellite instability; MMRd, mismatch repair-deficient; ND, no data; ORR, odds ratio; OS, overall survival; PFS, progression-free survival; PR, partial response; PD, progression disease; RR, objective response rate; SD, stable disease; TMB, tumour mutation burden.

two had SD, whereas the remaining seven patients had PD (Carneiro et al. 2019).

Avelumab was evaluated in a phase 1b study of 50 patients with metastatic ACC despite previous platinum- based therapy who were followed for a median of 16.5 months (Table 1) (Le Tourneau et al. 2018). The ORR was 6.0% with only three patients exhibiting a PR. Twenty- one patients (42.0%) had SD with a median PFS of 2.6 months and a median OS of 10.6 months. The ORR of patients with ACC expressing PD-L1 (n = 12) was 16.7% vs 3.3% of those with PD-L1-negative tumours (n = 30) (P=0.192) (Le Tourneau et al. 2018).

In the only retrospective study, several ICIs (anti- PD-L1 or anti-CTLA-4) were used as monotherapy or in combination with mitotane in 13 patients (Remde et al. 2023) (Table 1). Patients with metastatic progressive ACC obtained 24% disease control with a PFS of 3 months and a median OS of 10.4 months. After adjusting for concomitant mitotane use, treatment with nivolumab was associated with a lower progression risk (hazard ratio (HR): 0.36, 0.15-0.90) and death (HR: 0.20, 0.06-0.72) compared to pembrolizumab (Remde et al. 2023).

Regarding the 32 patients included in case series/ reports, the main information about the efficacy of ICIs is presented in Supplementary Table 1, showing mixed results (Casey et al. 2018, Mota et al. 2018, Addington et al. 2019, Caccese et al. 2019, Head et al. 2019, Bedrose et al. 2020, Miller et al. 2020, Nevgi et al. 2020) (Supplementary Table 1).

Two multicentre studies have evaluated the combination of nivolumab and ipilimumab (Klein et al. 2021, McGregor et al. 2021). In the first study, (CA209-538) ipilimumab plus nivolumab was evaluated in six patients with metastatic ACC. Two patients obtained a PR, and a further two had SD; all responders had MSI-expressing tumours (Klein et al. 2021). In the second single-arm, phase II study of 16 patients with unresectable, locally recurrent, or metastatic ACC, one patient presented a PR, seven had SD, whereas eight had PD (McGregor et al. 2021).

Currently, there is no head-to-head comparison exploring the efficacy of the different types of ICIs in ACC. Indirectly, based on the existing data, monotherapy with pembrolizumab was associated with an ORR ranging between 14% and 23% (Habra et al. 2019, Naing et al. 2020, Raj et al. 2020), whereas monotherapy with nivolumab was associated with an ORR of 26%, and with avelumab of 6% respectively, considering though that these agents were studied in a very limited number of ACC patients (Carneiro et al. 2019, Remde et al. 2023).

The optimisation of the therapeutic effect of ICIs has led to the development of different combinations of therapeutic modalities that could have a synergistic effect with immunotherapy (Sharma et al. 2017, Wei et al. 2018). The rationale for these combinations is that tyrosine kinase inhibitors (TKIs) activate CD8+ T-cells through targeting vascular endothelial growth factor

(VEGF), which promotes immune cell mobilisation, enhancing the efficacy of immunotherapy (Jimenez et al. 2020a). Existing published data from a retrospective study of eight ACC patients progressive on prior lines of therapy, treated with pembrolizumab and lenvatinib, showed that two patients had PR, one had SD, whereas five patients had PD (Bedrose et al. 2020). The median PFS was 5.5 months, and the median duration of therapy was 8.5 months. In a series of four metastatic ACC patients, the combination of pembrolizumab and chemotherapy showed no response (Miller et al. 2020). Similarly, the combination of ICIs with mitotane showed no additional benefit (Le Tourneau et al. 2018, Remde et al. 2023). The NCT04187404 SPENCER multicentre phase I/II is the first-in-human trial evaluating the EO2401 vaccine against ACC in combination with nivolumab. This vaccine includes three microbiome-derived epitopes: the interleukin receptor alpha 2 (IL13R2), survivin (BIRC5) and mammalian forkhead box M1 (FOXM1) (Baudin et al. 2022, Jimenez et al. 2022). These antigens are overexpressed in adrenal tumours and may induce an immune response against tumour cells, sparing the normal adrenals.

Recently, high-dose brachytherapy in combination with pembrolizumab was also evaluated in three patients with progressive metastatic ACC (Schwarzlmueller et al. 2024) (Supplementary Table 1).

To establish personalised therapeutic strategies, genomic mutations, methylation profiles and miRNA expression patterns have classified ACC into three distinct subtypes: ACC1 is more responsive to PD-1 immunotherapy than chemotherapy in contrast to ACC2, which shows enhanced responses to chemotherapy, whereas ACC3 exhibits increased sensitivity to anti-CTLA-4 agents (Guan et al. 2022). Current ongoing trials evaluate the efficacy of combining immunotherapy with anti-VEGF, such as the ACCOMPLISH trial (NCT05036434), assessing pembrolizumab and lenvatinib, and the CABATEN trial (NCT04400474), evaluating cabozantinib and atezolizumab (Table 1).

Phaeochromocytoma/paraganglioma

The number of clinical trials or case reports/series published on immunotherapy in patients with metastatic phaeochromocytoma/paraganglioma (PC/PGL) is rather limited. PC/PGL are relatively rare neuroendocrine neoplasms (NEN) associated in 25-30% with somatic mutations when sporadic, whereas 35% are familial associated with germline mutations in over 20 susceptibility genes (Gupta et al. 2017) Up to 20% of PC/ PGL are metastatic, with a 5-year OS rate ranging from 40% to 77% (Hescot et al. 2019). Metastatic or locally unresectable PC/PGL are often treated with combination chemotherapy with cyclophosphamide, vincristine and dacarbazine (CVD), exhibiting a modest response rate of 25-33%, highlighting the need for alternative therapies such as peptide receptor radionuclide therapy (PRRT),

temozolomide, sunitinib and recently immunotherapy (Fassnacht et al. 2020, Nölting et al. 2022).

Up to date, three prospective phase II clinical trials (Jimenez et al. 2020b, Naing et al. 2020, McGregor et al. 2021), including 22 patients and two case reports (Economides et al. 2020, Rodriguez et al. 2021) have been published (Table 2). One phase II prospective clinical trial including 11 patients with metastatic PC/ PGL treated with pembrolizumab showed a modest response of 9%, with a median PFS of 5.7 months, while the best responses were noted in tumours not expressing PD-L1 (Jimenez et al. 2020b). In the other phase II study including 9 patients with metastatic PC/ PGL treated with pembrolizumab, SD was achieved in six (Naing et al. 2020). Three patients with metastatic PC were treated with combination treatment of ipilimumab and nivolumab, with two developing disease control at 8.5 months and 20 months, respectively, whereas the third had PD (McGregor et al. 2021, Rodriguez et al. 2021). A single patient with progressive metastatic PGL previously treated with cabozantinib and nivolumab monotherapy showed a PR with the combination of cabozantinib and nivolumab (Economides et al. 2020) (Table 2).

A multicohort phase II study of cabozantinib and atezolizumab in advanced endocrine tumours, including PGL, is currently recruiting and may provide important clinical data (CABATEN, NCT04400474).

Thyroid tumours

Differentiated thyroid cancer

Most cases of differentiated thyroid cancer (DTC) respond well to surgery and radioactive iodine; however, patients with aggressive DTC present a therapeutic challenge. Recent studies have evaluated the immune landscape of thyroid cancer and its potential immunotherapeutic implications, while clinical trials have demonstrated moderate activity of immunotherapy in DTC (Nagayama 2018).

The KEYNOTE-028 phase Ib trial evaluated the efficacy and safety of pembrolizumab in 22 patients with advanced DTC exhibiting PD-L1 expression, showing an ORR of 9% and a median PFS of 9 months; PR/SD was 50% at 6 months (Mehnert et al. 2017).

The efficacy and safety results of the TKI cabozantinib with atezolizumab were presented at the American Thyroid Association (ATA) meeting in 2022 (COSMIC-21 study). After a median follow-up of 24.9 months, the disease control rate was 97%, while the PFS was 15.2 months (Hamidi et al. 2023). A phase II trial assessing the efficacy of the combination of pembrolizumab with lenvatinib in radioiodine-refractory DTC reported an ORR of 62% and a PFS of 74% at 12 months (Haugen et al. 2020, Hamidi et al. 2023).

Medullary thyroid cancer

Medullary thyroid cancer (MTC) accounts for 4% of thyroid neoplasms but represents 13% of thyroid cancer-related deaths (Garcia-Alvarez et al. 2022). Following surgical resection, two TKIs, vandetanib and cabozantinib, are the only approved treatment options for unresectable, progressive, advanced MTC (Angelousi et al. 2022), paving the way for new therapeutic approaches such as immunotherapy (Garcia-Alvarez et al. 2022).

Historically, the first strategy of immunotherapy against metastatic MTC was generating autologous dendritic cells pulsed with tumour antigens, carcinoembryonic antigen (CEA) and calcitonin (Naoum et al. 2018). Three out of seven patients decreased serum calcitonin and CEA levels, and one developed complete regression of metastases (Schott et al. 2001). A second study, of ten patients treated with dendritic cells loaded with autologous tumour lysate, showed a minor response in one and SD in two patients (Stift et al. 2004).

Contemporary immunotherapy for the treatment of advanced MTC in the form of ICIs has so far been evaluated only in two trials (Patel et al. 2020, Garcia- Alvarez et al. 2022) (Table 3). The phase II (NCT03246958) trial investigated the combination of nivolumab and ipilimumab in three cohorts with advanced thyroid carcinoma, including seven patients with MTC; preliminary results showed a lack of response in all patients (Garcia-Alvarez et al. 2022). The second phase II trial of nivolumab and ipilimumab in rare tumours (Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumours ‘DART’ study: NCT02834013) reported no response in four MTC patients (Patel et al. 2020), whereas two case reports showed variable responses (Yamamoto et al. 2017, Del Rivero et al. 2020).

Currently, several registered clinical trials are investigating various ICIs in advanced MTC (Table 3). Three phase II studies are evaluating the role of dual ICIs for MTC; the DUTHY trial using the combination of durvalumab and tremelimumab, while both the DART (NCT02834013) and NCT03246958 studies are evaluating the activity of nivolumab combined with ipilimumab (Di Molfetta et al. 2021, Garcia-Alvarez et al. 2022).

Anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC), the least common albeit with the worst prognosis type of thyroid cancer, is an aggressive undifferentiated tumour with poor response to conventional treatment (Garcia-Alvarez et al. 2022, Haddad et al. 2022). Systemic therapy for metastatic ATC includes targeted therapies, such as the combination of dabrafenib and trametinib for BRAFV600E mutation- positive tumours and/or chemotherapy with paclitaxel or doxorubicin (Haddad et al. 2022). The combination of an unfavourable prognosis and a lack of efficacious treatment options in ATC highlights the need to explore the

Table 2 Clinical trial data of the use of immunotherapy in phaeochromocytoma (PC)/paraganglioma (PGL) and future studies.

Reference	Study (n)	Age in years median (range)	Previous treatments	Type of ICIs	PC or PGL (n)/secretion	PD-L1/MSI expression or other mutational status	Response	Grade 3/4 AEs
Clinical trials
Jimenez et al.	Phase II	53.6	n = 3 naïve of any treatment	Pembrolizumab	Metastatic PC (n = 4)	n = 3/11 (27%)	- ORR: 9% (95%	n = 4/11 with
(2020a,b)	(n = 11)	(22.7-74.4)	and n = 8 had received >1		and PGLs (n = 7)	with PD-L1	CI: 0-41%).	anaemia
			systematic treatment		non-resectable	expression/ n = 4	- CBR: 72% (95%
			(cabozantinib, CVD, lenvatinib)		histopathologically confirmed/n = 7 had	(36%) with germline	CI: 39-94%). - PFS at 27
					norepinephrine secretion	mutations; n = 2 had PGL	weeks: 40% (95% CI:
						syndrome type 4 (SDHB), n = 1 had PGL syndrome type 1 (SDHD), n = 1 had Lynch syndrome (PMS2).	12-74%). - Median PFS: 5.7 months (95% CI: 4.37 - not reached).
Naing et al.	Phase II	ND	Previous systematic	Pembrolizumab	Metastatic PC/PGLs/	n = 50% of the	- PFS at 27	ND
(2020)	(n = 9)		treatments		ND	tissues with	weeks: 43%
						PD-L1/PD-L2 expression	(95% CI: 10 -82%). - n = 9 had disease control for ≥4 months. - CBR: 6/9 (75%) (95% CI: 35-97%) - n = 6 had SD
							- n = 2 had PD
McGregor et al.	Phase II	ND	Patients treated with >1	Ipilimumab and	Advanced or recurrent	ND	n = 1 had SD	ND
(2021)	(n = 2)		therapies	nivolumab	or metastatic PGL/nd		and n = 1 had PD (median follow-up: 8.9 (2.6-27) months
Economides	Case report	32	Adrenalectomy, cabozantinib	(i)	Metastatic PGL/	ND	(i) PD	Cutaneous
et al. (2020)				Pembrolizumab followed by (ii) nivolumab and cabozantinib	metanephrine- secreting		(ii) PR at 22 months	ulceration
Rodriguez et al.	Case report	60	Non-surgically resectable, Rx	Ipilimumab and	Metastatic PC	ND	PFS = 20	ND
(2021)			therapy, CVD, radiopeptides	nivolumab	unresectable		months
			Lu 177 dotatate, octreotide + temozolomide,		histopathologically confirmed stage III (cT3, cNX, cM0)/ non-secreting

(Continued)

Table 2 Continued.

		AEs			overall	utility of novel therapies, such as immunotherapy. Pembrolizumab is suggested in the recent NCCN
		3/4			OS,	guidelines as a treatment option for the management of
		Grade			data;	ATC with high TMB (above ten mutations per megabase), following failure to respond to TKIs and chemotherapy
					no	(Haddad et al. 2022). This recommendation is based on
					ND,	the results of the phase II KEYNOTE-158 study (Marabelle
						et al. 2020).
		Response			months;	Five studies have so far evaluated the efficacy of immunotherapy alone in ATC (Capdevila et al. 2020, De
PD-L1/MSI					mo,	Leo et al. 2020, Boudin et al. 2022, Hatashima et al. 2022).
	expression or	status other mutational	ND ND ND		microsatellite instability;	The first, a phase II study evaluating spartalizumab, a monoclonal antibody against PD-1 receptor, in patients with locally advanced progressive ATC, reported a 19% ORR, including a CR in 7% and PR in 12%, with a duration of response ranging from 17 weeks to 1.6 years (Capdevila et al. 2020). The response rate was much higher in PD-L1-
			therapy, PRRT PGLS			positive ATC (29% vs 0%), with the highest rate of 35% found in patients with PD-L1 expression >50%. This is
			or /PGL		MSI,	the first clinical trial showing promising clinical activity
		PGL (n)/secretion	chemotherapy biological progression to PC as somatostatin PC after are		inhibitor;	and a good safety profile, especially for the BRAF wild- type cases (Capdevila et al. 2020). The second study of 13 patients treated with pembrolizumab or nivolumab
		PC or of ICIs	Metastatic (vaccin)	Prior and such Metastatic PC/PGL analogues, allowed. PC Cabozantinib atezolizumab nivolumab Pembrolizumab	immune checkpoint survival. ,	reported an ORR of 16% with two patients showing a PR and three SD (Hatashima et al. 2022). The third phase II trial (NCT03246958) showed a 30% ORR in ten patients with advanced ATC treated with the combination of nivolumab and ipilimumab (Boudin et al. 2022, Garcia-Alvarez et al. 2022). Initial data from a cohort of 16 ATC cases in the AcSé Pembrolizumab Study
			EO2401		ICI,	(NCT03012620) showed an 18.8% ORR with a short
		Type		and plus –	clinical benefit; PFS, progression-free	response duration of 1.6 months and a median PFS of 2.3 months (Jannin et al. 2022). Preliminary data from a phase II, single-arm, open-label (NCT02688608) trial have shown more promising results, reporting an ORR of 60% in five patients (De Leo et al. 2020).
					CBR, 1;	Immunotherapy has also been studied as part of
		Previous treatments		recruiting	dacarbazine; protein-ligand	multimodality treatment, especially in combination with TKIs, mainly lenvatinib (Boudin et al. 2022, Garcia- Alvarez et al. 2022). Six patients with metastatic ATC received lenvatinib and pembrolizumab, showing a high
	years				vincristine, death	ORR of 66% and a median PFS of 17.7 months (Dierks et al. 2021). All cases with CR had either high TMB or PD-L1
	in		Active/not Recruiting Recruiting Recruiting		cell	expression >50% (Dierks et al. 2021). The Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab (ATLEP),
	Age	median (range) (n)	Observational I/II II 2		cyclophosphamide, programmed	a prospective phase II trial evaluating lenvatinib and pembrolizumab in 27 metastatic ATC, showed a 52% ORR with a median PFS of 9.5 months (Boudin et al. 2022). A retrospective study suggested pembrolizumab as an effective salvage therapy in ATC that progressed
		Study	Phase Phase Phase		PD-L1,	on lenvatinib, as evidenced by a 60% ORR with a
					CVD, ratio;	median PFS of 8.3 months in six ATC treated with
						the combination of pembrolizumab and lenvatinib
			trial		odds	(Iyer et al. 2018). In addition, six case reports of ATC
			studies		events; ORR:	treated with the combination of pembrolizumab and
		Reference	SPENCER NCT04400474 NCT04187404 NCT02721732 NCT04028479 (CABATEN) Future		AE, adverse survival;	lenvatinib have been published with highly variable responses (Luongo et al. 2021, Mccrary et al. 2022, Shih et al. 2022). The combination of pembrolizumab with chemoradiotherapy as initial therapy for ATC was tested

in a small phase II trial of three patients who received pembrolizumab with docetaxel/doxorubicin and radiotherapy, but all patients died within 6 months after treatment initiation despite initial favourable responses (Chintakuntlawar et al. 2019).

In light of the significant unmet need for effective systemic therapies in patients with ATC, multiple clinical trials are currently in progress, exploring the role of immunotherapy alone or in combination with other systemic therapies (Table 4). Two studies are assessing pembrolizumab alone (Jannin et al. 2022), and three are studying the combination of CTLA-4 and PD-1/ PD-L1 agents (Boudin et al. 2022, Garcia-Alvarez et al. 2022). Other therapeutic modalities include ICIs with

TKIs (Araque et al. 2020, De Leo et al. 2020, Moretti et al. 2020, Garcia-Alvarez et al. 2022, Jannin et al. 2022), chemotherapy or external beam radiation therapy (Moretti et al. 2020).

Neuroendocrine neoplasms and neuroendocrine carcinomas

Neuroendocrine neoplasms are rare and heterogeneous tumours that primarily develop in the gastrointestinal tract, pancreas and bronchopulmonary system (Tsoli et al. 2019). They can be non-functioning and/or present with a variety of clinical syndromes (functioning NEN) secondary to the hypersecretion of metabolically

Table 3 Registered clinical trials evaluating the use of ICIs for the treatment of medullary thyroid carcinoma (MTC).

Clinicaltrials.gov identifier	Trial title	Drug, study phase and study status	Disease, estimated enrollment	Intervention
NCT03753919 (DUTHY Trial)	Phase II trial of durvalumab (MEDI4736) plus tremelimumab for the treatment of progressive, refractory advanced thyroid carcinoma	Durvalumab plus tremelimumab, phase II (recruiting)	Metastatic thyroid cancer, including DTC, ATC and MTC, n = 46	Durvalumab plus tremelimumab every 4 weeks up to four cycles, followed by durvalumab every 4 weeks
NCT03246958	Phase II trial of nivolumab plus ipilimumab in radioactive iodine- refractory thyroid cancer with exploratory cohorts in ATC and MTC	Nivolumab plus ipilimumab, phase II (active, not recruiting)	Metastatic thyroid cancer, including radioactive iodine refractory DTC, ATC and MTC, n = 53	Nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks)
NCT02834013 (DART study)	Phase II trial of nivolumab plus ipilimumab for rare tumours	Nivolumab plus ipilimumab, phase II (active, not recruiting)	53 types of rare cancer, including carcinomas of pituitary, thyroid, parathyroids and adrenal cortex, n = 818	Nivolumab (240 mg every 2 weeks) plus Ipilimumab (1 mg/kg every 6 weeks)
NCT03072160	Phase II trial of pembrolizumab in recurrent or metastatic MTC	Pembrolizumab, phase II (completed)	Recurrent or metastatic MTC, n = 17	Cancer vaccine followed by pembrolizumab or pembrolizumab monotherapy (200 mg i.v. every 3 weeks)
NCT03012620	Secured access to pembrolizumab for selected rare cancer types	Pembrolizumab, phase II (active, not recruiting)	Seven cohorts of unresectable, locally advanced or metastatic, rare cancers with no other treatment options (including MTC), n = 350	Pembrolizumab (200 mg i.v. every 3 weeks)
NCT02054806	Phase IB trial of pembrolizumab (MK-3475) in advanced solid tumours (MK-3475-028/ KEYNOTE-28)	Pembrolizumab, phase IB, completed	Locally advanced or metastatic solid tumours (including MTC), n = 477	Pembrolizumab (10 mg/kg i.v. every 2 weeks) up to 2 years
NCT04514484	Phase I trial testing the combination of nivolumab plus cabozantinib in patients with HIV and advanced cancer	Nivolumab plus cabozantinib, phase I (recruiting)	Patients with HIV and 17 types of advanced solid tumours (including MTC), n = 18	Nivolumab plus cabozantinib every 28 days

ATC, anaplastic thyroid cancer; DTC, differentiated thyroid cancer; MTC, medullary thyroid cancer.

Table 4 Clinical trials in progress evaluating immunotherapy in anaplastic thyroid carcinoma (ATC).

Clinicaltrials.gov identifier	Trial title	Drug, study phase, study status	Disease, estimated enrollment, included patients, n	Intervention
NCT05119296	Phase II trial of Pembrolizumab in metastatic or locally advanced ATC	Pembrolizumab, phase II, recruiting	Metastatic or locally advanced ATC, n = 20	Pembrolizumab 200 mg every 3 weeks
NCT03012620 (AcSé Pembrolizumab Study) NCT05453799	Secured access to pembrolizumab for selected rare cancer types Phase II trial of vudalimab in metastatic or locally advanced ATC or Hurthle cell thyroid cancer	Pembrolizumab, phase II, active, not recruiting	Seven cohorts of rare metastatic cancers with no other treatment options (including ATC), n = 16 Metastatic or locally advanced ATC or Hurthle cell thyroid cancer, n=54	Pembrolizumab 200 mg every 3 weeks Vudalimab every 2 weeks
		Vudalimab, phase II, recruiting
NCT03246958	Phase II trial of nivolumab plus ipilimumab in radioactive iodine- refractory thyroid cancer with exploratory cohorts in ATC and MTC	Nivolumab and ipilimumab, phase II, active, not recruiting	Metastatic thyroid cancer, including ATC, n = 10	Nivolumab 3 mg/kg every 2 weeks) plus ipilimumab 1 mg/kg every 6 weeks
NCT03753919 (The DUTHY Trial)	Phase II trial of durvalumab plus tremelimumab for the treatment of progressive, refractory advanced thyroid carcinoma	Durvalumab plus tremelimumab, phase II, recruiting	Metastatic thyroid cancer, including DTC, ATC and MTC, n = 46	Durvalumab plus tremelimumab every 4 weeks for up to four cycles followed by durvalumab every 4 weeks
NCT04171622	Phase II trial of pembrolizumab and lenvatinib for the treatment of stage IVB (locally advanced) or stage IVC (metastatic) ATC	Pembrolizumab and lenvatinib, phase II, recruiting	Metastatic or locally advanced ATC, n = 25	Pembrolizumab every 3 weeks plus Lenvatinib daily
NCT04675710	Phase II trial of pembrolizumab, dabrafenib and trametinib before surgery in BRAF- mutated ATC	Pembrolizumab, dabrafenib and trametinib, phase II, recruiting	ATC with BRAF V600E mutation before surgery, n = 30	Pembrolizumab 200 mg every 3 weeks plus daily combination of dabrafenib and trametinib
NCT04400474 (The CABATEN Study)	Phase II trial of atezolizumab plus cabozantinib in advanced and progressive neoplasms of the endocrine system	Atezolizumab plus cabozantinib, phase II, active, not recruiting	Six cohorts of endocrine neoplasms, including a cohort of ATC) first-line or after progression following chemotherapy/other therapy, n = 93	Atezolizumab every 3 weeks plus cabozantinib
NCT04579757	Phase II trial of tislelizumab in combination with Surufatinib in advanced solid tumours	Tislelizumab in combination with surufatinib, phase II, active, not recruiting	Six cohorts of advanced solid tumours (including a cohort of ATC), n = 135	Tislelizumab every 3 weeks plus surufatinib daily
NCT03181100	Phase II trial of atezolizumab with chemotherapy in treating patients with unresectable ATC or poorly differentiated thyroid cancer	Four arms of treatment: atezolizumab in all arms - Arm 1 (BRAF mutation): plus vemurafenib and cobimetinib - Arm 2 (RAS mutation): plus cobimetinib - Arm 3 (non-BRAF and non-RAS mutation): plus bevacizumab - Arm 4: plus nab-paclitaxel phase II, active, not recruiting	Unresectable locally advanced or metastatic ATC or poorly differentiated thyroid cancer, n = 50	Atezolizumab every 3 weeks plus - Arm 1: vemurafenib and cobimetinib - Arm 2: cobimetinib - Arm 3: bevacizumab - Arm 4: nab- paclitaxel

(Continued)

Table 4 Continued.

Clinicaltrials.gov identifier	Trial title	Drug, study phase, study status	Disease, estimated enrollment, included patients, n	Intervention
NCT03360890 (iPRIME study)	A phase II trial of pembrolizumab with chemotherapy for poorly chemoresponsive thyroid and salivary gland tumours	Pembrolizumab and docetaxel, phase II, recruiting	Two cohorts, one of salivary gland cancer and the other of aggressive thyroid cancer (including ATC), n = 46	Pembrolizumab 200 mg every 3 weeks plus docetaxel every 3 weeks
NCT03122496	Pilot study of immunotherapy and stereotactic body radiotherapy (SBRT) for metastatic ATC	Durvalumab and tremelimumab plus SBRT, phase I trial, completed	Metastatic ATC, n = 13	Durvalumab plus tremelimumab every 4 weeks plus SBRT at a dose of 9 Gray x 3 fractions

AcSé, Secured Access to Pembrolizumab, MEK, mitogen-activated protein kinase kinase; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor.

active substances (Tsoli et al. 2019). According to their proliferative index (PI) Ki-67, NEN are classified into grade 1 (G1) or 2 (G2) if Ki-67 PI is ≤2 or between 3% and 20%, respectively, and grade 3 (G3) if Ki-67 PI is >20, while G3 neoplasms are further divided into well- differentiated G3 neuroendocrine tumours (G3 NEN) or poorly differentiated G3 neuroendocrine carcinomas (G3 NEC) (Basturk et al. 2015). Surgery is the mainstay of treatment for NEN, while systemic treatment options include somatostatin analogues, targeted agents, PRRT and chemotherapy. Immunotherapy is mainly used to treat lung tumours, and several clinical trials have shown heterogeneous results for other NEN primary sites (Bai et al. 2022). There is evidence that PD-L1 expression in NEN is associated with a higher tumour grade and poorer PFS and OS (Bösch et al. 2019). However, a recent study on 102 NEN of different sites and grades showed that PD-L1 expression was higher in lung NEN and lower in small intestinal NEN (si-NEN), while there was no correlation with tumour grade (Pinato et al. 2021). In addition, in a recent cohort of 136 patients with G3 gastro-entero-pancreatic (GEP)-NEN, only 10% expressed PD-L1 without any correlation between PD-L1 immunoreactivity and OS and/or PFS (Ali et al. 2020).

The evidence for the use of ICIs in NEN is currently limited to phase I and II trials evaluating the efficacy as monotherapy or combination treatment. The Keynote-028 phase Ib trial evaluated 16 pancreatic NEC (panNEC) exhibiting PD-L1 positivity and showed an ORR of 6% and 12-month PFS and OS rates of 27% and 87%, respectively; 25 patients with typical carcinoids (TC) or atypical carcinoids (AC) displayed an ORR of 12% and 12-month PFS and OS rates of 27% and 65%, respectively (Ott et al. 2019). The phase II Keynote-158 trial demonstrated an ORR of 3.7% and a PFS of 4.1 months in 107 patients with previously treated advanced well-differentiated NEN (Strosberg et al. 2020) .

A phase II multi-centre study that evaluated the efficacy of spartalizumab in patients with well-differentiated GEP

and lung NET, as well as GEP-NEC, reported an ORR of 7.4% and 4.8%, respectively (Yao et al. 2021). In addition, a phase Ib trial assessing the efficacy of toripalimab, an anti-PD-1 antibody, in patients with NEN that displayed recurrence or metastasised after first-line treatment demonstrated an ORR of 20% and a median duration of response of 15.2 months (Lu et al. 2020).

Recent studies assessing the efficacy of treatment with dual ICIs using anti-PD-1/PD-L1 and anti-CTLA-4 antibodies have been performed. A phase II trial, evaluating the efficacy of ipilimumab with nivolumab in patients with NEN, showed an overall ORR of 24% and a PFS and OS of 4.8 and 14.8 months, respectively. Patients with panNEN or AC achieved an objective response of 43% and 33%, respectively (Klein et al. 2020). The phase II DART trial reported that the combination of ipilimumab and nivolumab displays higher efficacy in high-grade NEN or NEC (Patel et al. 2020). Furthermore, Dune is a non-randomised controlled multicohort phase II clinical trial that evaluated durvalumab plus tremelimumab activity and safety in patients with advanced NEN that progressed on standard treatment (Capdevila et al. 2023). The study included four cohorts of patients: lung AC/TC (n = 27), G1 and G2 gastrointestinal NET (GI-NETs) (n = 31), G1 and G2 panNET (n = 32), and G3 GEP-NEN (n = 33, 91% NECs). The 9-month clinical benefit rate was 25.9%/35.5%/25% for the first three cohorts, respectively, while the 9-month OS rate for the fourth cohort was 36.1%. The ORR was 7.4%, 0%, 6.3% and 9.1% for the four cohorts, respectively. The benefit in G3 GEP-NEN was not associated with the tumour differentiation and Ki-67 levels.

In an attempt to overcome the potential resistance of NEN to immunotherapy, multiple clinical trials have evaluated the combination of ICIs with other therapies. The NICE-NEC phase II trial assessed the combination of nivolumab and platinum-doublet chemotherapy as first-line treatment in G3 GEP-NEN or NEN of unknown primary origin and demonstrated an ORR of 53% with a

median PFS of 5.7 months (Riesco Martinez et al. 2022). The efficacy of atezolizumab with bevacizumab was evaluated in advanced, progressive G1/G2 panNEN and extra-pancreatic NEN (Halperin et al. 2022). Preliminary results showed that the ORR was 20% and 15% in panNEN and extra-pancreatic NEN, and the median PFS was 14.9 and 14.2 months, respectively.

A recent systematic review and meta-analysis of 464 patients with advanced or metastatic NEN reported an ORR of 15% that varied according to the primary site (thoracic, 24.7%; GEP, 9.5%), tumour differentiation (poorly differentiated, 22.7%; well-differentiated, 10.4%) and drug regimen (combination, 25.3%; monotherapy, 10.1%) (Park et al. 2022). In addition, prospective clinical trials of ICIs in combination with other treatment options such as somatostatin receptor ligands, PRRT, chemotherapy and targeted agents are currently being conducted and may provide promising results for the proper clinical application of immunotherapy (Garcia- Alvarez et al. 2022).

Parathyroid carcinoma

Parathyroid carcinoma (PTC) is rare, accounting for approximately 1% of all cases of primary hyperparathyroidism (Roser et al. 2023). Surgery is the mainstay of treatment, while medical management, such as bisphosphonates, denosumab and cinacalcet, is directed towards hypercalcaemia control. The lack of efficacy of radiotherapy and chemotherapy highlights the unmet need for effective therapeutic options for refractory PTC (Betea et al. 2015).

Periodical immunisation with synthetic human and bovine parathyroid hormone (PTH) peptides, stimulating the production of autoantibodies against PTH, has been tested in four cases with refractory metastatic PTC, resulting in a significant lowering of serum calcium levels but with variable anti-tumour responses (Bradwell & Harvey 1999, Betea et al. 2015). Contemporary immunotherapy in the form of ICIs has been administered in only two PTC cases so far. One patient with metastatic PTC treated with pembrolizumab showed a PR (Park et al. 2020), and a further developed a three-fold decrease in serum PTH levels and short- lasting radiological disease stabilisation (Lenschow et al. 2021). In addition to any anti-tumour effect, PD-1 blockade may contribute to the mitigation of PTC-related hypercalcaemia, as suggested by the development of immune-mediated hypoparathyroidism as a rare complication of PD-1 blockade in non-parathyroid tumours (Fanciulli et al. 2021).

Aggressive pituitary tumours and pituitary carcinomas

A small proportion of pituitary tumours (pituitary neuroendocrine tumours, pitNET) exhibit unusually

aggressive behaviour and are classified as aggressive pituitary tumours (APT), showing a rapid growth rate despite optimal standard treatment, or pituitary carcinomas (PitC), defined by the presence of metastases within or outside the central nervous system (Raverot et al. 2018, Burman et al. 2023). Until 2018, the mainstay therapy for APT/PitC was temozolomide, with second-line therapies including everolimus, bevacizumab and PRRT (Raverot et al. 2018). Subsequently, the frequent occurrence of hypophysitis as an adverse event to treatment with ICIs suggested a potential role of ICIs.

Since 2018, 28 patients with APT and PitC have been treated with ICIs; 17 corticotroph, 10 lactotroph, and a single null-cell pitNET (Table 5) (Majd et al. 2020, Feola et al. 2022, Ilie et al. 2022). The largest cohort of patients treated with ICIs included 15 patients (6 PitC and 9 APT) treated with the combination of ipilimumab and nivolumab (Ilie et al. 2022), exhibiting an ORR of 26.6% with four patients showing PR, two SD and nine PD (Ilie et al. 2022). Amongst the whole 28 cases, the radiological response was CR/PR in 12 (42.8%), SD in four (14.4%) and PD in 12 (42.8%), with PitC responding better to ICIs than APT and corticotroph tumours showing higher response rates of 33.3% compared to 16.6% of lactotroph tumours (Ilie et al. 2022). A small open-label phase II clinical trial of pembrolizumab monotherapy for advanced rare cancers included four previously treated PitC (Majd et al. 2020). Two adrenocorticotropic hormone (ACTH)-secreting PitCs showed a PR as well as improvement in ACTH levels, while the remaining two patients, a non-functioning corticotroph and a lactotroph PitC, showed no response (Majd et al. 2020). In these two cohorts, the majority of tumours showing a response to ICIS after temozolomide failure were PD-L1 negative, suggesting that the absence of PD-L1 staining should not preclude treatment with ICIs (Majd et al. 2020, Ilie et al. 2022). In the nine published case reports, the most commonly used regimen was a combination of ipilimumab and nivolumab, often followed by maintenance nivolumab, associated with a high ORR of 6/9 (66.6%) (Lin et al. 2018, 2021, Duhamel et al. 2020, Lamb et al. 2020, Sol et al. 2021, Shah et al. 2022, Goichot et al. 2023). It remains unclear whether combined CTLA-4 and PD-L1 inhibition is superior to monotherapy with PD-L1 (Raverot & Ilie 2022).

Future studies should incorporate data about the tumour histology and type (PC vs APT and corticotroph vs other PitNET), treatment protocol (combination vs monotherapy of ICIs), full immunohistochemical analysisand molecular data (PD-L1, TMB, MSI and dMMR) in order to identify predictors of response to ICIs and provide personalised treatment pathways (Bai et al. 2020, Feola et al. 2022, Raverot & Ilie 2022). In addition, a key hypothesis that needs to be tested is whether temozolomide-induced mutations could enhance the sensitivity of pituitary tumours to immunotherapy.

Table 5 Case reports of aggressive pituitary tumours (APT) and pituitary carcinomas (PitCs) treated with ICIs; characteristics and treatment response.

First author,

year, country	Sex, age	Tumour subtype	ICIs	Biomarkers	Response	Adverse events
Lin et al.	F, 42	- Functioning	- Ipilimumab and nivolumab (five	- PD-L1 <1%	- PR (radiologic),	Grade 1 (transient
(2018,		- Corticotroph	cycles), nivolumab maintenance	TMB high and - TMB low	CR (hormonal)
2021), USA		- PitC - Liver metastases - After 8 months, recurrence of liver metastases	(for 6 months) and - Ipilimumab and nivolumab (four cycles), nivolumab maintenance (for 3 months)		sustained for 8 months and - PR (radiologic), CR (hormonal) sustained for 6 months	transaminitis and fever after first infusion) and ND
Sol et al. (2021),	M, 41	- Functioning - Corticotroph	Ipilimumab and Nivolumab (four cycles),	Not available	SD (radiologic), PR	ND
Belgium		- PitC - Cerebrospinal metastases	nivolumab maintenance (for 6 months)		(hormonal) sustained at 12 months
Duhamel et al. (2020),	F, 42	- Functioning - Corticotroph - PitC	Ipilimumab and nivolumab (five cycles), nivolumab maintenance (for 6 months)	PD-L1 (-)	PR (radiologic), PR (hormonal)	ND
France		- Liver metastases			sustained for 12 months
Duhamel et al. (2020),	60, M	- Functioning - Lactotroph - PitC	Ipilimumab and nivolumab (two cycles)	TMB low Absence of MSI	PD after 6 weeks	Grades 3-4 (diarrhoea) - withdrawal of
France		- Liver metastases				ICIS
Caccese et al. (2019),	M, 47	- Functioning - Corticotroph APT	Pembrolizumab (four cycles)	PD-L1 0% Presence of dMMR	Rapid PD	ND
Italy
Lamb et al. (2020),	F, 72	- Non-functioning - Lactotroph - PitC	Ipilimumab and nivolumab (two cycles), nivolumab maintenance (for 8 months)	PD-L1 < 1% TMB low Absence of	PR (radiologic) sustained for 8 months	Grades 3-4 (autoimmune nephritis and
Australia		- Spinal metastases		dMMR		AKI) - withdrawal of ICIS
Goichot et al.	M, 41	- Functioning - Lactotroph	Ipilimumab and nivolumab (four cycles), nivolumab maintenance	PD-L1 95%	CR (radiologic), CR	ND
(2023), France		- PitC - Lung, pancreatic and cerebral metastases	(for 24 months)		(hormonal) sustained at 24 months
Shah et al. (2022),	M, 57	- Non-functioning - Corticotroph	Ipilimumab and nivolumab (four cycles), nivolumab maintenance (10 months)	Presence of dMMR	CR (radiologic) sustained at 34	ND
USA		APT			months
Feola et al.	M, 57	- Non-functioning - Null cell	Pembrolizumab (eight cycles), pembrolizumab	PD-L1 95%	PR (radiologic) sustained at 12	Grades 2-3, cutaneous
(2022),
Italy		- PitC - Cerebrospinal metastases	Maintenance (for 4 months)		months	(rash) and renal (autoimmune nephritis and AKI) - withdrawal of ICIS

AKI, acute kidney injury; APT, aggressive pituitary tumour; CR, complete response; dMMR, mismatch repair deficiency; F, female; ICIs, immune checkpoint inhibitors; M, male; MSI, microsatellite instability; ND, not detected; PitC, pituitary carcinoma; PD, progressive disease; PD-L1, programmed-death-ligand 1; PR, partial response; SD, stable disease; TMB, tumour mutational burden.

Treatment-related side effects

Immune-related adverse events associated with ICIs treatment in endocrine tumours are similar to those previously reported in the literature (Postow et al. 2018). In all cases studied, the most frequent adverse events were classified as mild to moderate (according to CTCAE, 2010, version 4.0), with only rare side effects of grades 3-4. Hepatitis and transaminasemia emerged as the predominant side effects across the majority of studies, ranging from mild to severe. Cutaneous toxicities are also common, especially in PD-1 inhibitors like pembrolizumab (Madan et al. 2023).

Additionally, infrequent but severe side effects included colitis, pneumonitis, cutaneous manifestations (eczema, rash) or autoimmune nephritis (see Tables 1, 2 and 5) (Mehnert et al. 2017, Habra et al. 2019, Economides et al. 2020, Feola et al. 2022, Remde et al. 2023).

Conclusion

Current evidence, along with the favourable safety profile of ICIs in the treatment of several solid tumours, suggests a potential role for these agents in the management of refractory or metastatic endocrine tumours, where standard treatments have proven ineffective. However, their application in endocrine tumours is at an early stage, and most data are based on a small number of treated patients. Pembrolizumab could be a therapeutic option in patients with advanced ACC that have progressed on standard treatment, either alone or in combination with other agents, exhibiting a reasonable safety profile. Clinical data about ICIs efficacy in the treatment of PC/PGL are scarce and based mainly on small series. DTC and MTC exhibit, in general, a low response to ICIs, albeit they could have a role in tumours with extensive TMB expression. On the contrary, ATC seems to show a clinically significant response to ICIs, whereas the response rate in NEN is rather variable, mostly encountered in higher grade tumours or with a combination with other agents. For the rare cases of APT/ PitC and PTC, there is relative paucity of data, although ICIs may have a role in PTC. Current guidelines endorse the utilisation of pembrolizumab in some endocrine tumours with MSI or elevated TMB based on a tissue- agnostic approach. However, international multicenter randomised controlled studies are notably lacking, preventing the formulation of robust conclusions. Promising data in treatment-naive patients should be validated through randomised prospective studies that employ a more refined patient selection process based on predictive markers and well-designed combination treatments.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/ ERC-23-0296.

Declaration of interest

We declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author contribution statement

GK had the conception of this manuscript, AA, PT and MT performed independent research on the databases and selected the included articles, they also edited part of the manuscript. AK, LC and GK edited part of the manuscript and critically revised the whole manuscript.

References

Addington T, Hagman T, Hawk N, Nicole CMA & Bedano P 2019 CMA PB impressive response to immunotherapy in a patient with metastatic adrenocortical carcinoma. Clinical Oncology Case Reports 2 1.

Ali AS, Langer SW, Federspiel B, Hjortland GO, Grønbæk H, Ladekarl M, Welin S, Weber Vestermark L, Arola J, Osterlund P, et al. 2020 PD-L1 expression in gastroenteropancreatic neuroendocrine neoplasms grade 3. PLoS One 15 e0243900. (https://doi.org/10.1371/journal.pone.0243900)

Angelousi A, Hayes AR, Chatzellis E, Kaltsas GA & Grossman AB 2022 Metastatic medullary thyroid carcinoma: a new way forward. Endocrine- Related Cancer 29 R85-R103. (https://doi.org/10.1530/ERC-21-0368)

Arai Y, Nonomura N, Nakai Y, Nishimura K, Oka D, Shiba M, Nakayama M, Takayama H, Mizutani Y, Miki T, et al. 2008 The growth- inhibitory effects of dexamethasone on renal cell carcinoma in vivo and in vitro. Cancer Investigation 26 35-40. (https://doi. org/10.1080/07357900701638418)

Araque KA, Gubbi S & Klubo-Gwiezdzinska J 2020 Updates on the management of thyroid cancer. Hormone and Metabolic Research 52 562-577. (https://doi.org/10.1055/a-1089-7870)

Bai R, Lv Z, Xu D & Cui ] 2020 Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors. Biomarker Research 8 34. (https://doi.org/10.1186/s40364-020-00209-0)

Bai R, Li W & Cui J 2022 Potential new applications of immunotherapy for neuroendocrine neoplasms: immune landscape, current status and future perspectives. Cancer Biology and Medicine 19 1649-1661. (https:// doi.org/10.20892/j.issn.2095-3941.2022.0489)

Basturk O, Yang Z, Tang LH, Hruban RH, Adsay V, McCall CM, Krasinskas AM, Jang KT, Frankel WL, Balci S, et al. 2015 The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. American Journal of Surgical Pathology 39 683-690. (https://doi.org/10.1097/PAS.0000000000000408)

Baudin E, Jimenez C, Fassnacht M, Grisanti S, Menke CW, Haak H, Subbiah V, Capdevila J, De La Fouchardiere C, Granberg D, et al. 2022 EO2401, a novel microbiome-derived therapeutic vaccine for patients with adrenocortical carcinoma (ACC): preliminary results of the Spencer study. Journal of Clinical Oncology 40 4596-4596. (https://doi. org/10.1200/JCO.2022.40.16_suppl.4596)

Bedrose S, Miller KC, Altameemi L, Ali MS, Nassar S, Garg N, Daher M, Eaton KD, Yorio JT, Daniel DB, et al. 2020 Combined lenvatinib and pembrolizumab as salvage therapy in advanced adrenal cortical carcinoma. Journal for ImmunoTherapy of Cancer 8 e001009. (https://doi. org/10.1136/jitc-2020-001009)

Betea D, Potorac I & Beckers A 2015 Parathyroid carcinoma: challenges in diagnosis and treatment. Annales d’Endocrinologie 76 169-177. (https://doi.org/10.1016/j.ando.2015.03.003)

Bösch F, Brüwer K, Altendorf-Hofmann A, Auernhammer CJ, Spitzweg C, Westphalen CB, Boeck S, Schubert-Fritschle G, Werner J, Heinemann V, et al. 2019 Immune checkpoint markers in gastroenteropancreatic neuroendocrine neoplasia. Endocrine-Related Cancer 26 293-301. (https:// doi.org/10.1530/ERC-18-0494)

Boudin L, Morvan JB, Thariat J, Métivier D, Marcy PY & Delarbre D 2022 Rationale efficacy and safety evidence of lenvatinib and pembrolizumab association in anaplastic thyroid carcinoma. Current Oncology 29 7718-7731. (https://doi.org/10.3390/curroncol29100610)

Bradwell AR & Harvey TC 1999 Control of hypercalcaemia of parathyroid carcinoma by immunisation. Lancet 353 370-373. (https://doi. org/10.1016/S0140-6736(98)06469-1)

Burman P, Casar-Borota O, Perez-Rivas LG & Dekkers OM 2023 Aggressive pituitary tumors and pituitary carcinomas: from pathology to treatment. Journal of Clinical Endocrinology and Metabolism 108 1585-1601. (https://doi.org/10.1210/clinem/dgad098)

Byun DJ, Wolchok JD, Rosenberg LM & Girotra M 2017 Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies. Nature Reviews Endocrinology 13 195-207. (https://doi. org/10.1038/nrendo.2016.205)

Caccese M, Ceccato F, Fassan M, Fassina A, Padovan M, Mammi I, Iacobone M, Scaroni C, Zagonel V & Lombardi G 2019 Letter to editor: reply to R.T. Casey (Semin Oncol. 2018 Jun;45(3):151-155). Seminars in Oncology 46 104-105. (https://doi.org/10.1053/j. seminoncol.2018.12.005)

Calsina B, Piñeiro-Yáñez E, Martínez-Montes ÁM, Caleiras E, Fernández- Sanromán Á, Monteagudo M, Torres-Pérez R, Fustero-Torre C, Pulgarín- Alfaro M, Gil E, et al. 2023 Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma. Nature Communications 14 1122. (https://doi.org/10.1038/s41467-023-36769-6)

Capdevila J, Wirth LJ, Ernst T, Ponce Aix S, Lin CC, Ramlau R, Butler MO, Delord JP, Gelderblom H, Ascierto PA, et al. 2020 PD-1 blockade in anaplastic thyroid carcinoma. Journal of Clinical Oncology 38 2620-2627. (https://doi.org/10.1200/JCO.19.02727)

Capdevila J, Hernando J, Teule A, Lopez C, Garcia-Carbonero R, Benavent M, Custodio A, Garcia-Alvarez A, Cubillo A, Alonso V, et al. 2023 Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin. Nature Communications 14 2973. (https://doi.org/10.1038/s41467-023- 38611-5)

Carneiro BA, Konda B, Costa RB, Costa RLB, Sagar V, Gursel DB, Kirschner LS, Chae YK, Abdulkadir SA, Rademaker A, et al. 2019 Nivolumab in metastatic adrenocortical carcinoma: results of a Phase 2 trial. Journal of Clinical Endocrinology and Metabolism 104 6193-6200. (https://doi.org/10.1210/jc.2019-00600)

Casey RT, Giger O, Seetho I, Marker A, Pitfield D, Boyle LH, Gurnell M, Shaw A, Tischkowitz M, Maher ER, et al. 2018 Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab. Seminars in Oncology 45 151-155. (https://doi.org/10.1053/j. seminoncol.2018.06.001)

Celada L, Cubiella T, San-Juan-Guardado J, Gutiérrez G, Beiguela B, Rodriguez R, Poch M, Astudillo A, Grijalba A, Sánchez-Sobrino P, et al. 2023 Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype. Journal of Pathology 259 103-114. (https://doi.org/10.1002/path.6026)

Chintakuntlawar AV, Yin J, Foote RL, Kasperbauer JL, Rivera M, Asmus E, Garces NI, Janus JR, Liu M, Ma DJ, et al. 2019 A Phase 2 study of pembrolizumab combined with chemoradiotherapy as initial treatment

for anaplastic thyroid cancer. Thyroid 29 1615-1622. (https://doi. org/10.1089/thy.2019.0086)

Cui G, Qu D, Bai Y, Sun X, Li Y & Yang Y 2023 Postoperative pathological complete response in a patient with PDL1negative stage IIIB lung squamous cell carcinoma following neoadjuvant tislelizumab treatment combined with chemotherapy: a case report and literature review. Oncology Letters 26 388. (https://doi.org/10.3892/ol.2023.13974)

De Leo S, Trevisan M & Fugazzola L 2020 Recent advances in the management of anaplastic thyroid cancer. Thyroid Research 13 17. (https://doi.org/10.1186/s13044-020-00091-w)

Del Rivero J, Donahue RN, Marté JL, Gramza AW, Bilusic M, Rauckhorst M, Cordes L, Merino MJ, Dahut WL, Schlom J, et al. 2020 A case report of sequential use of a yeast-CEA therapeutic cancer vaccine and anti-PD-L1 inhibitor in metastatic medullary thyroid cancer. Frontiers in Endocrinology 11 490. (https://doi.org/10.3389/fendo.2020.00490)

Di Molfetta S, Dotto A, Fanciulli G, Florio T, Feola T, Colao A & Faggiano A 2021 Immune checkpoint inhibitors: new weapons against medullary thyroid cancer? Frontiers in Endocrinology 12 667784. (https:// doi.org/10.3389/fendo.2021.667784)

Dierks C, Seufert J, Aumann K, Ruf J, Klein C, Kiefer S, Rassner M, Boerries M, Zielke A, la Rosee P, et al. 2021 Combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma. Thyroid 31 1076-1085. (https:// doi.org/10.1089/thy.2020.0322)

Duhamel C, Ilie MD, Salle H, Nassouri AS, Gaillard S, Deluche E, Assaker R, Mortier L, Cortet C & Raverot G 2020 Immunotherapy in corticotroph and lactotroph aggressive tumors and carcinomas: two case reports and a review of the literature. Journal of Personalized Medicine 10 88. (https://doi.org/10.3390/jpm10030088)

Economides MP, Shah AY, Jimenez C, Habra MA, Desai M & Campbell MT 2020 A durable response with the combination of nivolumab and cabozantinib in a patient with metastatic paraganglioma: a case report and review of the current literature. Frontiers in Endocrinology 11 594264. (https://doi.org/10.3389/fendo.2020.594264)

Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, Jolly S, Miller BS, Giordano TJ & Hammer GD 2014 Adrenocortical carcinoma. Endocrine Reviews 35 282-326. (https://doi.org/10.1210/er.2013-1029)

Fanciulli G, Di Molfetta S, Dotto A, Florio T, Feola T, Colao A, Faggiano A & NIKE Group 2021 Commentary: case report: abdominal lymph node metastases of parathyroid carcinoma: diagnostic workup, molecular diagnosis, and clinical management. Frontiers in Endocrinology 12 700806. (https://doi.org/10.3389/fendo.2021.700806)

Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, et al. 2012 Combination chemotherapy in advanced adrenocortical carcinoma. New England Journal of Medicine 366 2189-2197. (https://doi.org/10.1056/ NEJMoa1200966)

Fassnacht M, Assie G, Baudin E, Eisenhofer G, de la Fouchardiere C, Haak HR, de Krijger R, Porpiglia F, Terzolo M, Berruti A, et al. 2020 Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO- EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 31 1476-1490. (https://doi.org/10.1016/j. annonc.2020.08.2099)

Feola T, Carbonara F, Verrico M, Di Crescenzo RM, Gianno F, Colonnese C, Arcella A, de Alcubierre D, Tomao S, Esposito V, et al. 2022 Immunotherapy for aggressive and metastatic pituitary neuroendocrine tumors (PitNETs): state-of-the art. Cancers 14 4093. (https://doi. org/10.3390/cancers14174093)

Garcia-Alvarez A, Hernando J, Carmona-Alonso A & Capdevila J 2022 What is the status of immunotherapy in thyroid neoplasms? Frontiers in Endocrinology 13 929091. (https://doi.org/10.3389/ fendo.2022.929091)

Gaujoux S, Mihai R, Joint Working Group of ESES and ENSAT, Dousset B, Fiori C, Porpiglia F, Hellman P, Iacobone M, Kraimps J-L & Donatini G 2017 European Society of Endocrine Surgeons (ESES) and European Network for the Study of Adrenal Tumours (ENSAT) recommendations for the surgical management of adrenocortical carcinoma. British Journal of Surgery 104 358-376. (https://doi.org/10.1002/bjs.10414)

Goichot B, Taquet MC, Baltzinger P, Baloglu S, Gravaud M, Malouf GG, Noël G & Imperiale A 2023 Should pituitary carcinoma be treated using a NET-like approach? A case of complete remission of a metastatic malignant prolactinoma with multimodal therapy including immunotherapy. Clinical Endocrinology 98 633-637. (https://doi. org/10.1111/cen.14645)

Guan Y, Yue S, Chen Y, Pan Y, An L, Du H & Liang C 2022 Molecular cluster mining of adrenocortical carcinoma via multi-omics data analysis Aids precise clinical therapy. Cells 11 3784. (https://doi.org/10.3390/ cells11233784)

Gupta G, Pacak K & AACE Adrenal Scientific Committee 2017 Precision medicine: an update on genotype/biochemical phenotype relationships in pheochromocytoma/paraganglioma patients. Endocrine Practice 23 690-704. (https://doi.org/10.4158/EP161718.RA)

Habra MA, Stephen B, Campbell M, Hess K, Tapia C, Xu M, Rodon Ahnert J, Jimenez C, Lee JE, Perrier ND, et al. 2019 Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma. Journal for ImmunoTherapy of Cancer 7 253. (https://doi. org/10.1186/s40425-019-0722-x)

Haddad RI, Bischoff L, Ball D, Bernet V, Blomain E, Busaidy NL, Campbell M, Dickson P, Duh Q-Y, Ehya H, et al. 2022 Thyroid carcinoma, version 2.2022, NCCN clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network 20 925-951. (https://doi. org/10.6004/jnccn.2022.0040)

Halperin DM, Liu S, Dasari A, Fogelman D, Bhosale P, Mahvash A, Estrella JS, Rubin L, Morani AC, Knafl M, et al. 2022 Assessment of clinical response following atezolizumab and bevacizumab treatment in patients with neuroendocrine tumors. JAMA Oncology 8 904-909. (https://doi.org/10.1001/jamaoncol.2022.0212)

Hamidi S, Hofmann MC, Iyer PC, Cabanillas ME, Hu MI, Busaidy NL & Dadu R 2023 Review article: new treatments for advanced differentiated thyroid cancers and potential mechanisms of drug resistance. Frontiers in Endocrinology 14 1176731. (https://doi.org/10.3389/ fendo.2023.1176731)

Hatashima A, Archambeau B, Armbruster H, Xu M, Shah M, Konda B, Lott Limbach A & Sukrithan V 2022 An evaluation of clinical efficacy of immune checkpoint inhibitors for patients with anaplastic thyroid carcinoma. Thyroid 32 926-936. (https://doi.org/10.1089/thy.2022.0073)

Haugen B, French J, Worden FP, Konda B, Sherman EJ, Dadu R, Gianoukakis AG, Wolfe EG, Foster NR, Bowles DW, et al. 2020 Lenvatinib plus pembrolizumab combination therapy in patients with radioiodine- refractory (RAIR), progressive differentiated thyroid cancer (DTC): results of a multicenter phase II international thyroid oncology group trial. Journal of Clinical Oncology 38 6512-6512. (https://doi.org/10.1200/ JCO.2020.38.15_suppl.6512)

Head L, Kiseljak-Vassiliades K, Clark TJ, Somerset H, King J, Raeburn C, Albuja-Cruz M, Weyant M, Cleveland J, Wierman ME, et al. 2019 Response to immunotherapy in combination with mitotane in patients with metastatic adrenocortical cancer. Journal of the Endocrine Society 3 2295-2304. (https://doi.org/10.1210/js.2019-00305)

Hescot S, Curras-Freixes M, Deutschbein T, van Berkel A, Vezzosi D, Amar L, de la Fouchardière C, Valdes N, Riccardi F, Do Cao C, et al. 2019 Prognosis of malignant pheochromocytoma and paraganglioma (MAPP- Prono study): a European network for the study of adrenal tumors retrospective study. Journal of Clinical Endocrinology and Metabolism 104 2367-2374. (https://doi.org/10.1210/jc.2018-01968)

Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. 2010 Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine 363 711-723. (https://doi.org/10.1056/ NEJMoa1003466)

Ilie MD, Villa C, Cuny T, Cortet C, Assie G, Baussart B, Cancel M, Chanson P, Decoudier B, Deluche E, et al. 2022 Real-life efficacy and predictors of response to immunotherapy in pituitary tumors: a cohort study. European Journal of Endocrinology 187 685-696. (https://doi. org/10.1530/EJE-22-0647)

Intlekofer AM & Thompson CB 2013 At the Bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. Journal of Leukocyte Biology 94 25-39. (https://doi.org/10.1189/jlb.1212621)

Iyer PC, Dadu R, Gule-Monroe M, Busaidy NL, Ferrarotto R, Habra MA, Zafereo M, Williams MD, Gunn GB, Grosu H, et al. 2018 Salvage pembrolizumab added to kinase inhibitor therapy for the treatment of anaplastic thyroid carcinoma. Journal for ImmunoTherapy of Cancer 6 68. (https://doi.org/10.1186/s40425-018-0378-y)

Jannin A, Escande A, Al Ghuzlan A, Blanchard P, Hartl D, Chevalier B, Deschamps F, Lamartina L, Lacroix L, Dupuy C, et al. 2022 Anaplastic thyroid carcinoma: an update. Cancers 14 1061. (https://doi.org/10.3390/ cancers14041061)

Jimenez C, Fazeli S & Román-Gonzalez A 2020a Antiangiogenic therapies for pheochromocytoma and paraganglioma. Endocrine-Related Cancer 27 R239-R254. (https://doi.org/10.1530/ERC-20-0043)

Jimenez C, Subbiah V, Stephen B, Ma J, Milton D, Xu M, Zarifa A, Akhmedzhanov FO, Tsimberidou A, Habra MA, et al. 2020b Phase II clinical trial of pembrolizumab in patients with progressive metastatic pheochromocytomas and paragangliomas. Cancers 12 2307. (https://doi. org/10.3390/cancers12082307)

Jimenez C, Armaiz-Pena G, Dahia PLM, Lu Y, Toledo RA, Varghese J & Habra MA 2022 Endocrine and neuroendocrine tumors special issue- checkpoint inhibitors for adrenocortical carcinoma and metastatic pheochromocytoma and paraganglioma: do they work? Cancers 14 467. (https://doi.org/10.3390/cancers14030467)

Klein O, Kee D, Markman B, Michael M, Underhill C, Carlino MS, Jackett L, Lum C, Scott C, Nagrial A, et al. 2020 Immunotherapy of ipilimumab and nivolumab in patients with advanced neuroendocrine tumors: a subgroup analysis of the CA209-538 clinical trial for rare cancers. Clinical Cancer Research 26 4454-4459. (https://doi. org/10.1158/1078-0432.CCR-20-0621)

Klein O, Senko C, Carlino MS, Markman B, Jackett L, Gao B, Lum C, Kee D, Behren A, Palmer J, et al. 2021 Combination immunotherapy with ipilimumab and nivolumab in patients with advanced adrenocortical carcinoma: a subgroup analysis of CA209-538. OncoImmunology 10 1908771. (https://doi.org/10.1080/2162402X.2021.1908771)

Lamb LS, Sim HW & McCormack AI 2020 Case report: a case of pituitary carcinoma treated with sequential dual immunotherapy and vascular endothelial growth factor inhibition therapy. Frontiers in Endocrinology 11 576027. (https://doi.org/10.3389/fendo.2020.576027)

Le Tourneau C, Hoimes C, Zarwan C, Wong DJ, Bauer S, Claus R, Wermke M, Hariharan S, von Heydebreck A, Kasturi V, et al. 2018 Avelumab in patients with previously treated metastatic adrenocortical carcinoma: phase 1b results from the JAVELIN solid tumor trial. Journal for ImmunoTherapy of Cancer 6 111. (https://doi.org/10.1186/s40425-018- 0424-9)

Lenschow C, Fuss CT, Kircher S, Buck A, Kickuth R, Reibetanz J, Wiegering A, Stenzinger A, Hübschmann D, Germer CT, et al. 2021 Case report: abdominal lymph node metastases of parathyroid carcinoma: diagnostic workup, molecular diagnosis, and clinical management. Frontiers in Endocrinology 12 643328. (https://doi.org/10.3389/ fendo.2021.643328)

Lin AL, Jonsson P, Tabar V, Yang TJ, Cuaron J, Beal K, Cohen M, Postow M, Rosenblum M, Shia J, et al. 2018 Marked response of a hypermutated ACTH-secreting pituitary carcinoma to ipilimumab and nivolumab. Journal of Clinical Endocrinology and Metabolism 103 3925-3930. (https://doi.org/10.1210/jc.2018-01347)

Lin AL, Tabar V, Young RJ, Cohen M, Cuaron J, Yang TJ, Rosenblum M, Rudneva VA, Geer EB & Bodei L 2021 Synergism of checkpoint inhibitors and peptide receptor radionuclide therapy in the treatment of pituitary carcinoma. Journal of the Endocrine Society 5 bvab133. (https://doi. org/10.1210/jendso/bvab133)

Lu M, Zhang P, Zhang Y, Li Z, Gong J, Li J, Li J, Li Y, Zhang X, Lu Z, et al. 2020 Efficacy, safety, and biomarkers of toripalimab in patients with recurrent or metastatic neuroendocrine neoplasms: a multiple-center phase Ib trial. Clinical Cancer Research 26 2337-2345. (https://doi. org/10.1158/1078-0432.CCR-19-4000)

Luongo C, Porcelli T, Sessa F, De Stefano MA, Scavuzzo F, Damiano V, Klain M, Bellevicine C, Matano E, Troncone G, et al. 2021 Combination of lenvatinib and pembrolizumab as salvage treatment for paucicellular variant of anaplastic thyroid cancer: a case report. Current Oncology 28 5401-5407. (https://doi.org/10.3390/curroncol28060450)

Madan V, Marchitto MC & Sunshine JC 2023 Pembrolizumab-induced Lichen Planus Pemphigoides in a patient with metastatic adrenocortical cancer: A case report and literature review. Dermatopathology 10 244-258. (https://doi.org/10.3390/dermatopathology10030033)

Majd N, Waguespack SG, Janku F, Fu S, Penas-Prado M, Xu M, Alshawa A, Kamiya-Matsuoka C, Raza SM, Mccutcheon IE, et al. 2020 Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study. Journal for ImmunoTherapy of Cancer 8 e001532. (https://doi.org/10.1136/jitc-2020-001532)

Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, Chung HC, Kindler HL, Lopez-Martin JA, Miller WH, et al. 2020 Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncology 21 1353-1365. (https://doi.org/10.1016/S1470- 2045(20)30445-9)

Mccrary HC, Aoki J, Huang Y, Chadwick B, Kerrigan K, Witt B, Hunt JP & Abraham D 2022 Mutation based approaches to the treatment of anaplastic thyroid cancer. Clinical Endocrinology 96 734-742. (https://doi. org/10.1111/cen.14679)

McGregor BA, Campbell MT, Xie W, Farah S, Bilen MA, Schmidt AL, Sonpavde GP, Kilbridge KL, Choudhury AD, Mortazavi A, et al. 2021 Results of a multicenter, phase 2 study of nivolumab and ipilimumab for patients with advanced rare genitourinary malignancies. Cancer 127 840-849. (https://doi.org/10.1002/cncr.33328)

Mehnert JM, Rugo HS, O’Neil BH, Santoro A, Schellens JHM, Cohen RB, Doi T, Ott PA, Pishvaian MJ, Puzanov I, et al. 2017 Pembrolizumab for patients with PD-L1-positive advanced carcinoid or pancreatic neuroendocrine tumors: results from the KEYNOTE-028 study. Annals of Oncology 28 v142. (https://doi.org/10.1093/annonc/mdx368)

Miller KC, Chintakuntlawar AV, Hilger C, Bancos I, Morris JC, Ryder M, Smith CY, Jenkins SM & Bible KC 2020 Salvage therapy with multikinase inhibitors and immunotherapy in advanced adrenal cortical carcinoma. Journal of the Endocrine Society 4 bvaa069. (https://doi.org/10.1210/ jendso/bvaa069)

Moretti S, Menicali E, Nucci N, Guzzetti M, Morelli S & Puxeddu E 2020 THERAPY OF ENDOCRINE DISEASE Immunotherapy of advanced thyroid cancer: from bench to bedside. European Journal of Endocrinology 183 R41-R55. (https://doi.org/10.1530/EJE-20-0283)

Mota JM, Sousa LG, Braghiroli MI, Siqueira LT, Neto JEB, Chapchap P, Hoff AAO & Hoff PM 2018 Pembrolizumab for metastatic adrenocortical carcinoma with high mutational burden. Medicine 97 e13517. (https:// doi.org/10.1097/MD.0000000000013517)

Murugaesu N, Wilson GA, Birkbak NJ, Watkins TBK, McGranahan N, Kumar S, Abbassi-Ghadi N, Salm M, Mitter R, Horswell S, et al. 2015 Tracking the genomic evolution of esophageal adenocarcinoma through neoadjuvant chemotherapy. Cancer Discovery 5 821-831. (https://doi. org/10.1158/2159-8290.CD-15-0412)

Nagayama Y 2018 Thyroid autoimmunity and thyroid cancer - the pathogenic connection: A 2018 update. Hormone and Metabolic Research 50 922-931. (https://doi.org/10.1055/a-0648-4593)

Naing A, Meric-Bernstam F, Stephen B, Karp DD, Hajjar J, Rodon Ahnert J, Piha-Paul SA, Colen RR, Jimenez C, Raghav KP, et al. 2020 Phase 2 study of pembrolizumab in patients with advanced rare cancers. Journal for ImmunoTherapy of Cancer 8 e000347. (https://doi.org/10.1136/ jitc-2019-000347)

Naoum GE, Morkos M, Kim B & Arafat W 2018 Novel targeted therapies and immunotherapy for advanced thyroid cancers. Molecular Cancer 17 51. (https://doi.org/10.1186/s12943-018-0786-0)

Nevgi A, Klein O & Cheung AS 2020 Sustained remission of Lynch syndrome-associated metastatic adrenocortical carcinoma following checkpoint inhibitor therapy-associated multiorgan autoimmunity. Clinical Endocrinology 93 214-216. (https://doi.org/10.1111/cen.14258)

Nolting S, Bechmann N, Taieb D, Beuschlein F, Fassnacht M, Kroiss M, Eisenhofer G, Grossman A & Pacak K 2022 Personalized management of pheochromocytoma and paraganglioma. Endocrine Reviews 43 199-239. (https://doi.org/10.1210/endrev/bnab019)

Ott PA, Bang YJ, Piha-Paul SA, Razak ARA, Bennouna J, Soria JC, Rugo HS, Cohen RB, O’Neil BH, Mehnert JM, et al. 2019 T-cell-inflamed gene- expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. Journal of Clinical Oncology 37 318-327. (https://doi.org/10.1200/JCO.2018.78.2276)

Pardoll DM 2012 The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer 12 252-264. (https://doi. org/10.1038/nrc3239)

Park D, Airi R & Sherman M 2020 Microsatellite instability driven metastatic parathyroid carcinoma managed with the anti-PD1 immunotherapy, pembrolizumab. BMJ Case Reports 13 e235293. (https:// doi.org/10.1136/bcr-2020-235293)

Park EJ, Park HJ, Kim KW, Suh CH, Yoo C, Chae YK, Tirumani SH & Ramaiya NH 2022 Efficacy of immune checkpoint inhibitors against advanced or metastatic neuroendocrine neoplasms: a systematic review and meta-analysis. Cancers 14 794. (https://doi.org/10.3390/ cancers14030794)

Patel SP, Othus M, Chae YK, Giles FJ, Hansel DE, Singh PP, Fontaine A, Shah MH, Kasi A, Baghdadi TA, et al. 2020 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. Clinical Cancer Research 26 2290-2296. (https://doi.org/10.1158/1078-0432.CCR-19-3356)

Pinato DJ, Vallipuram A, Evans JS, Wong C, Zhang H, Brown M, Dina RE, Trivedi P, Akarca AU, Marafioti T, et al. 2021 Programmed cell death ligand expression drives immune tolerogenesis across the diverse subtypes of neuroendocrine tumours. Neuroendocrinology 111 465-474. (https://doi.org/10.1159/000506745)

Postow MA, Sidlow R & Hellmann MD 2018 Immune-related adverse events associated with immune checkpoint blockade. New England Journal of Medicine 378 158-168. (https://doi.org/10.1056/ NEJMra1703481)

Raj N, Zheng Y, Kelly V, Katz SS, Chou J, Do RKG, Capanu M, Zamarin D, Saltz LB, Ariyan CE, et al. 2020 PD-1 blockade in advanced adrenocortical carcinoma. Journal of Clinical Oncology 38 71-80. (https://doi. org/10.1200/JCO.19.01586)

Raverot G & Ilie MD 2022 Immunotherapy in pituitary carcinomas and aggressive pituitary tumors. Best Practice and Research Clinical

Endocrinology and Metabolism 36 101712. (https://doi.org/10.1016/j. beem.2022.101712)

Raverot G, Burman P, McCormack A, Heaney A, Petersenn S, Popovic V, Trouillas J, Dekkers OM & European Society of Endocrinology 2018 European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas. European Journal of Endocrinology 178 G1-G24. (https://doi.org/10.1530/EJE-17-0796)

Remde H, Schmidt-Pennington L, Reuter M, Landwehr LS, Jensen M, Lahner H, Kimpel O, Altieri B, Laubner K, Schreiner J, et al. 2023 Outcome of immunotherapy in adrenocortical carcinoma: a retrospective cohort study. European Journal of Endocrinology 188 485-493. (https://doi.org/10.1093/ejendo/lvad054)

Ribeiro RC, Sandrini F, Figueiredo B, Zambetti GP, Michalkiewicz E, Lafferty AR, DeLacerda L, Rabin M, Cadwell C, Sampaio G, et al. 2001 An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proceedings of the National Academy of Sciences of the United States of America 98 9330-9335. (https://doi. org/10.1073/pnas.161479898)

Riesco Martinez MC, Capdevila Castillon J, Alonso V, Jimenez-Fonseca P, Teule A, Grande E, Sevilla I , Benavent M, Alonso-Gordoa T, Custodio A, et al. 2022 Final overall survival results from the NICE-NEC trial (GETNE-T1913): A phase II study of nivolumab and platinum-doublet chemotherapy (CT) in untreated advanced G3 neuroendocrine neoplasms (NENs) of gastroenteropancreatic (GEP) or unknown (UK) origin. Annals of Oncology 33(Suppl 7) S769. (https://doi.org/10.1016/j. annonc.2022.07.624)

Rodriguez RR, Rizwan S, Alhamad K & Finley GG 2021 The use of immunotherapy treatment in malignant pheochromocytomas/ paragangliomas: a case report. Journal of Medical Case Reports 15 172. (https://doi.org/10.1186/s13256-021-02733-5)

Roser P, Leca BM, Coelho C, Schulte KM, Gilbert J, Drakou EE, Kosmas C, Ling Chuah L, Wassati H, Miras AD, et al. 2023 Diagnosis and management of parathyroid carcinoma: a state-of-the-art review. Endocrine-Related Cancer 30 220287. (https://doi.org/10.1530/ERC-22-0287)

Schott M, Seissler J, Lettmann M, Fouxon V, Scherbaum WA & Feldkamp J 2001 Immunotherapy for medullary thyroid carcinoma by dendritic cell vaccination. Journal of Clinical Endocrinology and Metabolism 86 4965-4969. (https://doi.org/10.1210/jcem.86.10.7949)

Schwarzlmueller P, Corradini S, Seidensticker M, Zimmermann P, Schreiner J, Maier T, Triebig A, Knösel T, Pazos M, Pfluger T, et al. 2024 High-dose rate brachytherapy combined with PD-1 blockade as a treatment for metastatic adrenocortical carcinoma: a single center case series. Hormone and Metabolic Research 56 30-37. (https://doi. org/10.1055/a-2150-3944)

Shah S, Manzoor S, Rothman Y, Hagen M, Pater L, Golnik K, Mahammedi A, Lin AL, Bhabhra R, Forbes JA, et al. 2022 Complete response of a patient with a mismatch repair deficient aggressive pituitary adenoma to immune checkpoint inhibitor therapy: a case

report. Neurosurgery 91 e51-e56. (https://doi.org/10.1227/ neu.0000000000002024)

Sharma P, Hu-Lieskovan S, Wargo JA & Ribas A 2017 Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168 707-723. (https://doi.org/10.1016/j.cell.2017.01.017)

Shih SR, Chen KH, Lin KY, Yang PC, Chen KY, Wang CW, Chen CN, Lin CF & Lin CC 2022 Immunotherapy in anaplastic thyroid cancer: case series. Journal of the Formosan Medical Association 121 1167-1173. (https://doi. org/10.1016/j.jfma.2022.01.003)

Sol B, de Filette JMK, Awada G, Raeymaeckers S, Aspeslagh S, Andreescu CE, Neyns B & Velkeniers B 2021 Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: a new emerging treatment? European Journal of Endocrinology 184 K1-K5. (https://doi.org/10.1530/EJE-20-0151)

Song Y, Long J, Su X, Chen Z, He Y, Shao W, Wang B & Chen C 2023 Case Report: genetic and immune microenvironmental characteristics of a rectal cancer patient with MSS/PD-L1-negative recurrent hepatopulmonary metastasis who achieved complete remission after treatment with PD-1 inhibitor. Frontiers in Immunology 14 1197543. (https://doi.org/10.3389/fimmu.2023.1197543)

Stift A, Sachet M, Yagubian R, Bittermann C, Dubsky P, Brostjan C, Pfragner R, Niederle B, Jakesz R, Gnant M, et al. 2004 Dendritic cell vaccination in medullary thyroid carcinoma. Clinical Cancer Research 10 2944-2953. (https://doi.org/10.1158/1078-0432.CCR-03-0698)

Strosberg J, Mizuno N, Doi T, Grande E, Delord JP, Shapira-Frommer R, Bergsland E, Shah M, Fakih M, Takahashi S, et al. 2020 Efficacy and safety of pembrolizumab in previously treated advanced neuroendocrine tumors: results from the Phase II KEYNOTE-158 study. Clinical Cancer Research 26 2124-2130. (https://doi.org/10.1158/1078- 0432.CCR-19-3014)

Tsoli M, Chatzellis E, Koumarianou A, Kolomodi D & Kaltsas G 2019 Current best practice in the management of neuroendocrine tumors. Therapeutic Advances in Endocrinology and Metabolism 10 2042018818804698. (https://doi.org/10.1177/2042018818804698)

Wei SC, Duffy CR & Allison JP 2018 Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discovery 8 1069-1086. (https://doi. org/10.1158/2159-8290.CD-18-0367)

Yamamoto N, Nokihara H, Yamada Y, Shibata T, Tamura Y, Seki Y, Honda K, Tanabe Y, Wakui H & Tamura T 2017 Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant solid tumors. Investigational New Drugs 35 207-216. (https://doi.org/10.1007/ s10637-016-0411-2)

Yao JC, Strosberg J, Fazio N, Pavel ME, Bergsland E, Ruszniewski P, Halperin DM, Li D, Tafuto S, Raj N, et al. 2021 Spartalizumab in metastatic, well/poorly differentiated neuroendocrine neoplasms. Endocrine-Related Cancer 28 161-172. (https://doi.org/10.1530/ERC-20- 0382)