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The Utility of Cabozantinib in the Therapy of Endocrine Tumours

Eleni Armeni1 . Tu-Vinh Luong2 . Ashley Grossman1

Received: 7 September 2025 / Accepted: 3 November 2025 / Published online: 26 November 2025 @ The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025

Abstract

Endocrine and neuroendocrine malignancies, including epithelial neuroendocrine neoplasms (NENs), phaeochromocy- toma/paraganglioma (PPGL), adrenocortical carcinoma (ACC) and thyroid cancers, represent a heterogeneous group of tumours often characterised by dysregulated receptor tyrosine kinase signalling and with limited systemic treatment options. Cabozantinib is a multikinase inhibitor implicated in tumour angiogenesis, growth, and therapeutic resistance, and its use has been reported in many of these tumours. We performed a narrative review assessing cabozantinib monotherapy or combination regimens in patients with progressive neuroendocrine neoplasms. In NENs, monotherapy achieved a dis- ease control rate (DCR) of up to 83% and a progression-free survival (PFS) of 8.4 months in extra-pancreatic subtypes, and 13.8 months in pancreatic subtypes. Combination therapies yielded modest efficacy with a PFS up to 13.0 months. In metastatic PPGLs, monotherapy achieved an objective response rate (ORR) of 25%, a median PFS of 16.6 months and overall survival (OS) of 24.9 months; combination with atezolizumab showed an ORR of 15.4% and a PFS of 8.4 months. In adrenocortical cancer, the DCR reached 78%, PFS up to 7.2 months, and OS up to 23.9 months. In differentiated thyroid cancer, PFS 11.4 months and OS 26.3 months; in RET M918T-mutant medullary thyroid cancer, OS improved to 44.3 months. Cabozantinib represents a promising therapeutic option across endocrine and neuroendocrine malignancies, particularly in settings with limited treatment alternatives, although the reported rates of control have not been dramatic and adverse effects not insignificant. However, it offers the possibility of exploring more effective molecular approaches, especially with biomarker-based stratification and combinatorial approaches.

Keywords Cabozantinib . Endocrine malignancies . Neuroendocrine neoplasms . Thyroid cancer . Adrenocortical carcinoma · Phaeochromocytoma · Paraganglioma

Abbreviations ACC	Adrenocortical carcinoma	CABINET	Phase III trial of cabozantinib in neuroendo- crine neoplasms
AE1/AE3	Pan-cytokeratin antibodies used in immunohistochemistry	caboACC	Phase II trial of cabozantinib monotherapy in advanced ACC
AKT AXL	Protein kinase B	CABOTEM	Cabozantinib and temozolomide in progres- sive NENs trial
AKT AXL	AXL receptor tyrosine kinase	CABOTEM	Cabozantinib and temozolomide in progres- sive NENs trial
CABATEN	Cabozantinib plus Atezolizumab in Endo-	CI	Confidence interval
	crine Neoplasms (GETNE-T1914) trial	COSMIC	311-Phase III trial of cabozantinib in radio- iodine-refractory DTC
		CTNNB1	ß-catenin gene
☒ Eleni Armeni		DCR	Disease control rate
eleni.armeni@nhs.net		DoR	Duration of response
		DTC	Differentiated thyroid carcinoma
1 Department of Diabetes and Endocrinology, and		EMT	Epithelial-mesenchymal transition
Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital NHS Foundation Trust,		ENSAT	European Network for the Study of Adrenal
London NW3 2QG, UK			Tumors staging system
2 Department of Cellular Pathology, Royal Free Hospital		EPAS1	Endothelial PAS domain protein 1

London, London NW3 2QG, UK

EXAM	Phase III trial of cabozantinib in medullary thyroid carcinoma
FGF	Fibroblast growth factor
FGFR	Fibroblast growth factor receptor
FLT3	Fms-like tyrosine kinase 3
FTC	Follicular thyroid carcinoma
G3/G4	Grade 3 or Grade 4 toxicity (per CTCAE criteria)
GEP	NEN-Gastroenteropancreatic neuroendo- crine neoplasm
GEPNET	Gastroenteropancreatic neuroendocrine tumour
HIF	2a-Hypoxia-inducible factor 2-alpha
HPF	High-power field
HPF	High-power field
HR	Hazard ratio
IGF2	Insulin-like growth factor 2
IHC	Immunohistochemistry
Ki	67-Marker of cellular proliferation
KIT	Stem cell factor receptor (CD117)
LOLA	Cabozantinib plus lanreotide phase II trial
MAML3	Mastermind-like transcriptional coactivator 3
MAPK	Mitogen-activated protein kinase pathway
MEN2	Multiple endocrine neoplasia type 2
MET	Hepatocyte growth factor receptor (MET proto-oncogene)
MTC	Medullary thyroid carcinoma
mTOR	Mammalian target of rapamycin
NEC	Neuroendocrine carcinoma
NEN	Neuroendocrine neoplasm
ORR	Objective response rate
OS	Overall survival
PDGF	Platelet-derived growth factor
PDGFR	Platelet-derived growth factor receptor
PFS	Progression-free survival
PI3K	Phosphoinositide 3-kinase
PPGL	Phaeochromocytoma and paraganglioma
PTC	Papillary thyroid carcinoma
RAI	Radioactive iodine
RET	Rearranged during transfection proto-oncogene
RTK	Receptor tyrosine kinase
SAE	Serious adverse event
SDHB	Succinate dehydrogenase subunit B
TIE2	Tyrosine kinase with immunoglobulin-like and EGF-like domains 2
TKI	Tyrosine kinase inhibitor
TME	Tumour microenvironment
TNM	Tumour-node-metastasis staging system
TP53	Tumour protein p53 gene
TRAE	Treatment-related adverse event

VEGF

VEGFR

VHL

WHO WNT

Vascular endothelial growth factor Vascular endothelial growth factor receptor von Hippel-Lindau tumour suppressor gene World Health Organization classification Wingless-type signalling pathway

Introduction

Endocrine and neuroendocrine neoplasms (NENs) repre- sent a diverse group of epithelial and neural crest-derived tumours with distinct and variable biological behaviour, secretory profiles and organ-specific patterns, posing sub- stantial diagnostic and therapeutic challenges. While well- differentiated NENs retain the phenotypic and molecular features of their regular counterparts, poorly-differentiated neuroendocrine carcinomas (NECs) exhibit marked atypia and high proliferative indices, necessitating distinct prog- nostic and therapeutic considerations [1]. Since the pub- lication of the 5th edition of the WHO classification, the diagnostic framework for NENs has been based on prolif- erative grading, morphological differentiation, and lineage- specific biomarkers, as well as secretory vesicle proteins [2]. However, despite advances in pathological classifica- tion, the clinical management of NENs remains hindered by limited treatment options, especially for high-grade NECs, variable responses to targeted therapies, and a lack of pre- dictive biomarkers, highlighting critical unmet needs in pre- cision oncology for these complex tumours [1].

Over the past two decades, a growing body of research has shed light on the pivotal role of tyrosine kinase receptors (RTKs), particularly in mediating cellular proliferation, dif- ferentiation, and the transmission of extracellular signals into the cell. At least half of the cancer hallmark traits involve the activation of RTKs and their ligands; over-expression of these receptors and/or functional alterations can lead to dysregulated cell growth and cancer [3]. These observa- tions have led to the emergence of tyrosine kinase inhibitors (TKIs) as potential therapeutic agents in endocrine oncology. First-generation VEGFR-targeted TKI, including sunitinib, sorafenib, pazopanib, and axitinib, primarily inhibit vascular endothelial growth factor receptors (VEGFR1-3) and, while effective, have limited activity against additional oncogenic drivers implicated in tumour progression and metastasis [4].

Tyrosine kinase signalling pathways play a central role in the pathogenesis of various endocrine and neuroendocrine malignancies, supporting the rationale for the therapeutic application of TKIs. Endocrine and NENs are characterised by pronounced angiogenesis and cellular proliferation, pri- marily driven by the elevated secretion of vascular endo- thelial growth factor (VEGF) and the over-expression of VEGF receptor-2 (VEGFR2). In addition, endocrine and

NEN tumorigenesis is influenced by aberrant activation of multiple receptor tyrosine kinase (RTK) pathways, includ- ing fibroblast growth factor (FGF) and RET signalling [5]. In medullary thyroid carcinoma (MTC), activating RET mutations have been implicated in both hereditary and spo- radic forms of the disease [6], while RET/PTC gene fusions define biologically-distinct subsets of papillary thyroid car- cinoma (PTC) with diverse clinical behaviour [7]. In adre- nocortical carcinoma (ACC), a pathologically very different type of endocrine tumour, the over-expression of insulin- like growth factor 2 (IGF2) drives tumour progression through the activation of RTKs and downstream MAPK, PI3K/Akt, and mTOR signalling pathways [8]. Similarly, in phaeochromocytomas and paragangliomas (PPGLs), RTKs such as RET, VEGFR, and c-KIT contribute to oncogenesis through inherited mutations, most notably RET in the con- text of multiple endocrine neoplasia type 2 (MEN2A), and through dysregulated angiogenic signalling [9, 10].

Cabozantinib is a ‘next-generation’, orally-administered multikinase inhibitor with a distinctive target profile that includes key molecular drivers of tumour angiogenesis, pro- liferation, invasion, and resistance to therapy [11]. Unlike first-generation TKIs with limited selectivity, cabozantinib offers a broader and more strategically integrated mecha- nism of action, making it particularly effective in tumours with complex signalling crosstalk [11]. Although no head- to-head trials have compared cabozantinib with other TKIs in endocrine neoplasms and NENs, evidence from non- endocrine malignancies indicates a potentially broader spec- trum of activity. Data from these malignancies, for example in the phase II CABOSUN trial, show that cabozantinib was associated with significantly longer progression-free survival (PFS) than sunitinib in treatment-naïve advanced clear cell renal cell carcinoma (8.6 vs. 5.3 months; HR 0.48, p=0.0008) [12]. In a separate randomised phase II study in advanced papillary renal cell carcinoma, cabozantinib achieved a higher objective response rate (23%) compared with sunitinib (4%) [13]. These findings support the ratio- nale that multi-targeted inhibition may confer therapeutic advantages in tumours with complex angiogenic and mes- enchymal signalling profiles, a concept that merits evalua- tion in endocrine neoplasms through disease-specific trials.

This review aims to critically examine the emerging role of the multikinase inhibitor cabozantinib in the management of endocrine and neuroendocrine malignancies, its efficacy, toxicity, and also its limitations.

Mechanism of Action and Molecular Targets of Cabozantinib

Activation of the RTK MET by its ligand, hepatocyte growth factor, initiates a cascade of downstream signalling

pathways that promote cell proliferation, survival, anti- apoptotic activity, invasion, and metastasis [14]. Aberrant MET signalling, arising from gene mutations, amplification, or over-expression, has been strongly implicated in thera- peutic resistance, tumour progression, and the emergence of highly aggressive phenotypes in various cancers, includ- ing advanced endocrine tumours [14, 15]. On the other hand, the VEGFR family, particularly VEGFR-2, serves as the primary mediator of angiogenesis [16]. Binding of its ligand, vascular endothelial growth factor A (VEGF-A), triggers endothelial cell proliferation, migration, increased vascular permeability, and neovascularisation (Fig. 1) [17]. These processes collectively support tumour growth, dis- semination, and the development of a treatment-resistant vasculature [17]. A well-established functional crosstalk pathway exists between MET and VEGF signalling path- ways, whereby activation of the MET axis promotes angio- genesis; VEGF-mediated signalling can, in turn, enhance tumour cell invasiveness and metastatic potential, and thus RTKs appear to support tumour progression and therapeutic resistance (Fig. 1) [18].

This MET/VEGF interaction underpins the rationale for co-targeting these pathways in oncology. Cabozantinib, a potent small-molecule inhibitor of MET and VEGFR2 (as well as AXL and RET), is designed to therapeutically dis- rupt this signalling network (Fig. 1). Preclinical and clini- cal data have demonstrated the efficacy of cabozantinib in malignancies such as renal cell carcinoma and MTC, where enhanced angiogenesis and invasive behaviour often coex- ist and contribute to disease progression and drug resistance [18, 19].

Cabozantinib demonstrates a broad-spectrum inhibitory profile, targeting a diverse array of RTKs beyond VEGFR2, thereby contributing to its prolonged and multi-faceted anti- tumour activity across various malignancies [11, 20]. Its essential targets include AXL, a receptor frequently impli- cated in epithelial-mesenchymal transition (EMT) as well as metastatic dissemination, an immunosuppressive tumour microenvironment, and therapeutic resistance (Fig. 1) [14, 21]. Inhibition of AXL has been shown to attenuate tumour invasiveness and enhance anti-tumour immune responses, supporting its role in transformative cancer biology [11, 14, 21]. Additionally, cabozantinib effectively inhibits RET (Rearranged during Transfection), an oncogenic driver recurrently altered in MTC and several other endo- crine malignancies [11, 18, 20]. RET mutations and fusions are central to the pathogenesis of MTC, and clinical data indicate that RET inhibition by cabozantinib leads to sig- nificant improvements in progression free survival (PFS) in this patient population [22]. Furthermore, cabozantinib targets additional RTKs, including KIT, FLT3, and TIE2, which are variably expressed in tumour types with complex

Fig. 1 Dendrogram with the tyrosine kinase inhibitor properties of cabozantinib. Footnote: Primary targets of cabozantinib include VEGFR1-3 and TIE2 (angiogenesis), MET and AXL (tumor pro- liferation, invasion, and metastasis), and RET (oncogenic driver in thyroid cancer). Secondary targets comprise KIT, FLT3, and ROS1, which broaden the inhibitory spectrum but are less central to approved clinical indications. VEGFR1-3: Vascular Endothelial Growth Factor Receptors 1-3; TIE2: Tyrosine kinase with immunoglobulin-like and EGF-like domains 2; MET: Mesenchymal-Epithelial Transition factor / HGF receptor; AXL: Anexelekto receptor tyrosine kinase (epithelial- mesenchymal transition, drug resistance); RET: "Rearranged during Transfection" receptor tyrosine kinase; KIT (CD117): Stem cell fac- tor receptor; FLT3: FMS-like Tyrosine Kinase 3; ROS1: ROS proto- oncogene 1. The figure was created using Biorender

Cabozantinib

Tumor growth and metastasis

RET, ROS1, KIT, FLT3

AXL MET

KIT & FLT3

Fibroblast

VEGFR1 VEGFR2 VEGFR3 TIE2

Oncogenesis Tumour cells

Angiogenesis & endothelial proliferation

Myeloid differentiation and proliferation; haematopoietic signalling

kinase signalling networks [11, 23] (Fig. 1). By inhibiting these pathways, cabozantinib exerts anti-proliferative, anti- angiogenic and anti-metastatic effects beyond its primary targets, positioning it as an integrative therapeutic option for tumours that rely on redundant or compensatory kinase circuits for continued growth and survival [11, 20].

Neuroendocrine Neoplasms

Neuroendocrine neoplasms (NENs) are derived from two main neuroendocrine cell groups: epithelial and neuronal/ paraneuronal [24]. Epithelial NENs comprise a heteroge- neous spectrum of tumours arising from the diffuse neuro- endocrine system, encompassing both well-differentiated tumours and poorly-differentiated carcinomas [25]. Their biological behaviour ranges from indolent to highly aggres- sive forms depending on grade, proliferative activity, and

molecular profile. Non-epithelial NENs are paragangliomas, including intra-adrenal paragangliomas known as phaeochro- mocytomas. Their postulated origin from neural crest-like Schwann cell precursors is new information. The 2022 WHO classification provides a unified framework for grading across gastrointestinal, pancreatic, pulmonary, and extra-pulmonary sites, underscoring the clinical importance of accurate histo- pathological and molecular characterisation [24].

Histopathological Diagnosis and Molecular Hallmarks

Histopathologically, NENs typically demonstrate nested, trabecular, or insular growth patterns, with uniform tumour cells showing round to oval nuclei, salt-and-pepper chro- matin, and granular cytoplasm [2]. Immunohistochemis- try plays a pivotal role in confirming the neuroendocrine nature of these tumours. This can be accomplished by using

immunohistochemical stains for several antibodies (INSM1, synaptophysin, chromogranin A); they each have different degrees of specificity and sensitivity [2, 26]. CD56 may be expressed but exhibits very low specificity and is regarded as largely obsolete in contemporary diagnostic practice [27].

The Ki-67 index and mitotic count are critical for grad- ing epithelial NENs (WHO Grades 1, 2 or 3: Grade 1: Ki-67<3%, <2 mitoses/10 HPF; Grade 2: Ki-67 3-20%, 3-20 mitoses/10 HPF; Grade 3: Ki-67>20%, >20 mito- ses/10 HPF [2, 24]. It is now standard-of-care to perform Ki-67 on all NENs including paragangliomas and pheochro- mocytomas [2]. Once a tumour is confirmed to be a NEN, it is critical to distinguish an epithelial NEN from a non- epithelial one. Cytokeratin immunohistochemistry (most commonly pan-cytokeratin, e.g. AE1/AE3, CAM5.2) is valuable for confirming the epithelial nature of a suspected NEN. Demonstration of cytokeratin expression helps dis- tinguish epithelial NENs from non-epithelial neoplasms, thereby supporting accurate classification [2].

At the molecular level, the tumour microenvironment in NENs is a complex and dynamic ecosystem that signifi- cantly influences tumour behaviour and therapy responses [28]. NENs are among the most vascularised cancers, char- acterised by overexpression of pro-angiogenic factors such as VEGF, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and angiopoietins, leading to tumours with dense vascular networks [28]. A complex interplay of pro-angiogenic molecules, primarily involving the VEGF/ VEGFR, PDGF/PDGFR and FGF pathways, is produced by tumour and stromal cells, facilitating the “angiogenic switch” required for tumour growth and metastasis [29]. VEGF directly stimulates endothelial cell proliferation (mitogenesis) and increases vascular permeability, playing a central role in both angiogenesis and vascular leakage [30]. FGFs promote endothelial cell migration, proliferation, and differentiation, thereby driving new vessel formation, while PDGF supports angiogenesis by recruiting pericytes to sta- bilise and cover nascent vessels [31].

NENs possess a highly vascular tumour microenviron- ment driven by over-expression of pro-angiogenic factors and sustained activation of VEGF/VEGFR, PDGF/PDGFR, and FGF/FGFR pathways that promote growth and metasta- sis [11]. Cabozantinib, through dual inhibition of VEGFR2 and MET/AXL signalling, effectively targets this angio- genic-mesenchymal axis, disrupting vascular remodelling and tumour progression in advanced NENs [21].

Evidence Supporting the Use of Cabozantinib in Neuroendocrine Neoplasms

Emerging data are beginning to support the potential therapeutic effects of cabozantinib, either in the form of

monotherapy or combined with other medications, to con- trol the progression of NENs (Table 1).

One preclinical study evaluated the effect of cabozantinib on NEN cell lines, both in vitro and in vivo, and compared the cytotoxicity of cabozantinib with that of sunitinib [32]. Cabozantinib significantly reduced cell viability and pro- liferation in three human NEN cell lines (pancreatic-NEN, typical pulmonary carcinoid, and an atypical pulmonary car- cinoid) in a dose- and time-dependent manner. These effects were primarily cytostatic, associated with impaired cell cycle progression and downregulation of c-MET expres- sion, but were not accompanied by substantial induction of apoptosis (Fig. 1). In vivo, using a zebrafish embryo xeno- graft model, cabozantinib demonstrated significant inhibi- tion of tumour-induced angiogenesis and cell migration. Although overall tumour burden reduction was modest, the zebrafish system provided a rapid, ethically compliant, and physiologically relevant platform to evaluate early-phase anti-tumour activity.

Cabozantinib-Only Treatment: Phase II

The Phase II CaboNEN study investigated the effect of cabozantinib in 41 patients with G3 NENs of low prolif- erative activity, i.e., a Ki-67 between 20% and 60% (53.3% pancreatic primary, 20% gastrointestinal, 11.1% lung; 39 patients with NET G3 and 6 with NEC but low Ki-67) [33]. The interim analysis of this study revealed disease control rates of 92.1% and 83% at 3 and 6 months, respectively. Reported treatment-related adverse events (TRAEs) were mainly grade 3 (74 episodes) and occurred very infrequently at grades 4 (1 episode) and grade 5 (4 episodes) [33]. The serious treatment-related events (SREs) included ileus, acute pain, infection, cholangiosepsis, stroke, and small intestinal perforation. Because these figures derive from an interim analysis of a small Phase II cohort, the disease-con- trol and safety outcomes should be interpreted with caution until mature and confirmatory data are available.

Cabozantinib-Only Treatment: Phase III

The clinical efficacy of cabozantinib in patients previously treated for progressive pancreatic or extra-pancreatic NENs was investigated in the CABINET phase III trial [34]. The trial showed that treatment with cabozantinib was associ- ated with an improved PFS in 203 patients with extra-pan- creatic and 95 patients with pancreatic NENs: median PFS vs. placebo, 8.4 (extra-pancreatic) and 13.8 (pancreatic) months compared with 3.9 and 4.4 months, respectively [34]. In the pancreatic NET cohort of the CABINET trial, cabozantinib significantly reduced the risk of disease pro- gression or death both in patients previously treated with

Table 1 Studies on the effect of Cabozantinib in the treatment of neuroendocrine neoplasms
Study	Number of patients & tumour characteristics	Treatment characteristics (median dose & duration of treatment)	Mean PFS (months) [95% CI] and/or OS (months)	Efficacy objective response rate (ORR) & disease control rate (DCR)	Treatment related adverse events
Prospective, single arm, multicenter Phase II Cabo- NEN trial - Pancreatic NETs (Koenig et al., 2025) - Interim analysis	39 patients with NET G3 6 patients with NEC low Ki-67 Pancreas 53.3%, GI tract 20%, lung 11.1%, others 15.5%	Duration of treatment: 36 monhts	Median PFS 9.7 months OS not reported yet	First interim analysis, ORR after 3 months: PR 10%, SD 75%, PD 15% Second interim analysis Best ORR 16% DCR at 6 months: 83% DCR at 3 months 92.1%	SREs: Ileus, acute pain, infection, cholangiosepsis, stroke, small intestinal perforation
		Duration of treatment: 36 monhts
Prospective Phase III CABI- NET trial - Pancreatic NETs (Chan et al., 2025)	Cohort 1: pts with pancreatic NENs (N=95)	Median dose Cabozantinib 60 mg/day vs. placebo Duration of treatment 5 years	PNET vs. placebo: PFS 13.8 vs. 4.4 months, stratified HR, 0.23 [95% CI: 0.12 to 0.42, p<0.001] OS 40 monhts vs. 31.1 monhts, HR for death 0.95 (95% CI: 0.45 to 2.00)	P-NET, ORR 19% (95%CI: 10% to 30%) - PR 19% - SD 61% PD 8% - Missing 13%	SREs grade 3-5: fatigue (11%), diarrhoea, AST/ALT increase, hypertension (22%), nausea, oral mucositis, palmar plantar eryth- rodysesthesia (10%), anorexia, neutropenia, vomiting, thromboembolic event (11%)
	Cohort 2: pts with extra-pancreatic NENs (N=203)	Median dose Cabozantinib 60 mg/day vs. placebo Duration of treatment 5 years	Extra-pancreatic NET vs. placebo PFS: 8.4 vs. 3.9 months; stratified HR for progression or death, 0.38 [95% CI: 0.25 to 0.59, p<0.001] OS 21.9 monhts vs. 19.7 monhts (HR 0.86, 95% CI: 0.56 to 1.31)	Extra-pancreatic, ORR 5% (95% CI: 2% to 10%) - PR 5% SD 65% – - PD 11% Missing 19%	SREs grades 3-5: fatigue (13%), diarrhoea (11%), AST/ALT increase, hypertension (11%), thrombocytopenia, nausea, oral mucositis, palmar plantar erythro- dysesthesia, anorexia, neutropenia, leukopenia, anemia, lymphopenia, weight loss
Prospective, Phase II open label, single arm CABOTEM - Cabozantinib+Temozolo- mide (Clemente et al., 2023)	35 patients recruited: - Pancreas, 12 pts - GI, 9 pts - Lung, 8 pts - Unknown primary, 4 pts	Median dose Cabozantinib 40 mg/day con- tinuously and TMZ 100mg/ m2/day (one week on one week off)	OS not reported	After median of 6 months, 12% ORR, 72% clinical benefit rate	Most common G3/G4 TRAE: Thrombocytopenia, palmar/plantar erythrodysesthesia, nausea, vomit- ing, dysgeusia, appetite loss
	33 patients enrolled	Median follow up 6 months	OS not reported

Table 1 (continued)
Study	Number of patients & tumour characteristics	Treatment characteristics (median dose & duration of treatment)	Mean PFS (months) [95% CI] and/or OS (months)	Efficacy objective response rate (ORR) & disease control rate (DCR)	Treatment related adverse events
Prospective, multicentre,	Study included six cohorts with advanced refractory tumours: Lung NEN (n=9), GEP-NENs (n=24), grade 3 EP-NENs (n=9)	Median dose Cabozantinib 40 mg/day Atezo 1200 mg Q3W Median duration of treatment Lung NEN, - cabo: 10.4 months (95% CI: 2.6 to 31.2) - atezo 11.2 months (95% CI: 0.8 to 33.0) GEP-NEN - cabo: 12.4 months (95% CI:	GEP-NENs:	GEP NENS: ORR: 4, 16.67%, DCR: 22, 91.7% (95% CI: 73.0 to 99.0) DoR 15.8 months (range 10.6 to 20.2) Lung NENs: ORR 0% DCR: 100% DoR N/A Grade 3 EP-NEN: ORR 0% DCR: 3, 33.3% (95% CI: 7.5 to 70.1) DoR: N/A	Grade≥3 toxicities: fatigue (10%), increased ALT (9%), neutropenia (7%) and hypertension (5%), case of myocardial infarction, case of fatal treatment-related acute pan- creatitis and fatal treatment-related cerebral artery stroke.
Phase II basket study, CABATEN - Cabozan- tinib+Atezolizumab (Cap- devila et al., 2025; Castillon et al., 2023)			Median PFS 13.0 months (95% CI: 11.2 to NR) Median OS not reached for G1-G2 Lung-NENs: Median PFS 8.4 months (95% CI: 7.7 to NR) Median OS not reached Grade 3 EP-NENs: Median PFS 2.7 months (95% CI: 2.6 to NR) Median OS 5.4 (95% CI: 3.6 to NR)
		8.6 to 30.5) - atezo: 11.6 months (95% CI: 6.8 to 31.5) EP-NEN - cabo: 2.7 months (95% CI: 2.3 to 6.8) - atezo: 3.0 months (95% CI: 1.5 to 6.8)

** Note: ** ‘Efficacy/Response to Treatment’ refers to the proportion of patients achieving complete or partial tumour shrinkage per RECIST criteria (Objective Response Rate). PR rate Partial Response rate, the proportion of patients with ≥30% tumour shrinkage; stable disease is not included.

Abbreviations: PFSProgression-Free Survival, ORR Objective Response Rate, PRPartial Response, CR Complete Response, DCRDisease Control Rate, SD Stable disease, PD Progressive disease, NR Not Reached, CIConfidence Interval, OSOverall Survival, GEP-NENGastroenteropancreatic Neuroendocrine Neoplasm, EP extra pulmonary, Atezo atezolizumab, TMZtemozol- amide, NR Not reached, Q3W every three weeks, SREs serious related events, TRAE treatment related adverse events, AST aspartate aminotransferase AST, ALT alanine transaminase

sunitinib (HR=0.27; 95% CI 0.10-0.71) and in those with- out prior sunitinib exposure (HR=0.20; 95% CI 0.10-0.41), with the slightly higher HR in the former subgroup indicat- ing a numerically smaller, though still substantial, benefit after prior sunitinib [34]. Common treatment-related grade 3 or higher TRAEs (e.g., fatigue, diarrhoea, palmar-plantar erythrodesia, thromboembolic events, and hypertension) were noted in 62-65% of patients who received cabozan- tinib and 23-27% of those receiving placebo [34].

Cabozantinib Combination Therapy: Phase II

The efficacy of combined treatment for progressive lung and GEP NENs with cabozantinib and temozolomide was investigated in the phase II CABOTEM trial [35]. The trial enrolled 33 patients with progressive disease follow- ing treatment with everolimus, sunitinib, somatostatin ana- logues, or peptide receptor radionuclide therapy. The ORR, recorded after a median follow-up of 6 months, was 12%, with a clinical benefit rate of 72%. Severe TRAEs leading to premature discontinuation of treatment were recorded in 10 patients, with the most common G3/G4 being nausea, vomiting, dysgeusia, appetite loss, thrombocytopenia, and palmar/plantar erythrodysethesia [35].

The ongoing LOLA phase II trial (ClinicalTrials.gov NCT04427787) is evaluating the therapeutic potential of cabozantinib in combination with lanreotide in patients with well-differentiated, non-functioning progressive NENs, who have received one prior line of systemic therapy for metastatic disease. The trial continues to recruit patients with tumours of thoracic, gastro-enteropancreatic (GEP), or unknown pri- mary origin, characterised by a Ki-67 proliferation index of at least 10% and demonstrable somatostatin receptor subtype-2 expression confirmed by immunohistochemical analysis [36]. Among its exploratory objectives, the LOLA trial incorpo- rates a translational research component designed to assess the intra-tumoural expression of c-MET, AXL, and VEGFR2 through immunohistochemical analysis.

The prospective, multicentre, phase II CABATEN study evaluated the combination of cabozantinib and atezolizumab (a PD-L1 immunotherapeutic antagonist) in patients with advanced and treatment-refractory endocrine neoplasms [37]. The study included six independent cohorts: lung NENs, anaplastic thyroid carcinoma (ATC), ACCs, pha- eochromocytoma/paraganglioma (PPGL), GEPNET, and grade 3 extra-pulmonary NENs (G3 EP-NEN). All partici- pants received atezolizumab 1200 mg intravenously every 3 weeks and cabozantinib 40 mg orally once-daily until disease progression or unacceptable toxicity. The primary endpoint was the overall response rate (ORR) as assessed by RECIST criteria. In the cohorts encompassing well-differen- tiated GEPNETs, Lung NENs, and grade 3 extra-pulmonary

NENs, the combination of cabozantinib and atezolizumab demonstrated modest to very limited activity. Specifically, the ORR was 16.7% in GEPNETs (n=24), 0% in Lung NET (n=9), and 0% in G3 EP-NEN (n=9). The median PFS was 13.0 months (95% CI: 11.2-NR) for GEPNETs, 8.4 months (95% CI: 7.7-NR) for Lung NET, and 2.7 months (95% CI: 2.6-NR) for G3 EP-NEN. Important TRAEs (grade≥3) included fatigue (10%), increase alanine aminotransferase levels (ALT, 9%, grade≥3), neutropenia (7%) and hyper- tension (5%), as well as one case of myocardial infarction (grade 3), plus a case of fatal acute pancreatitis and fatal treatment-related stroke [37].

An important subanalysis of the CABATEN study evalu- ated cabozantinib plus atezolizumab in patients with vari- ous NEN subtypes, including gastro-enteropancreatic NENs (GEP-NEN), lung neuroendocrine tumours (Lung NEN), and grade 3 extra-pulmonary NENs (G3 EP-NEN). The median PFS varied among these subtypes: 13 months for GEP-NEN, 8.4 months for Lung NEN, and 2.7 months for G3 EP-NEN. Objective response rates (ORR) were 16.7% for GEP-NET, with no responses identified in Lung NEN or G3 EP-NEN groups. However, the duration of response (DoR) in responders was durable, approximately 15.8 months for GEP-NEN. Although the combination showed limited objective activity overall, it achieved prolonged disease control in a subset of patients with GEP-NEN. No significant differences in outcomes were observed based on cabozantinib relative to the dose intensity [38, 39].

Phaeochromocytoma and Paraganglioma (PPGL)

PPGLs are rare neural-crest-derived neuroendocrine tumours originating from chromaffin cells of the adrenal medulla and extra-adrenal paraganglia, respectively. The 2022 WHO classification emphasises a molecular taxonomy that integrates genomic, metabolic, and immune features, reflecting an evolving understanding of PPGL pathobiology. Recent studies underscore that transcriptional and epigen- etic signatures better capture tumour biology and clinical behaviour than traditional site-based classification [40].

Classification and Molecular Clustering

Following the 2022 WHO classification, PPGLs have been stratified into two major (and one minor) molecular clusters, reflecting fundamental differences in underlying tumour biology with direct therapeutic implications [41].

Pseudo-hypoxic cluster 1 phaeochromocytomas and paragangliomas (PPGLs) develop due to mutations that either impair the Krebs cycle or enhance hypoxia signalling

[41, 42]. Cluster 1a mutations in genes coding for succinate dehydrogenase subunit-x (SDHx), fumarate hydratase (FH), isocitrate dehydrogenase (IDH), malate dehydrogenase 2 (MDH2), dihydrolipoamide S-succinyltransferase (DLST), and solute carrier family 25 member 11 (SLC25A11). Cluster 1b includes mutations in genes related to von Hip- pel-Lindau tumour suppressor (VHL) and endothelial PAS domain protein 1 (EPAS1, also known as hypoxia-inducible factor 2-alpha, HIF-2a) [43]. Cluster 1 tumours display pro- nounced angiogenic activation through HIF-2a-mediated VEGF upregulation, resulting in highly vascular, treatment- resistant phenotypes [41-43].

PPGL cluster 2 tumours arise from mutations that cause persistent activation of key kinase signalling pathways regulating cell growth and survival [41, 42, 44]. The main affected pathways are the MAPK pathway and the PI3K/ AKT/mTOR pathway [41, 42, 44].

Cluster 3 phaeochromocytomas and paragangliomas (PPGLs) are defined by somatic Wingless type (Wnt) path- way activation via mastermind-like transcriptional coactiva- tor-3 (MAML3) fusions or ‘cold shock domain containing El’ (CSDE1) mutations, which disrupt normal transcrip- tional regulation, apoptosis, and differentiation pathways, leading to enhanced cell proliferation and survival [41, 42]. Tumours of cluster 3 show enhanced invasiveness through aberrant Wnt/B-catenin signaling [9, 45].

Molecular Stratification and Therapeutic Implications

Cabozantinib’s dual inhibition of VEGFR2 and MET directly targets key pathogenic mechanisms in cluster 1 PPGLs, which are characterised by HIF-driven VEGF over- expression [11], marked angiogenesis, and invasive poten- tial (Fig. 1). By additionally blocking AXL-mediated MET pathways [46], cabozantinib may counteract the metastatic behaviour typical of SDHB-mutated tumours [47], provid- ing a mechanistically justified treatment option for progres- sive or metastatic PPGLs.

Evidence Supporting Cabozantinib Treatment in PPGLs

There is now emerging evidence that cabozantinib shows encouraging activity in metastatic PPGL, both as mono- therapy or as part of combination therapy with either of the immunomodulators, nivolumab or atezolizumab (Table 2).

Cabozantinib Monotherapy: Phase II

The efficacy and safety of cabozantinib monotherapy in patients with metastatic PPGL were assessed in the

single-arm, phase II NATALIE trial [47]. This study enrolled 17 adult patients with histologically-confirmed, progres- sive, unresectable PPGL and low-to-moderate performance status. Cabozantinib administered at a dose of 60 mg daily demonstrated an ORR of 25% (95% CI: 7.3 to 52.4), clinical benefit rate of 93.8% (95% CI: 69.8 to 99.8), and median PFS of 16.6 months (95% CI: 8.1 to 34.9); the median OS was 24.9 months (95% CI, 23.6 to ‘not reached’). Interest- ingly, the trial’s molecular profiling revealed no pathogenic c-MET mutations or MET amplification, yet cabozantinib produced high rates of tumour shrinkage or disease stabili- sation across both SDHB-mutated and sporadic PPGL cases. This strongly suggests that, in metastatic PPGL, cabozan- tinib’s efficacy is largely mutation-agnostic and driven by potent anti-angiogenic activity rather than by selective inhibition of an oncogenic MET pathway. Of note, grade 3 TRAEs were reported in 35% of participants and included hypertension, Qt-interval prolongation, asymptomatic ele- vations of pancreatic enzymes, as well as hypomagnesae- mia (noted in one patient, 6%). In one case, therapy was interrupted for two weeks due to grade 3 hypertension; dur- ing this period, anti-hypertensive treatment was optimised, including adjustments to both a-adrenergic (doxazosin) and B-adrenergic (metoprolol) blockade. Other grade 3 TRAEs included hand and foot syndrome as well as rectal fistulas (6%).

Cabozantinib Combination Therapy

Evidence on the possible combination of cabozantinib with nivolumab can be considered from the case report of a 32-year-old man diagnosed with a non-secretory right- sided neck paraganglioma, confirmed on surgical resection [48]. In 2011, he developed a hypertensive crisis during ankle surgery, with elevated catecholamines and a tumour at the organ of Zuckerkandl, resected following a-adreno- ceptor blockade. Genetic testing in 2012 revealed no muta- tions in SDHB, SDHC, SDHD, SDHA, SDHAF2, VHL or FH. He later experienced a transient ischaemic attack in 2014, and by 2015-2016 had developed metastatic disease to the retroperitoneum, liver, bone, and skull base, treated with multiple operations, ureteral stenting, and transarterial chemoembolisation. Initial systemic treatment with cabo- zantinib (60 mg) led to 7.5 months of stable disease before progression. This was followed by 5.5 months on pembroli- zumab (200 mg every 3 weeks), which also resulted in sta- ble disease before further progression. He then received 2.5 cycles of cyclophosphamide, vincristine, and dacarbazine (CVD), with a minor radiological response (12.2% reduc- tion) but severe myelosuppression. In 2017, he began off- label cabozantinib (40 mg) and nivolumab (240 mg every

Table 2 Studies on the effect of Cabozantinib in the treatment of phaeochromocytomas/paragangliomas
Study	Number of patients & tumour characteristics	Treatment characteristics (median dose & duration of treatment)	Mean PFS (months) [95% CI] and/or OS (months)	Objective response rate (ORR) & disease control rate (DCR)	Treatment related adverse events
Phase II NATALIE - Cabozantinib Monotherapy (Jimenez et al., 2024)	pts with progressive, unresectable metastatic PPGL (N=17)	Median dose Cabozantinib, 60 mg/day Median duration of treatment 25 months (IQR 18-49).	Mean PFS 16.6 months (95% CI: 8.1 to 34.9) OS 24.9 months (95% CI: 23.6 to NR)	ORR 25% (95% CI: 7.3 to 52.4) Clinical benefit rate 93.8% (95% CI: 69.8 to 99.8)	Grade 3: increased lipase or amylase (12%), hypo- magnesaemia, diarrhoea, hand-and-foot syndrome, hypertension, rectal fistulas and QT interval prolongation (all 6%)
CABATEN Phase II - Cabozan- tinib+Atezoli- zumab (Capdevila et al., 2025; Her- nando et al., 2024)	Focusing on data for PPGL group (N=13)	Initial treatment Cabo 40 mg/day, -> Cabo dose reduction 20 mg/ day in 58.2% of pts due to side effects Atezo 1200 mg Q3W Duration of treatment Cabo: median duration of treat- ment: 8.5months (95% CI: 2.3 to 21.9) Atezo: median 8.2 months, (95% CI: 3.0 to 23.2)	Median PFS 8.6 months (95% CI: 5.7 to NR) Median OS: 26.7 (95% CI: 9.7 to NR)	ORR 15.38% (95% CI: 1.92 to 45.54) DCR: 11, 84.6% (95% CI: 54.6 to 98.1) DoR 12.2 months (range, 5.5 to 19.0)	Grade≥3 toxicities: fatigue (10%), increased ALT (9%), neutropenia (7%) and hypertension (5%), case of myocardial infarction, case of fatal treatment-related acute pancreatitis and fatal treatment-related cere- bral artery stroke.
Case Report - Cabozan- tinib+ Nivolumab (Economides et al., 2020)	Case report metastatic PPGL after multiple lines of systemic treatetment	Median dose, cabo 40 mg/day; nivolumab 240 mg every 2 weeks; Duration of treatment 22 months.	Non applicable	Stable disease for 22 months	Hypersensitivity related skin ulcerations

Abbreviations: PFSProgression-Free Survival, ORR Objective Response Rate, PR Partial Response, CR Complete Response, DCR Disease Con- trol Rate, NR Not Reached, CIConfidence Interval, OSOverall Survival, PPGL phaeochromocytoma or paraganglioma

2 weeks), achieving sustained clinical benefit with signifi- cant tumour regression, reduction of plasma metanephrines, improved symptoms, and controlled blood pressure. Despite hypersensitivity-related skin ulcerations managed with dose interruptions, he remained on therapy 22 months later with ongoing disease control [48].

More data on cabozantinib plus atezolizumab in PPGL comes from the prospective multi-cohort basket phase II trial called the CABATEN trial (GETNE-T1914) [38, 39]. This study included patients with advanced and progressive NENs and PPGL, with a median patient age of 60 years and a male-to-female ratio of 62%. In the PPGL subgroup, cabozantinib plus atezolizumab treatment resulted in a median PFS of 8.4 months (95% CI: 5.7 to ‘not reached’) and an ORR of 15.4% (95% CI: 1.9 to 45.5), with a durable median DoR of 12.2 months. TRAEs frequently caused treatment interruptions, 80% for cabozantinib and 40% for atezolizumab, with the cabozantinib dose reduced to 20 mg/day in 58.2% of patients. Importantly, clinical ben- efit in PPGL patients was independent of cabozantinib dose intensity.

Future Directions: Cabozantinib in the Post- Belzutifan Landscape

The therapeutic landscape for metastatic PPGL has changed following the FDA approval of the HIF-2a inhibitor belzu- tifan on the basis of the LITESPARK 015 trial [49]. Many patients in this trial had progressed on TKIs, and then responded to belzutifan in a significant number of cases. It is possible that this agent could be used as a well-tolerated first-line systemic therapy in pseudohypoxic (cluster 1) tumours, but currently our review suggests that cabozantinib remains relevant as a subsequent-line option because of its mutation-agnostic anti-angiogenic and anti-invasive profile, its activity in SDHB-mutated disease, and the encouraging disease-control rates seen in NATALIE and in the PPGL cohort of CABATEN. Given that 25% of LITESPARK 015 participants had prior TKI exposure, future studies should explore the optimal sequencing, and potentially combina- tion, of belzutifan with cabozantinib to overcome VEGF/ MET/AXL-mediated escape and to prolong progression- free survival.

Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) represents a rare but highly aggressive malignancy whose diagnosis and prog- nostication increasingly rely on integrating histopathologic evaluation with molecular and multi-omic profiling, reflect- ing major advances in our understanding of adrenal cortical tumorigenesis over the past decade [50].

Classification and Molecular Pathogenesis

Primary Neoplasm Description

Morphologically, ACC is classified into conventional, onco- cytic, myxoid, and sarcomatoid subtypes, based on the 2022 WHO guidelines [51]. Tumour aggressiveness is evaluated on the basis of mitotic count and the Ki-67 index. Clinically, disease is staged using the TNM and ENSAT systems from Stage I (tumours ≤5 cm confined to the adrenal) to Stage IV (tumours with distant metastases) [52].Aggressive behav- iour correlates with high mitotic counts and Ki-67 index, this often exceeding 20% [51].

Histopathologic and Molecular Hallmarks

The histopathologic diagnosis of malignancy in ACC is based on established multiparameter scoring systems, including: Weiss score≥3, modified Weiss score≥3, Helsinki score>8.5 and reticulin algorithm for conventional ACC; Lin-Weiss- Bisceglia (any major criterion), Helsinki score>8.5 and retic- ulin algorithm for oncocytic ACC and AFIP criteria score≥4 for paediatric ACC [51]. The Weiss system remains the standard histopathological method to diagnose malignancy in conventional ACC [52]. The Helsinki score combines mitotic activity, necrosis, and the Ki-67 proliferation index into a composite numerical scale that stratifies tumors by malignant potential, with scores≥8 strongly correlating with clinically aggressive disease [53]. The reticulin algorithm focuses on architectural derangement, whereby disruption of the normal reticulin framework, combined with at least one adverse feature such as necrosis, vascular invasion, or mitotic count>5/50 HPF, supports a diagnosis of carcinoma [51]. These tools offer enhanced reproducibility and prognostic discrimination, particularly in borderline or oncocytic lesions where the classical Weiss criteria may be equivocal, and their integration into multidisciplinary assessment has been endorsed in recent expert reviews [51, 53].

Molecular and Therapeutic Implications

The Cancer Genome Atlas Study on ACC (ACC-TCGA [54]) identified three distinct molecular subtypes - COC1

(favourable), COC2 (intermediate), and COC3 (poor prog- nosis) - distinguished by IGF2 over-expression and tran- scriptional signatures linked to proliferation and DNA damage [54-56].

Recent pan-genomic studies of ACC have found that Wnt signalling is the most commonly affected pathway (in 39-66% of cases), followed by alterations in the p53 apop- tosis/Rb1 cell cycle pathway (in 19.5-44.9%), with somatic TP53 mutations and associated tumour suppressor pathway alterations linked to more aggressive tumour phenotypes, some occurring alongside CTNNB1 (ß-catenin) mutations [54, 56, 57]. These hallmarks have direct therapeutic rel- evance for cabozantinib targeting, as aberrant VEGF, MET, and AXL signalling, key downstream effectors of Wnt and p53 dysregulation, promote angiogenesis, epithelial-mes- enchymal transition, and metastatic spread. Cabozantinib’s dual inhibition of VEGFR2 and MET therefore provides a mechanistic rationale for its evaluation in metastatic or refractory ACC, particularly in COC3/C1A-type tumours with high angiogenic and invasive potential (Fig. 1) [54].

Evidence Supporting Cabozantinib Treatment in ACC

The latest clinical data also support the consideration of cabozantinib as a potential treatment option for advanced ACCs (Table 3).

Cabozantinib-Monotherapy

The phase II clinical trial NCT03370718 evaluated cabozan- tinib as a treatment for advanced ACC in 18 adult patients [58]. Patients received 60 mg of cabozantinib daily, with dose adjustments permitted for side effects. The primary goal was to assess PFS at 4 months. The results showed that 72.2% of patients were progression-free at 4 months, with a median PFS of 6 months (95% CI: 4.3 to ‘not reached’). Cabozantinib demonstrated only modest objective response rates in advanced ACC, but achieved promising disease con- trol in a heavily pretreated population, defined as patients with advanced adrenocortical carcinoma who had received at least one prior systemic therapy (including mitotane, chemotherapy, or immunotherapy) before starting cabozan- tinib, with 72% PFS at 4 months and a median overall sur- vival of 24 months. The trial was the first prospective study confirming credible activity for a targeted agent in this set- ting, where prior TKIs had largely failed. Pharmacokinetic analysis showed that prior mitotane treatment depressed cabozantinib plasma levels, impacting efficacy. The feasi- bility of safely treating hormonally active (cortisol-secret- ing) ACC was established, and translational data, such as shifts in VEGF-A, HGF, and regulatory T-cell markers,

Table 3 Studies on the effect of Cabozantinib in the treatment of adrenocortical carcinoma
Study	Number of patients & tumour characteristics	Treatment character- istics (median dose & duration of treatment)	Mean PFS (months) [95% CI] and/or OS (months)	Objective response rate (ORR) & disease control Rate (DCR)	Treatment related adverse events
Phase II study NCT03370718 - Monotherapy (Campbell et al., 2024)	Pts with advanced ACC (N=18)	Median dose 60 mg per day Median duration of treatment, 5.7 monhts (range: 2.5 to 7.2)	Median PFS 6 months (95% CI: 4.3 to 'not reached') Median OS, 24 months (95% CI: 15.6 to NR)	4 months progres- sion free, 76% (95% CI: 59 to 100)	Most comment grade 3 SREs: lipase eleva- tion (17%), elevated y-glutamyl transferase concentrations (11%), elevated ALT (11%) hypophosphatemia (11%), and hyperten- sion (11%). Grade 4 hypertension(6%).
Phase II trial, Retrospective Analysis - Mono-	Pts with advanced ACC on treatment with mitotane or other systemic options (N=16)	Median dose at treat- ment initiation, 60 mg (range: 20-140) Treatment duration 10.6 weeks (range, 6.0 to 13.9)	Median PFS 16.2 weeks (95% CI, 2.8 to 61 weeks) At the time of data cutoff, median OS 58 weeks (95% CI, 5.6 to 83.1 weeks)	PR in 3 patients, SD in 5 patients, prolonged disease control	Grade 3: decrease in neutrophils; hyperten- sion, thromboembo- lism (for all 7.6%)
therapy (Kroiss et al., 2020)
Phase II Open- label - Mono- therapy (Campbell et al., 2022)	Pts with advanced ACC (N=18)	Dose: NR Median F-up: 19.4 months (range: 2.9 to 45.6)	Median PFS 7.2 months (95% CI: 3.3 to 9.2); OS 23.9 months (95% CI: 12.9 to 'not reached')	PR in 2 patients, SD in 12 DCR 78% (95% CI: 52% to 94%)	Possible treatment related grade 3 or 4 events in 72.2% of patients (no details reported)
Prospective Phase II Open-label	Unresectable/ metastatic ACC progressing to standard of care	oral cabozantinib 60 mg Median duration of treatment 22 weeks	Not reported	- SD for minimum 4 months, 14 pts 41.2% - PR 2/34 pts	No safety aspects reported
- Monotherapy caboACC trial				- SD for minimum 4 months, 14 pts 41.2% - PR 2/34 pts	No safety aspects reported
(NCT03612232) (Miriam Reuter, 2025)	therapy (N=34 pts evaluable)			- Disease con- trol>10 months, 4 pts
Prospective, mul- ticentre, phase II CABATEN study	Study included six cohorts with advanced refrac- tory tumours Preliminary results for ACC (n=24)	Median dose Cabozantinib 40 mg/ day, median dura- tion of treatment 3.0 months (95% CI: 2.7 to 6.1) Atezo 1200 mg Q3W: median 3.4 months, (95% CI: 3.0 to 6.0)	Median PFS 2.9 months (95% CI: 2.8 to 5.7) - Cushing Yes, 2.8 (95% CI: 2.6 to NR) - Cushing No, 2.9 (95% CI: 2.8 to NR) Median OS 13.5 months (95% CI: 9.2 to NR) - Cushing Yes: 3.8 months (95% CI: 3.4 to NR) - Cushing No, 13.5 months (95% CI: 12.6 to NR) - High grade (mitotic grade≥20), 10.8 months (95% CI: 4.6 to NR) - Low grade (mitotic rate<20), 18.8 months (95% CI: 4.2 to NR)	ORR 8.3% (1.03 to 27) - DCR 33.3% (15.6 to 55.3) - DOR median 13.1 monhts (range: 5.4 to 20.9)	Grade≥3 tox- icities: fatigue (10%), increased ALT (9%), neutropenia (7%) and hypertension (5%), case of myocardial infarction, case of fatal treatment-related acute pancreatitis and fatal treatment-related cerebral artery stroke.
(Capdevila et al.,
2025; Castillon et al., 2023; Grande
et al., 2024)
NCT06006013 (Nazha, 2025)	Not recruiting	Cabozantinib and pembrolizumab

supported further investigation of cabozantinib in combi- nation with immunotherapy. However, it should be empha- sised that it is effectively only used as a last resort, but it offers promise that this type approach could be expanded in future. Treatment-related grade 3 or higher TRAEs occurred in 61% of patients, commonly involving elevated lipase and liver enzymes, hypophosphataemia (11%), and hyperten- sion (grade 4, 6%); there were no treatment-related deaths.

A further retrospective analysis of the results of a phase II trial [59] evaluated the effect of cabozantinib monother- apy. It demonstrated acceptable safety and modest clinical benefit in 16 patients with advanced ACC who had previ- ously received mitotane or other systemic therapies. Partial responses were observed in three patients, with a median PFS and OS of 16.2 (95% CI: 2.8 to 61) weeks and 58 (95% CI: 5.6 to 83.1) weeks, respectively, supporting further pro- spective evaluation. Serious TRAEs (grade 3) included a decrease in neutrophils (1 patient, 7.6%), thromboembolism (1 patient, 7.6%), and hypertension (1 patient, 7.6%).

Another open-label, phase II trial evaluated the effi- cacy and safety of cabozantinib in patients diagnosed with advanced ACC [60]. This study assessed 18 patients with advanced ACC, showing a 4-month PFS rate of 72% and a median PFS of 7.2 months (95% CI: 3.3 to 9.2). The disease control rate was 78%, with partial responses in two patients and stable disease in twelve. The median OS reached 23.9 months. Grade 3-4 treatment-related TRAEs occurred in 72.2% of patients. Cabozantinib demonstrated promis- ing efficacy and manageable safety in this difficult-to-treat population.

Preliminary findings from the ongoing prospective phase II caboACC trial (NCT03612232) assessing cabozantinib monotherapy in 34 patients with advanced ACC reported a median treatment duration of 22 weeks [61]. An interim analysis demonstrated that 41.2% of participants (n=14) achieved stable disease for at least 4 months, with an addi- tional 4 patients maintaining disease control for over 10 months. Notably, partial responses were observed in two individuals. Given that these are preliminary, interim data from a small ongoing Phase II trial, the reported disease- control and response rates should be interpreted with cau- tion until full, mature results are available.

Combination Therapy

The Phase II clinical trial NCT06006013 is evaluating the efficacy and safety of cabozantinib combined with pembrolizumab in patients with metastatic ACC, and is currently active but not recruiting (ClinicalTrials.gov NCT06006013) [62].

The CABATEN trial (NCT04400474) assessed cabo- zantinib plus atezolizumab in 24 patients with advanced/

metastatic ACC who had progressed after prior therapies [63]. The combination showed modest activity with an ORR of 8.3% (95% CI: 1-27%), a median PFS of 2.9 months (95% CI: 2.8-5.7), and a median OS of 13.5 months (95% CI: 8.8 to ‘not reached’). Treatment-related grade 3 or higher. TRAEs for the whole study population have been reported earlier [37]. Although the prespecified efficacy threshold was not met, durable responses in some patients encourage further investigation of predictive biomarkers for this therapy.

Thyroid Cancer

Classification and Molecular Pathogenesis

The 2022 WHO Classification of Tumours of the Thyroid Gland focuses on genetic alterations that drive tumour development, aiming to reflect biological diversity and inform therapeutic decision-making [64].

The molecular landscape of differentiated thyroid car- cinoma can be broadly divided into three biologically and clinically meaningful categories. [64, 65]:

a) BRAF V600 E-driven pathway: The majority of clas- sic papillary thyroid carcinomas (PTCs) are character- ised by constitutive activation of the MAPK pathway through the BRAF V600E mutation [66]. In addition to BRAF V600E, fusions of RET, BRAF, and the neuro- trophic tyrosine kinase receptors NTRK1 and NTRK3, converge on the same downstream signalling cascades [67]. These molecular events are clinically important because BRAF V600E confers reduced radioactive iodine (RAI) avidity, shaping initial and adjuvant treat- ment strategies, and identifies patients who may benefit from BRAF +MEK inhibitor therapy [66, 68]. RET and NTRK fusions similarly activate MAPK signalling but predict responsiveness to highly selective RET inhibi- tors such as selpercatinib or pralsetinib, and to NTRK inhibitors such as larotrectinib or entrectinib, which are now licensed for thyroid cancers harbouring these fusions [69].

b) RAS-driven pathway: A second group, typical of encap- sulated or circumscribed tumours with follicular growth patterns such as follicular thyroid carcinoma and inva- sive encapsulated follicular-variant PTC, is driven by oncogenic activation of RAS genes (NRAS, HRAS, KRAS) [70, 71]. These alterations are frequently accom- panied by secondary events including EIF1AX, EZH1, DICER1 and PTEN mutations, the BRAF K601E vari- ant, or gene fusions involving PPARG or THADA [70, 72]. Collectively, these lesions activate PI3K/AKT and

MAPK signalling and drive a more indolent, follicular- patterned tumour biology [70, 72].

c) nonBRAF V600E/non-RAS-like pathways: The third, heterogeneous group lacks canonical BRAF V600E or RAS mutations, and instead arises from alternative molecular events. This category includes cribriform- morular thyroid carcinoma, hyalinising trabecular tumour, tumours of uncertain malignant potential, and oncocytic (Hürthle cell) tumours. Their pathogenesis involves diverse pathways such as aberrant activation of the WNT/B-catenin signalling cascade and gene fusions exemplified by PAX8 :: GLIS [73].

These mechanisms produce variable histological appear- ances and clinical behaviours, distinct from the BRAF- and RAS-driven pathways [74]. Because BRAF V600E and related fusions drive constitutive MAPK signalling and reduce RAI uptake, tumours in this category are biologically primed for BRAF+MEK inhibitor therapy; RET and NTRK fusions likewise respond to their respective highly selective inhibitors, which are now approved in thyroid cancer [74]. By contrast, RAS-driven and non-BRAF/RAS-like tumours mainly signal through PI3K/AKT or WNT/ß-catenin path- ways and may retain RAI-sensitivity, limiting the applica- bility of current MAPK-directed agents but suggesting other targeted strategies under investigation [65].

Evidence Supporting Cabozantinib Therapy in Thyroid Cancer

The role of cabozantinib in the management of thyroid malignancies has been investigated in the setting of medul- lary thyroid cancer (MTC) and radioiodine-refractory dif- ferentiated thyroid cancer (Table 4).

Cabozantinib Monotherapy - Phase II

A retrospective evaluation [75] was conducted to investigate the efficacy of cabozantinib in treating poorly-differentiated thyroid carcinomas (DTC), with a specific focus on radio- iodine refractory (RAIR) tumours, in a cohort of 7 patients. After a median treatment duration of 10.53 months, a par- tial response was observed in 4 patients, while two patients achieved stable disease. The median OS was 14.21 months, and the median PFS from initiation of cabozantinib therapy was 12.9 months. Reported TREAs were predominantly low grade, indicating an acceptable tolerability profile, the most common being gastrointestinal (50%), dermatologic (17%), hypertension (33%).

In a multicentre, phase II trial conducted by the Interna- tional Thyroid Oncology Group, cabozantinib demonstrated clinically meaningful anti-tumour activity in patients with

progressive MTC previously treated with VEGFR-targeted TKIs (VEGFR-TKIs) [76]. A total of 25 patients were enrolled, the majority of whom had received one prior VEGFR-TKI (sorafenib, pazopanib, or cediranib). Radio- logical assessments were performed every 8 weeks. Partial responses were observed in 40% of patients, stable disease in 52%, and 8% were non-evaluable. Median PFS and OS were 12.7 months and 34.7 months, respectively. The most frequently reported TRAEs included fatigue (grade 3, 12%), weight loss (grade 3, 12%), diarrhoea (grade 3, 8%), palmar-plantar erythrodysesthesia (grade 3, 8%), and hypertension (grade 3, 4%), as well as neutropenia (grade 3, 12%), elevation in lipase or amylase (12%), elevation in liver transaminase (4%), hypocalcaemia and hypomagne- semia (4%), hyponatraemia and hypokalaemia (8%). One treatment-related death was reported. These findings high- light the durable efficacy and acceptable safety profile of cabozantinib in previously-treated advanced MTC.

Cabozantinib Monotherapy - Phase III

A double-blind phase III trial evaluated the role of cabozan- tinib compared to placebo in patients with documented pro- gressive MTC [77]. Treatment with cabozantinib resulted in a significantly prolonged median PFS of 11.2 months compared to 4.0 months with placebo (HR, 0.28; 95% CI, 0.19-0.40; p<0.001). This benefit in PFS was consistently observed across all subgroups, irrespective of age, RET mutation status, or prior exposure to TKIs. The ORR was 28% in the cabozantinib arm, compared to 0% with pla- cebo, with this difference maintained even after adjustment for RET mutation status. At 12 months, 47.3% of patients receiving cabozantinib remained alive and progression- free, in contrast to 7.2% in the placebo group. The most frequently reported TRAEs associated with cabozantinib included diarrhoea (15.9%), reduced weight and appetite (10%), palmar-plantar erythrodysesthesia (12.6%), and fatigue (9.3%), nausea (1.4%), hypertension (8.4%), dys- geusia and hair colour changes (0.5% both), stomatitis (1.9%), haemorrhage (3.3%), vomiting (2.3%), mucosal inflammation (3.3%), asthenia (5.6%) and, less frequently (<5%) rash, headache, oropharyngeal pain, abdominal pain, pain in extremity, back pain, dyspnea, arthralgia, dizziness, oral pain, dysphagia, cough and muscle spasms, erythema and glossodynia. These toxicities led to treatment discon- tinuation in 16% of patients in the cabozantinib group and 8% of those receiving placebo.

The efficacy of cabozantinib in advanced MTC was assessed in the pivotal EXAM trial, a randomised, double- blind, phase III study comparing cabozantinib to placebo in 330 patients with radiographically-progressive, meta- static MTC [78]. Treatment with cabozantinib 140 mg/

Table 4 Studies on the effect of Cabozantinib in the treatment of thyroid cancer
Study	Number of patients & tumour characteristics	Treatment characteristics (median dose & duration of treatment)	Mean PFS (months) [95% CI] and/or OS (months)	Efficacy objective response rate (ORR) & disease control Rate (DCR)	Treatment related adverse events
Phase II retrospec-	Pts with poorly differen-	Median time on treatment	Median PFS 12.9 months	57%	TRAEs: gastrointestinal (50%),hyper- tension (33%), dermatologic (17%)
tive study - Poorly Differentiated Thyroid Carcinoma (Elghawy et al., 2024)	tiated thyroid carcinomas progressing on treatment with lenvatinib (N=3), sorafenib (N=3) or no treatment (N=1)	10.53 months	Median OS 14.21 months (PR in 4/7 patients)	- PR, 4 patients (57%) - SD, 2 patients (29%) - PD, 1 patient (14%)
Prospective Phase II -	Pts with refractory MTC (N=25)	Starting dose 60 mg/day Median duration of follow-up was 22.8 (95% CI, 21.2 to 30.2) months	Median PFS 12.7 (95% CI: 10.9 to 34.7) months; Median OS 34.7 months (95% CI: 18.3 to NR)	PR rate 40%, - Median time to achieve: 2 months (range 2 to 8) - Median duration of PR 11.3 months (95% CI: 10.3 to NR) SD rate 52%	TRAEs (grade 3) fatigue & weight loss (both 12%), diarrhoea & palmar- plantar erythrodysesthesia (both 8%), hypertension (4%). Biochemical changes included: neutropenia, eleva- tion in lipase or amylase (both 12%) or liver transaminase (4%), hypocalcemia or hypomagnesemia (both 4%), hypo- natremia or hypokalemia (both 8%). Finally one treatment related death
MTC after VEGFR-TKI (Cabanillas et al., 2017)	Pts with refractory MTC (N=25)
Double blind phase III trial - MTC (Elisei et al., 2013)	Pts with documented radiological progres- sion of metastatic MTC (N=330)	Cabozantinib 140 mg/day or placebo Median time of follow up: 13.9 monhts (range 3.6 to 32.5)	Primary analysis: Cabozantinib vs. placebo, - median PFS: 11.2 months vs. 4.0 months (HR 0.28; 95% CI: 0.19-0.40) - median PFS at year 1: 47.3% vs. 7.2% Secondary analysis - after minimum F-up 42 months, median OS 26.6 months vs. 21.1 months (HR 0.85, 95% CI: 0.64 to 1.12) - RET+MTC, median OS 44.3 vs. 18.9 months (HR 0.60, 95% CI: 0.38 to 0.94)	Cabozantinib vs. placebo: ORR 28% vs. 0% (placebo)	TRAEs: diarrhoea (15.9%), reduced weight and appetite (10%), palmar- plantar erythrodysesthesia (12.6%), and fatigue (9.3%), nausea (1.4%), hyper- tension (8.4%), dysgeusia and hair colour changes (0.5% both), stomatitis (1.9%), hemorrhage (3.3%), vomiting (2.3%), mucosal inflammation (3.3%), asthenia (5.6%) and less frequently (<5%) rash, headache, oropharyngeal pain, abdominal pain, pain in extrem- ity, back pain, dyspnea, arthralgia, dizziness, oral pain, dysphagia, cough and muscle spasms, erythema and glossodynia
Double blind phase III EXAM trial (Schlum- berger et al., 2017)	Pts with documented radiological progres- sion of metastatic MTC (N=330)	Cabozantinib 140 mg/day or placebo Median treatment duration: - cabo 10.8 monhts -placebo 3.4 months	Median OS - Cabo vs. placebo: 5.5 months HR 0.85 (95% CI: 0.64 to 1.12) Stratified by RET mutation: RET positive, - cabo, median OS 44.3 months - placebo, median OS 18.9 months HR 0.60 (95% CI: 0.38 to 0.94) RET negative - cabo, median OS 20.2 months - placebo, median OS 21.5 months HR 1.12 (95% CI: 0.70 to 1.82)	Cabozantinib: ORR 28% vs. placebo - RET positive subgroup: ORR 34% - RET negative subgroup: 20%	Grade 3: Diarrhoea (21.5%), decreased weight (9.8%), palmar-plantar eryth- rodysesthesia (12.6%), low appetite (7%), nausea (1.9%), fatigue (9.8%), dysgeusia (0.5%), hair color changes (0.5%), hypertension (8.9%), stomatitis (2.3%) Grade 5: oesophageal bleeding (1 patient)

Table 4 (continued)
Study	Number of patients & tumour characteristics	Treatment characteristics (median dose & duration of treatment)	Mean PFS (months) [95% CI] and/or OS (months)	Efficacy objective response rate (ORR) & disease control Rate (DCR)	Treatment related adverse events
Randomized, double	pts with RAIR DTC	Cabozantinib 60 mg/day	ITT population vs. placebo:	OITT population, cabozantinib,	Grade 3 or 4 SREs: palmar-plantar
blind, placebo	progressing on treatment	or placebo	PFS	ORR 15% (95% CI: 5.8 to 29.3)	erythrodysaesthesia (10%), hyperten-
controlled, Phase III	with sorafenib, lenvatinib	Median f-up at data	- cabo, median 'not reached' (96% CI	vs. placebo 0 (95% CI: 0 to 14.8)	sion (9%), and fatigue (8%).
- RAIR-DTC (COS-	or both were assigned to	cut-off,	5.7-not estimable)	Disease stabilization rate
MIC-311) (Brose et al.,	cabozantinib (N=125)	ITT population 6.2	- placebo, 1.9 months (1.8-3.6);	OITT, cabo vs. placebo: 60% (95% CI: 47 to 71.5) vs. 27% (95% CI: 13.3 to 45.5) ITT
2021)	and placebo (N=62)	months (IQR 3.4-9.2) OITT population 8.9 months (IQR 7.1-10.5)	- HR 0.22 (96% CI 0.13-0.36)
			OS
			- cabo, median 'not reached' - survival estimates, cabo vs. placebo,
			85% (95% CI: 75 to 91) vs. 73%	Cabo: 43% (95% CI: 34.4 to 52.4)
			(95% CI: 58.4 to 83.7) HR 0.54 (95% CI: 0.27 to 1.11)	Cabo: 43% (95% CI: 34.4 to 52.4)
			(95% CI: 58.4 to 83.7) HR 0.54 (95% CI: 0.27 to 1.11)	Placebo: 16% (95% CI: 8.0 TO 27.7)
				DOR
				OITT: Cabo vs. placebo, NR (95% CI: 4.1 to NE) vs. NA ITT: Cabo vs. placebo, NR (95% CI: 4.1 to NE) vs. NA
Subgroup analysis - RAIR DTC (COSMIC - 311) (Capdevila et al.,	Pts on prior treatment were randomized to cabozantinib (N=170) or	cabo: Cabozantinib 60 mg/day Duration of treatment for	Stratified for prior treatment, Median PFS cabozantinib vs. placebo: - Prior sorafenib 16.6 months (HR	Stratified for prior treatment, ORR - Prior sorafenib, 21% (95% CI: 11.5 to 32.7) - Prior lenvatinib 4% (95% CI: 0.9 to 12.4)	Grade 3/4 TEAEs included hyperten- sion, palmar-plantar erythrodysethesia, fatigue, hypocalcemia Grade 5: no cases of treatment related adverse events
2024)	placebo (N=88) - Prior sorafenib, n=96 - Prior lenvatinib,	- Prior sorafenib, median 7 months (95% CI: 0.9 to 18.8)	0.13; 95% CI: 0.06-0.26), - Prior lenvatinib 5.8 months (HR
	placebo (N=88) - Prior sorafenib, n=96 - Prior lenvatinib,	- Prior sorafenib, median 7 months (95% CI: 0.9 to 18.8)	0.28; 95% CI: 0.16-0.48),
	n=102 - Prior treatment with both, n=60	- Prior lenvatinib, median 5.6 months (95% CI: 0.2 to 16.3) - Prior treatment with both, 5.9 months (95% CI: 0.6 to 16)	- Prior lenvatinib & sorafenib, 7.6	- Prior treatment with both, 8% (95% CI: 1.6 to 20.9) Disease stabilization rate - Prior sorafenib 70% (95% CI: 57 to 80.8) - Prior lenvatinib 41% (95% CI: 29.4 to 53.8)
			months (HR 0.27; 95% CI: 0.13-
			0.54), relative to placebo arms-
			Stratified per histology: Median PFS cabozantinib vs. placebo - papillary 9.2 vs. 1.9 months - Follicular 11.2 vs. 2.5 months
			- Oncocytic 11.2 vs. 2.5 months - Poorly differentiated 7.4 vs. 1.8 months	- Prior treatment with both, 46% (95% CI: 30.1 to 62.8) Stratified for histology, pts on cabozantinib vs. placebo,
				- Papillary 15% vs. 0% - Follicular 8% vs. 0% - Oncocytic 11% vs. 0% - Poorly differentiated 9% vs. 0%.

Table 4 (continued)
Study	Number of patients & tumour characteristics	Treatment characteristics (median dose & duration of treatment)	Mean PFS (months) [95% CI] and/or OS (months)	Efficacy objective response rate (ORR) & disease control Rate (DCR)	Treatment related adverse events
Phase II CaboNivolpi trial - Cabozan- tinib +Ipilimumab/ Nivolumab (Konda et al., 2025)	Pts with RAID DTC who progressed on treatment with VEGFR- targeted therapy (N=10 evaluable)	Cabozantinib 40 mg daily for 2 weeks -> Cabozantinib 40 mg/day, nivolumab 240 mg IV every 2 weeks and ipili- umab 1 mg/kg IV every 6 weeks for 4 cycles -> cabozantinib 40 mg/day and nivolumab 480 mg IV every 4 weeks Median f-up 13.4 months	Median PFS 8 months (95% CI: 3.0 to 'not reached') Median OS, 19.2 months (95% CI: 4.6 to 'not reached')	First 6 months of treatment - Evaluable patients, ORR 10% PR rate - ITT, ORR 9% Overall ORR, 20% (95% CI: 3 to 56) DoR 27.3 months	Grade 3/4 treatment-related adverse events (AEs) were noted in 55% (6/11) and grade 5 AEs in 18% (2/11) of patients. The most common treatment- related AE was hypertension.
Prospective, multi- centre, phase II study (Capdevila et al., 2025; Castillon et al., 2023)	Study included six cohorts with advanced refractory tumours Preliminary results for ATC (n=14)	Median dose Cabozantinib 40 mg/day, median duration of treat- ment 3.1 months (95% CI: 0.5 to 4.2) Atezo 1200 mg Q3W: median duration of treat- ment 4.5 months, (95% CI: 1.5 to 18.0)	Median PFS: - BRAF mutated 2.7 monhts (95% CI: 0.4 to NR) - BRAF-wild type 5.7 months (95% CI: 3.6 to NR) Median OS: - BRAF mutated: 4.2 months (1.7 to NR) - BRAF wild type: 18.9 monhts (95% CI: 4.2 to NR)	ORR: 2, 14.29% (95% CI: 1.78 to 42.81) DCR: 9, 64.3% (95% CI: 35.1 to 87.2) DoR median 20.4 (range: 11.5 to 29.4)	Most frequent grade ≥ 3 toxicities: Fatigue (7.5%), neutropenia (6.5%), liver enzyme increase (6.5%), two deaths due to drug-related ischemic stroke and pancreatitis

Abbreviations: PFS Progression-Free Survival, ORR Objective Response Rate, PR Partial Response, CR Complete Response, DCR Disease Control Rate, NR Not Reached, CIConfidence Inter- val, OS Overall Survival, GEP-NENGastroenteropancreatic Neuroendocrine Neoplasm, RAIR radioiodine refractory, DTC differentiated thyroid cancer (papillary or follicular and their vari- ants), MTC medullary thyroid cancer, ITTintention to treat population, Pts Patients, VEGFR vascular endothelial growth factor receptor, IVintravenously, TKItyrosine kinase inhibitors, IQR interquartile range

day resulted in a numerically-prolonged median OS of 5.5 months compared to placebo; however, this difference did not reach statistical significance (HR 0.85; 95% CI: 0.64-1.12; p=0.24). In a prespecified subgroup analysis stratified by RET M918T mutation status, patients harbour- ing the RET M918T mutation demonstrated a significantly improved median OS with cabozantinib (44.3 months) ver- sus placebo (18.9 months) (HR 0.60; 95% CI: 0.38-0.94; p=0.03). Conversely, in patients without the RET M918T mutation, no OS benefit was observed (median OS 20.2 vs. 21.5 months; HR 1.12; 95% CI: 0.70-1.82; p=0.63). Grade 3 TRAEs included diarrhoea (21.5%), decreased weight (9.8%), palmar-plantar erythrodysesthesia (12.6%), low appetite (7%), nausea (1.9%), fatigue (9.8%), dysgeusia (0.5%), hair colour changes (0.5%), hypertension (8.9%), and stomatitis (2.3%). The investigators also reported a sin- gle grade 5 event of oesophageal bleeding.

The COSM1 Phase III trial [79] investigated the efficacy of cabozantinib in patients with RAIR-DTC, including fol- licular and papillary subtypes and their variants. Patients were stratified based on prior exposure to lenvatinib or other VEGFR-targeted therapies, such as sorafenib. Interim anal- ysis of PFS demonstrated an ORR of 15% (95% CI: 5.8- 29.3), with responses observed in 10 out of 67 patients in the cabozantinib arm, whereas no responses were reported in the placebo group. The risk for disease progression or death was HR 0.22 (95% CI: 0.13-0.36; p<0.0001), indicating a statistically significant benefit in favour of cabozantinib. TRAEs Grade 3 or 4 included palmar-plantar erythrodys- aesthesia (10%), hypertension (9%), and fatigue (8%). As these data are from an interim analysis, the apparent ben- efit of cabozantinib should be interpreted with caution until final efficacy and survival results are available.

In the recently published results of the CABATEN trial [39], six cohorts of patients with advanced refractory tumours were enrolled, including a subgroup of 14 patients with anaplastic thyroid carcinoma (ATC). In this ATC cohort, patients received cabozantinib at a median dose of 40 mg/day for a median duration of 3.1 months (95% CI: 0.5-4.2) and atezolizumab 1200 mg every three weeks for a median of 4.5 months (95% CI: 1.5-18.0). Median PFS was 2.7 months (95% CI: 0.4-NR) in BRAF-mutated cases and 5.7 months (95% CI: 3.6-NR) in BRAF wild- type cases, whereas the median OS was 4.2 months (95% CI: 1.7-NR) for BRAF-mutated and 18.9 months (95% CI: 4.2-NR) for BRAF wild-type. The ORR was 14.3% (95% CI: 1.78-42.81), and the disease control rate was 64.3% (95% CI: 35.1-87.2), with a median DoR of 20.4 months (range 11.5-29.4). TRAEs Grade≥3 toxicities were rela- tively rare: fatigue (10%), alanine amino-transferase ele- vation (9%), neutropenia (7%), and hypertension (5%) predominated. Notably, one patient experienced a grade

3 myocardial infarction; two treatment-related deaths occurred (acute pancreatitis and ischemic stroke), both during the first week of cabozantinib plus atezolizumab at 40 mg/day. Across the trial, patient-reported quality of life was maintained.

Cabozantinib Combination Therapy - Phase II

The CaboNivolpi phase II trial evaluated the efficacy of cabozantinib treatment in combination with ipilimumab and nivolumab in patients with RAIR DTC [80]. The study assessed a total of 10 patients and reported an ORR of 10% within the first 6 months of treatment (partial response, one patient). The median OS was 19.2 months (95% CI: 4.6 to “not reached”) and the median PFS was 9 months (95% CI: 3.0 to ‘not reached’). TRAEs of grade 3/4 were docu- mented in 55% of patients and grade 5 in 18% of patients, with the most common being hypertension. TRAEs grade 3/4 treatment-related adverse events (AEs) were noted in 55% (6/11) and grade 5 AEs in 18% (2/11) of patients. The most common treatment-related AE was hypertension.

In a subgroup analysis of the referenced phase III trial [81], cabozantinib demonstrated significantly prolonged PFS across all prior treatment categories when compared to placebo. Specifically, median PFS was extended to 16.6 months in patients previously treated with sorafenib alone (HR 0.13; 95% CI: 0.06-0.26), 5.8 months in those treated with lenvatinib alone (HR 0.28; 95% CI: 0.16-0.48), and 7.6 months in patients who had received both agents (HR 0.27; 95% CI: 0.13-0.54), relative to placebo arms with PFS ranging from 1.9 to 3.2 months. ORRs to cabozan- tinib also varied by prior treatment: 21% for patients who had been pretreated with sorafenib only, 4% for those who had been pretreated with lenvatinib only, and 8% for those exposed to both, with no responses observed in any of the placebo groups. Histological subgroup analysis further supported the efficacy of cabozantinib, with a median PFS (cabozantinib vs. placebo) observed as follows: papillary (9.2 vs. 1.9 months; HR 0.27; 95% CI: 0.17-0.43), fol- licular (11.2 vs. 2.5 months; HR 0.18; 95% CI: 0.10-0.31), oncocytic (11.2 vs. 2.5 months; HR 0.06; 95% CI: 0.02- 0.21), and poorly-differentiated thyroid carcinoma (7.4 vs. 1.8 months; HR 0.18; 95% CI: 0.08-0.43). Corresponding ORRs were 15%, 8%, 11%, and 9%, respectively, with no responses reported in placebo-treated patients across histo- logical subtypes. TRAEs were also noted; grade 3/4 effects occurred in up to 63% of patients with prior sorafenib treatment, up to 57% of patients with prior lenvatinib and 69% of those with prior lenvatinib and sorafenib. Most common side effects were hypertension,,palmar-plantar erythrodysesthesia, hypocalcaemia and fatigue. No grade 5 TRAEs were reported.

Conclusions

In this review, we have critically summarised the avail- able clinical evidence on the use of cabozantinib, admin- istered either as monotherapy or in combination regimens, across endocrine malignancies. In NENs, cabozantinib demonstrated clinically meaningful activity, particularly in well-differentiated pancreatic and extra-pancreatic sub- types, with small but consistent improvements in PFS and disease control rates across Phase II and III studies. The addition of temozolomide or lanreotide in select regi- mens appears promising, although further validation in biomarker-selected populations is warranted. In patients with PPGLs, the data suggest that cabozantinib achieves durable disease control and progression delay, with toler- ability largely acceptable. Cabozantinib exerts clinically meaningful activity across PPGL molecular subtypes, driven predominantly by its broad anti-angiogenic and anti- invasive effects rather than genotype-specific mechanisms. In ACC, cabozantinib has shown encouraging results in some patients who have received prior treatment. Cabo- zantinib may appear to fill a critical therapeutic gap in this otherwise chemoresistant disease. Finally, in thyroid can- cer, particularly RAIR-DTC and MTC, cabozantinib has consistently outperformed placebo, improving PFS and objective response rates. The observed activity extends to poorly differentiated subtypes and lenvatinib/sorafenib- refractory settings, supporting its role as a second-line or salvage therapeutic option. However, limitations should be recognised, including variability in histopathological clas- sification and grading, which remains an issue in PPGL and NEN research and may affect the interpretation and gener- alisability of reported outcomes.

Collectively, the emerging evidence supports the inte- gration of cabozantinib into the therapeutic landscape of endocrine oncology, particularly for tumours characterised by the dysregulation of angiogenic and mesenchymal sig- nalling pathways. However, even in true responders, the duration of response was not especially durable or impres- sive, although probably best results were seen in PPGLs. Its efficacy in ACC is significant, however, as there are very few therapeutic options for this disease. For MTC, the newer less broad-brush TKIs, such as pralsetinib and selp- ercatinib, may prove to be as or more effective with fewer side effects [82]. For all these tumours, however, escape in often a matter of months is of concern, and the presence of not insignificant adverse effects does bring into question whether a small increase in PFS is clinically valuable. We feel that the use of cabozantinib should be based on an indi- vidualised clinical assessment, with due consideration for efficacy, published data on the robustness of responses, and adverse event profile.

The problem of escape is also important theoretically, as it brings into focus the possibility of utilising multiple sig- nalling antagonists as important first-line combination ther- apies rather than sequential treatments when initial efficacy is lost. This has been shown in cell lines and patient-derived PPGLs, and it is possible that more aggressive combination therapies would allow for more durable responses in vitro [83]. In an in vivo model of acquired resistance of a pan- creatic NET to everolimus, an inhibitor of PI3Ka overcame such resistance, and possibly the use of both drugs ab initio would have blocked such resistance developing [84]. Future studies should prioritise consideration of combination strat- egies and biomarker-driven patient selection to optimise outcomes while minimising toxicity.

Author Contributions EA wrote the main manuscript text and pre- pared figures and tables. TVL reviewed the revised version of the manuscript, contributing as histopathologist. AG reviewed and revised the manuscript and tables/figures. All authors reviewed and approved the final version of the manuscript.

Data Availability No datasets were generated or analysed during the current study.

Declarations

Competing interests The authors declare no competing interests.

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The Utility of Cabozantinib in the Therapy of Endocrine Tumours

Abstract

Introduction

Mechanism of Action and Molecular Targets of Cabozantinib

Neuroendocrine Neoplasms

Histopathological Diagnosis and Molecular Hallmarks

Evidence Supporting the Use of Cabozantinib in Neuroendocrine Neoplasms

Cabozantinib-Only Treatment: Phase II

Cabozantinib-Only Treatment: Phase III

Cabozantinib Combination Therapy: Phase II

Phaeochromocytoma and Paraganglioma (PPGL)

Classification and Molecular Clustering

Molecular Stratification and Therapeutic Implications

Evidence Supporting Cabozantinib Treatment in PPGLs

Cabozantinib Monotherapy: Phase II

Cabozantinib Combination Therapy

Future Directions: Cabozantinib in the Post- Belzutifan Landscape

Adrenocortical Carcinoma

Classification and Molecular Pathogenesis

Primary Neoplasm Description

Histopathologic and Molecular Hallmarks

Molecular and Therapeutic Implications

Evidence Supporting Cabozantinib Treatment in ACC

Cabozantinib-Monotherapy

Combination Therapy

Thyroid Cancer

Classification and Molecular Pathogenesis

Evidence Supporting Cabozantinib Therapy in Thyroid Cancer

Cabozantinib Monotherapy - Phase II

Cabozantinib Monotherapy - Phase III

Cabozantinib Combination Therapy - Phase II

Conclusions

Declarations

References

Graph View

Table of Contents

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