Safety and dosimetry of [¹⁷⁷Lu]Lu-DOTA-TATE in adolescent patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumours, or pheochromocytomas and paragangliomas: Primary analysis of the Phase II NETTER-P study

Abstract

Purpose

NETTER-P, an open-label Phase II study, evaluated the safety and dosimetry of [¹⁷⁷Lu]Lu-DOTA-TATE (hereafter ¹⁷⁷Lu-DOTATATE) in adolescents with advanced, somatostatin receptor-positive, well-differentiated, Grade 1/2 gastroenteropancreatic neuroendocrine tumours (GEP-NET) or pheochromocytoma and paragangliomas (PPGL).

Methods

Patients (12–17 years old) received four cycles of ¹⁷⁷Lu-DOTATATE (7.4 GBq every 8 ± 1 weeks; cumulative administered activity: 29.6 GBq). Primary endpoints were absorbed dose (kidneys and bone marrow) and safety after first administration. Safety during treatment and comparative assessments of dosimetry and pharmacokinetics between adolescents and historical adult patients were evaluated.

Results

Eleven patients (4 GEP-NET, 7 PPGL; median age 15 [range, 13–17] years) were enrolled and received ≥ 1 administration of ¹⁷⁷Lu-DOTATATE. Median (range) cumulative administered activity was 28.2 (7.3–29.9) GBq. Lymphopenia/lymphocyte count decreased and headache were the most common adverse events (AEs) during Cycle 1 (each 4/11 [36%]). Cycle 1 Grade ≥ 3 AEs occurred in 4/11 patients (36%). During the treatment period, the most common AE was lymphopenia/lymphocyte count decreased (7/11 [64%]; Grade ≥ 3, 5/11 [45%]). No clinically meaningful impacts on safety biomarkers nor any treatment-related nephrotoxicities were observed. Projected median (range) cumulative absorbed doses (four administrations) were 21 (14–40) Gy in kidneys and 0.76 (0.55-1.0) Gy in bone marrow (using blood data). Dosimetry values were predicted to be within safety thresholds for adolescents and adults; pharmacokinetics were comparable in both populations.

Conclusion

No new safety signals attributable to ¹⁷⁷Lu-DOTATATE were identified in adolescents with GEP-NET or PPGL versus adults with GEP-NET. Long-term follow-up is ongoing.

Trial registration

ClinicalTrials.gov, NCT04711135. Registered 15 January 2021.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00259-025-07246-7.

Introduction

Management of gastroenteropancreatic neuroendocrine tumours (GEP-NET) and pheochromocytoma and paragangliomas (PPGL) in paediatrics can be challenging due to the very low incidence in children/adolescents and lack of clinical data [1–4]. Analysis of the US Surveillance, Epidemiology, and End Results registry identified only 37 cases of GEP-NET in children/young teenagers between 1975 and 2012 [4]. In Europe, estimated incidence rates (per 100,000) were 0.043, 0.005 and 0.003 for GEP-NET (non-functioning), pheochromocytoma and paraganglioma, respectively, in children aged 0–14 years (period of diagnoses 2000–2007). These rates were 0.222, 0.009 and 0.011, respectively, in those aged 15–24 years [3]. Though recent epidemiological data are lacking, incidence rates in the paediatric population, as for adults, appear to be on the rise [4, 5]. Late diagnosis of these tumours, such that they are unresectable and already metastatic, is not uncommon due to indolent disease and non-specific symptoms (e.g. decreasing weight and painful abdomen for GEP-NET and hypertension, headaches and sweating for PPGL) [6–10]. PPGL in paediatric patients often have germline mutations, which can result in more aggressive disease and a higher prevalence of metastases compared with adults [8, 9]. NETs have also been diagnosed in children with genetic syndromes, such as von Hippel–Lindau disease [1, 11].

The radioligand therapy (RLT; also called molecular radiotherapy [MRT] and peptide receptor radionuclide therapy [PRRT]), [¹⁷⁷Lu]Lu-DOTA-TATE (hereafter ¹⁷⁷Lu-DOTATATE), is a radiolabelled somatostatin analogue (SSA) with a high affinity for somatostatin receptor (SSTR) type 2 [12]. Many NETs, including GEP-NET and PPGL, have high expression of SSTR that can be exploited diagnostically and therapeutically [13]. The approval of ¹⁷⁷Lu-DOTATATE for adults with SSTR-positive GEP-NET [14, 15] was based on the results of the randomised Phase III NETTER-1 trial [16] and the Phase I/II Erasmus study [14, 15]. Although ¹⁷⁷Lu-DOTATATE is not approved for the treatment of PPGL, there are reports of its use in adults. A meta-analysis of 201 patients who received PRRT (¹⁷⁷Lu-DOTATATE, ⁹⁰Y-DOTATOC and ⁹⁰Y-DOTATATE) for advanced PPGL concluded it was a safe and effective therapeutic option [17]. Encouraging efficacy and a favourable safety profile in patients with PPGL have also been described in a systematic review evaluating ¹⁷⁷Lu-DOTATATE (97 patients) and in a report from a Spanish registry of patients treated with PRRT, which included 31 patients treated with ¹⁷⁷Lu-DOTATATE [18, 19].

As most research focusses on the adult population, and given the limited available therapies for the paediatric population and scarcity of paediatric data [20, 21], the treatment of unresectable GEP-NET and PPGL in children/adolescents constitutes an area of high unmet need. There are no published clinical studies on the use of ¹⁷⁷Lu-DOTATATE in paediatric GEP-NET, but case reports have shown effectiveness in children aged 8–13 years [22–24]. A high-specific activity ¹³¹I-metaiodobenzylguanidine agent was approved in the USA for paediatric patients with PPGL [25], but in early 2024 its production was to be discontinued, with the manufacturer citing its limited usage and high costs as unsustainable [26]. Some articles describing the treatment of PPGL with ¹⁷⁷Lu-DOTATATE have included children in the study population, but only a single patient in each report [27–30].

This publication documents the primary results of the Phase II NETTER-P study, which evaluated the safety and dosimetry of ¹⁷⁷Lu-DOTATATE in adolescents with SSTR-positive GEP-NET or PPGL, and compares the pharmacokinetics plasma exposure and dosimetry between adolescent and adult patients using a full efficacy extrapolation approach. As a result of this study, ¹⁷⁷Lu-DOTATATE has recently been approved by the US Food and Drug Administration (FDA) for paediatric patients aged ≥ 12 years with SSTR-positive GEP-NET [14, 31].

Materials and methods

Study design and patient population

NETTER-P (NCT04711135) was a multicentre, open-label, single-arm, Phase II study. Patients were enrolled across seven centres in France, Poland, Spain, the UK and the USA. The study is ongoing in terms of follow-up but has closed to recruitment. Eligible patients were aged from 12 to 17 years at the time of enrolment and were diagnosed with metastatic/locally advanced, inoperable (curative intent), histologically proven, Grade 1/2 (Ki-67 index ≤ 20%) well-differentiated GEP-NET (GEP-NET cohort) or PPGL (PPGL cohort). SSTR expression was confirmed by an SSTR imaging modality ≤ 3 months prior to enrolment; tumour uptake observed in the target lesions had to be greater than or equal to normal liver uptake. Performance status was ≥ 50 (Karnofsky score/Lansky Play-Performance Scale score). Key exclusion criteria included an estimated creatinine clearance < 70 mL/min (estimated by the Cockroft–Gault method); haemoglobin concentration < 5.0 mmol/L (< 8.0 g/dL); white blood cell count < 2 × 10/L; platelet count < 75 × 10⁹/L; total bilirubin > 3× upper limit of normal for age; and serum albumin < 3.0 g/dL, unless prothrombin time was within the normal range. Patients were also excluded if they had an established/suspected pregnancy; current spontaneous urinary incontinence; other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of uterine cervix, unless definitively treated and no proven evidence of recurrence for 5 years; or incompatibility to computed tomography (CT) scans with intravenous contrast due to allergic reaction/renal insufficiency, unless the patient was eligible for magnetic resonance imaging (MRI).

Treatment

Patients were treated with four cycles of ¹⁷⁷Lu-DOTATATE (4 × 7.4 GBq), intravenously infused over 30–40 min, every 8 ± 1 weeks for a cumulative administered activity of 29.6 GBq. Administered activity adjustments were permitted to enable patients who could not tolerate the protocol-specified dosing schedule (e.g. those with severe/intolerable adverse reactions or dose-modifying toxicities) to continue treatment. Patients also received an intravenous 2.5% Lys-Arg amino-acid infusion (25 g L-lysine-HCl and 25 g L-arginine-HCl in 1000 mL) for renal protection. This started ≥ 30 min before each ¹⁷⁷Lu-DOTATATE administration and continued for ≥ 3 h afterwards, for a total of 4 h, although an extension of up to 6 h was permitted if necessary. An antiemetic was administered prior to the amino-acid infusion for prevention of infusion-related nausea/vomiting. An external data safety monitoring board evaluated dosimetry and safety after the first ¹⁷⁷Lu-DOTATATE administration for each patient. If dosimetry measurements suggested patients were at risk of exceeding the cumulative absorbed dose thresholds of 29 Gy in the kidneys or 2 Gy in the bone marrow, administered activity adjustments were proposed by the data safety monitoring board. Regarding the cumulative absorbed dose threshold selected for the kidneys, it should be noted that the true threshold that predisposes patients to kidney toxicity has not been identified. However, 29 Gy was selected for this study based on other published literature describing nephrotoxicity with ¹⁷⁷Lu-DOTATATE [32, 33], notably the absence of Grade ≥ 3 nephrotoxicity in a long-term follow-up of 11 patients who received kidney absorbed doses exceeding 28 Gy [32].

Endpoints and assessments

The co-primary objectives were to evaluate ¹⁷⁷Lu-DOTATATE organ absorbed doses and safety/tolerability in adolescents with GEP-NET and PPGL (as a pooled cohort). The co-primary endpoints were incidence of adverse events (AEs) and laboratory toxicities after the first ¹⁷⁷Lu-DOTATATE administration and absorbed dose in target organs (kidneys and bone marrow).

Secondary objectives were to evaluate cumulative and long-term safety in the pooled cohort and perform comparative assessments of dosimetry and pharmacokinetics between adolescents (as a pooled cohort) and adult patients with GEP-NET (from the NETTER-1 and Erasmus studies for dosimetry; from NETTER-1 for pharmacokinetics). Safety-related secondary endpoints were the incidence of AEs and laboratory toxicities during treatment and short-term follow-up (until 6 months after the last ¹⁷⁷Lu-DOTATATE administration) and during long-term follow-up (until 5 years after the last administration). The final secondary endpoint was calculated organabsorbed doses and pharmacokinetic parameters based on imaging/blood radioactivity concentration data from adolescents with SSTR-positive GEP-NET and PPGL (as a pooled cohort) compared with the predicted distribution/organabsorbed doses.

Evaluation of patients as separate cohorts (for target organabsorbed doses and safety) and efficacy were exploratory endpoints. Efficacy endpoints were objective response rate (rate of complete and partial responses), progression-free survival (PFS; time from enrolment to disease progression/death) and overall survival (OS; time from enrolment to death) in adolescents with GEP-NET and PPGL as separate cohorts. Tumour dosimetry was also explored.

Safety assessments were performed during treatment and follow-up (see Supplementary Methods for details).

Dosimetry and pharmacokinetic assessments were performed locally during Week 1 after the first ¹⁷⁷Lu-DOTATATE administration (or, if not feasible, after the second). Whole-body planar images were acquired on Day 1 (1–3 h post-infusion), 2, 3, 4 and 8 after the first administration. Single-photon emission computed tomography/computed tomography (SPECT/CT) scans were taken on Day 2 (24 h after the first administration). Imaging protocols were standardised across all participating sites to reduce methodological error. Dosimetry analyses to project cumulative absorbed dose from four administrations of ¹⁷⁷Lu-DOTATATE were performed centrally using hybrid imaging (whole-body planar plus SPECT/CT) and blood radioactivity data (see Supplementary Methods for details of radioactivity measurements). Planar activities at the time point corresponding to SPECT/CT scans were scaled based on the results of the SPECT image quantification per the standard hybrid method [34].

Radioactivity concentrations were decay-corrected to the start of infusion and converted to mass units (ng/mL) by the specific activity of the individual patient dose at the start of infusion. The pharmacokinetic data set was analysed using a population approach to derive maximum blood concentration [C_max], time at which C_max was reached [T_max], area under the concentration-time curve from time zero extrapolated to infinity [AUC_inf], time for plasma concentration to decline by 50% during the distribution phase [T_1/2α] and the elimination phase [T_1/2β], systemic clearance and volume of distribution.

The pharmacokinetic parameters in adolescents were compared with those of adults (AUC from time zero to the time of last measured concentration [AUC_last], C_max, T_max, T_½α and T_½β) at the population level. The predicted cumulative absorbed radiation dose in target organs and the accuracy of the model were evaluated by comparing dosimetry values (i.e. the potential probability of exceeding 29 Gy for kidneys and 2 Gy for bone marrow after four cycles) to confirm a similar exposure-response relationship between adolescents and adults after four cycles of treatment at 7.4 GBq.

Tumour response was assessed locally according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Contrast-enhanced CT or MRI scans were performed at screening, before the third and fourth administrations, on Week 13 and 25 after the last administration and every 6 months thereafter.

Statistical analyses

All patients who received ≥ 1 administration of ¹⁷⁷Lu-DOTATATE were included in analyses of safety (safety set) and efficacy (full analysis set). Dosimetry and pharmacokinetic analysis sets included all patients with ≥ 1 valid dosimetry measurement and ≥ 1 valid pharmacokinetic measurement, respectively. No formal sample size or power calculations were made. Based on simulations from adult kidney and bone marrow dosimetry models using adolescent-specific characteristics (e.g. age, weight and creatinine clearance), it was thought that an overall sample size of ≥ 8 patients would provide an adequate probability of observing acute toxicities and confirm organ dosimetry results. For all statistical analyses, unless otherwise specified, SAS version 9.4 was used.

A full efficacy extrapolation approach was used for comparative assessment of kidney and bone marrow dosimetry and plasma pharmacokinetics in adolescents and adults. Adult pharmacokinetic data (blood radioactivity concentration) from NETTER-1 were analysed by a population approach using a two-compartmental model with a zero-order input and linear elimination. Adult kidney and bone marrow dosimetry data were described by empirical models, based on pooling adult data from the NETTER-1 and Erasmus studies and having radioactive injected activity and renal function (creatinine clearance) as predictors of kidney and bone marrow dosimetry. Furthermore, adolescent kidney and bone marrow dosimetry data from the NETTER-P trial were pooled with adult data (from the NETTER-1 and Erasmus studies) to re-estimate previously developed empirical dosimetry model parameters and describe the relationship between covariates and dosimetry. Plots of observed pharmacokinetic and dosimetry data from adolescent patients were overlaid with predictions using the adult model to verify that the model adequately characterised the adolescent population. Individually derived pharmacokinetic data were compared with the adult population to ensure that adolescent values were within the estimates determined from the adult population. For dosimetry, pooled analyses using all adolescent and adult data were conducted. Parameters from the dosimetry models were re-estimated based on population-based non-linear mixed-effect modelling.

Results

Patient characteristics

NETTER-P enrolled 11 adolescent patients (GEP-NET, n = 4; PPGL, n = 7) between 01 September 2022 and 23 October 2023 (Fig. 1). All patients with GEP-NET completed four cycles of ¹⁷⁷Lu-DOTATATE treatment. Among patients with PPGL, 5/7 had completed all four cycles at data cutoff (12 March 2024); one patient was still receiving treatment and one patient discontinued treatment but remained in the study follow-up after Cycle 1 (physician decision). At data cutoff, the median follow-up time was 10.2 months (range, 4.4–17.9) and nine patients were still being followed post-treatment (Fig. 1; GEP-NET, n = 3; PPGL, n = 6). One patient with GEP-NET discontinued the study after experiencing disease progression during the short-term follow-up period (physician decision).

Fig. 1.

Patient flow. GEP-NET gastroenteropancreatic neuroendocrine tumour, PPGL pheochromocytoma and paraganglioma

^a Data cutoff 12 March 2024

The median age of all patients (6 females and 5 males) was 15 years (range, 13–17) and all patients had distant metastases (Table 1). The primary tumour sites for patients with GEP-NET were the pancreas (n = 2), rectum (n = 1) and stomach (n = 1). The GEP-NET grade, according to Ki-67 index, was Grade 1 (Ki-67 < 3%) and Grade 2 (Ki-67 3–20%) for two patients each. The tumour types in the PPGL cohort were paragangliomas (extra-adrenal; n = 5 patients) and pheochromocytomas (adrenal; n = 2 patients). In total, ten patients (GEP-NET: 4/4; PPGL: 6/7) received prior antineoplastic therapy/procedures of any type. Of these patients, all ten had undergone prior antineoplastic surgery, including one case of nephrectomy and one case of nephroureterectomy in the PPGL cohort. Five patients received prior antineoplastic medications (GEP-NET, 4/4 [SSAs n = 3; alkylating agents n = 2; pyrimidine analogues n = 2]; PPGL, 1/7 [alkylating agents]). One patient with PPGL had undergone prior radiotherapy.

Table 1.

Baseline demographic and clinical characteristics (full analysis set)

Baseline characteristic	GEP-NET cohort N = 4	PPGL cohort N = 7	All patients N = 11
Age (years), median (range)	15.5 (15–16)	14.0 (13–17)	15.0 (13–17)
< 16 years	2 (50.0)	4 (57.1)	6 (54.5)
16–17 years	2 (50.0)	3 (42.9)	5 (45.5)
Sex
Female	2 (50.0)	4 (57.1)	6 (54.5)
Male	2 (50.0)	3 (42.9)	5 (45.5)
Race
White	2 (50.0)	3 (42.9)	5 (45.5)
Black or African American	1 (25.0)	0	1 (9.1)
Asian	0	1 (14.3)	1 (9.1)
Other	0	1 (14.3)	1 (9.1)
Not reported	1 (25.0)	2 (28.6)	3 (27.3)
CrCl (mL/min), median (range)	124.75 (86.0–156.0)	124.00 (90.0–160.0)	124.00 (86.0–160.0)
Weight (kg), median (range)	58.35 (50.0–71.8)	50.20 (40.6–64.2)	54.30 (40.6–71.8)
BMI (kg/m²), median (range)	22.46 (17.9–24.9)	19.18 (16.0–24.2)	21.21 (16.0–24.9)
Karnofsky or Lansky PS at baseline
100	3 (75.0)	6 (85.7)	9 (81.8)
90	0	1 (14.3)	1 (9.1)
80	1 (25.0)	0	1 (9.1)
Distant metastases present	4 (100.0)	7 (100.0)	11 (100.0)
Prior antineoplastic therapy/procedures
No	0	1 (14.3)	1 (9.1)
Yes	4 (100.0)	6 (85.7)	10 (90.9)
Primary site of GEP-NET
Pancreas	2 (50.0)	NA
Rectum	1 (25.0)	NA
Stomach	1 (25.0)	NA
NET status
Functional	2 (50.0)	NA
Nonfunctional	2 (50.0)	NA
GEP-NET grade (according to Ki67 index)
Grade 1 (< 3%)	2 (50.0)	NA
Grade 2 (3–20%)	2 (50.0)	NA
PPGL tumour type
Pheochromocytoma (adrenal)	NA	2 (28.6)
Paraganglioma (extra-adrenal)	NA	5 (71.4)
Abdominal cavity	NA	4 (80.0)
Other	NA	1 (20.0)
Chromaffin tissue
Sympathetic	NA	4 (57.1)
Missing	NA	3 (42.9)
123I-MIBG uptake
Positive	NA	4 (57.1)
Not done	NA	3 (42.9)

Data are presented as n (%) unless otherwise stated

¹²³I-MIBG¹²³I-metaiodobenzylguanidine, BMI body mass index, CrCl creatinine clearance, GEP-NET gastroenteropancreatic neuroendocrine tumour, NA not applicable, NET neuroendocrine tumour, PPGL pheochromocytoma and paraganglioma, PS performance status

Treatment exposure

The median number of ¹⁷⁷Lu-DOTATATE cycles administered was 4.0 (range, 1–4) (Supplementary Table S1). One patient (PPGL) received one cycle of ¹⁷⁷Lu-DOTATATE and discontinued treatment. The median cumulative decay-corrected administered activity was 28.2 GBq (range, 7.3–29.9); 29.1 GBq (28.2–29.5) for patients with GEP-NET and 22.1 GBq (7.3–29.9) for patients with PPGL. In the PPGL cohort, two patients received reduced administered activity (50%) after Cycle 1 after kidney dosimetry thresholds were exceeded; additionally, one patient received reduced administered activity (50%) at Cycle 4 due to Grade 3 neutropenia after Cycle 3. No patients with GEP-NET required administered activity reductions.

Safety

Two patients (18%), one from each cohort, experienced AEs (drug infusion reactions: headache, flush, nausea, weakness, hot flush; all Grade 1) that resulted in infusion interruptions. There were no ¹⁷⁷Lu-DOTATATE treatment discontinuations due to AEs.

During the first cycle of ¹⁷⁷Lu-DOTATATE, 10/11 patients (91%) experienced AEs (Table S2). The most common were lymphopenia/lymphocyte count decreased and headache (each 4/11; 36%) (Table S3). Five Grade ≥ 3 AEs were recorded in 4/11 patients (36%) in Cycle 1 (Table S3).

During the treatment period, all patients experienced ≥ 1 AE; the most common was lymphopenia/lymphocyte count decreased (7/11; 64%) (Table 2). Grade ≥ 3 AEs were recorded in 7/11 patients (64%) (Table 2). Grade ≥ 3 AEs relating to ¹⁷⁷Lu-DOTATATE were observed in 5/11 patients (45%); the most common were lymphopenia/lymphocyte count decreased (5/11; 45%) and neutropenia/neutrophil count decreased (3/11; 27%) (Table 3). AEs relating to nephrotoxicities (based on the broad search strategy) were experienced by two patients (one had Grade 3 portal vein thrombosis on Day 28 [Cycle 1]; another had Grade 3 proteinuria on Day 1 [Cycle 1] and Grade 3 deep vein thrombosis on Day 100 [Cycle 2]) but were considered unrelated to ¹⁷⁷Lu-DOTATATE.

Table 2.

Adverse events during treatment of Grade ≥ 3 severity or occurring in ≥ 2 patients (safety set)

Primary system organ class Preferred term	GEP-NET cohort N = 4		PPGL cohort N = 7		All patients N = 11
	All grades	Grade ≥ 3	All grades	Grade ≥ 3	All grades	Grade ≥ 3
Patients with at least 1 AE	4 (100.0)	2 (50.0)	7 (100.0)	5 (71.4)	11 (100.0)	7 (63.6)
Blood and lymphatic system disorders
Anaemia	2 (50.0)	1 (25.0)	2 (28.6)	0	4 (36.4)	1 (9.1)
Lymphopenia and lymphocyte count decreaseda	2 (50.0)	1 (25.0)	5 (71.4)	4 (57.1)	7 (63.6)	5 (45.5)
Neutropenia and neutrophil count decreasedb	1 (25.0)	1 (25.0)	4 (57.1)	2 (28.6)	5 (45.5)	3 (27.3)
GI disorders
Nausea	1 (25.0)	0	3 (42.9)	0	4 (36.4)	0
Abdominal pain	2 (50.0)	0	1 (14.3)	0	3 (27.3)	0
Diarrhoea	2 (50.0)	0	1 (14.3)	0	3 (27.3)	0
Vomiting	1 (25.0)	0	2 (28.6)	0	3 (27.3)	0
Lower GI haemorrhage	1 (25.0)	1 (25.0)	0	0	1 (9.1)	1 (9.1)
General disorders/administration site conditions
Fatigue	1 (25.0)	0	2 (28.6)	0	3 (27.3)	0
Influenza-like illness	1 (25.0)	0	1 (14.3)	0	2 (18.2)	0
Hepatobiliary disorders
Portal vein thrombosis	1 (25.0)	1 (25.0)	0	0	1 (9.1)	1 (9.1)
Infections and infestations
Upper respiratory tract infection	1 (25.0)	0	1 (14.3)	0	2 (18.2)	0
Urinary tract infection	1 (25.0)	0	1 (14.3)	0	2 (18.2)	0
Viral infection	1 (25.0)	0	1 (14.3)	0	2 (18.2)	0
Device-related infection	0	0	1 (14.3)	1 (14.3)	1 (9.1)	1 (9.1)
Investigations
WBC count decreased	1 (25.0)	1 (25.0)	2 (28.6)	1 (14.3)	3 (27.3)	2 (18.2)
Blood bilirubin increased	0	0	2 (28.6)	0	2 (18.2)	0
Metabolism/nutrition disorders
Hypercalcaemia	1 (25.0)	1 (25.0)	0	0	1 (9.1)	1 (9.1)
Nervous system disorders
Headache	2 (50.0)	0	4 (57.1)	0	6 (54.5)	0
Dizziness	1 (25.0)	0	1 (14.3)	0	2 (18.2)	0
Renal and urinary disorders
Proteinuria	0	0	1 (14.3)	1 (14.3)	1 (9.1)	1 (9.1)
Respiratory, thoracic and mediastinal disorders
Epistaxis	2 (50.0)	0	1 (14.3)	0	3 (27.3)	0
Skin/subcutaneous tissue disorders
Dry skin	1 (25.0)	0	1 (14.3)	0	2 (18.2)	0
Vascular disorders
Deep vein thrombosis	0	0	1 (14.3)	1 (14.3)	1 (9.1)	1 (9.1)

Data are presented as n (%)

GEP-NET gastroenteropancreatic neuroendocrine tumour, GI gastrointestinal, PPGL pheochromocytoma and paraganglioma, PT preferred term, SOC system organ class, WBC white blood cell

^a PT lymphopenia from SOC blood and lymphatic system disorders and PT lymphocyte count decreased from SOC investigations have been pooled together under PT lymphopenia and lymphocyte count decreased from SOC blood and lymphatic system disorders

^b PT neutropenia from SOC blood and lymphatic system disorders and PT neutrophil count decreased from SOC investigations have been pooled together under PT neutropenia and neutrophil count decreased from SOC blood and lymphatic system disorders

Table 3.

Adverse events relating to ¹⁷⁷Lu-DOTATATE during treatment (safety set)

Primary system organ class Preferred term	GEP-NET cohort N = 4		PPGL cohort N = 7		All patients N = 11
	All grades	Grade ≥ 3	All grades	Grade ≥ 3	All grades	Grade ≥ 3
Patients with at least1 AE	3 (75.0)	1 (25.0)	7 (100.0)	4 (57.1)	10 (90.9)	5 (45.5)
Blood and lymphatic system disorders
Lymphopenia and lymphocyte count decreaseda	2 (50.0)	1 (25.0)	4 (57.1)	4 (57.1)	6 (54.5)	5 (45.5)
Neutropenia and neutrophil count decreasedb	1 (25.0)	1 (25.0)	4 (57.1)	2 (28.6)	5 (45.5)	3 (27.3)
Anaemia	0	0	2 (28.6)	0	2 (18.2)	0
Leukopenia	0	0	1 (14.3)	0	1 (9.1)	0
GI disorders
Nausea	1 (25.0)	0	3 (42.9)	0	4 (36.4)	0
Abdominal pain	1 (25.0)	0	0	0	1 (9.1)	0
Abdominal pain upper	0	0	1 (14.3)	0	1 (9.1)	0
Diarrhoea	0	0	1 (14.3)	0	1 (9.1)	0
Vomiting	0	0	1 (14.3)	0	1 (9.1)	0
General disorders/administration site conditions
Fatigue	1 (25.0)	0	2 (28.6)	0	3 (27.3)	0
Asthenia	1 (25.0)	0	0	0	1 (9.1)	0
Injury, poisoning and procedural complications
Infusion-related reaction	1 (25.0)	0	0	0	1 (9.1)	0
Investigations
WBC count decreased	1 (25.0)	1 (25.0)	2 (28.6)	1 (14.3)	3 (27.3)	2 (18.2)
Alanine aminotransferase increased	0	0	1 (14.3)	0	1 (9.1)	0
Blood bilirubin increased	0	0	1 (14.3)	0	1 (9.1)	0
Weight decreased	1 (25.0)	0	0	0	1 (9.1)	0
Neoplasms benign, malignant and unspecified
Skin papilloma	1 (25.0)	0	0	0	1 (9.1)	0
Nervous system disorders
Headache	0	0	2 (28.6)	0	2 (18.2)	0
Skin/subcutaneous tissue disorders
Eczema	0	0	1 (14.3)	0	1 (9.1)	0
Vascular disorders
Hot flush	0	0	1 (14.3)	0	1 (9.1)	0

Data are presented as n (%)

GEP-NET gastroenteropancreatic neuroendocrine tumour, GI gastrointestinal, PPGL pheochromocytoma and paraganglioma, PT preferred term, SOC system organ class, WBC white blood cell

^a PT lymphopenia from SOC blood and lymphatic system disorders and PT lymphocyte count decreased from SOC investigations have been pooled together under PT lymphopenia and lymphocyte count decreased from SOC blood and lymphatic system disorders

^b PT neutropenia from SOC blood and lymphatic system disorders and PT neutrophil count decreased from SOC investigations have been pooled together under PT neutropenia and neutrophil count decreased from SOC blood and lymphatic system disorders

There were three serious AEs (SAEs; all Grade ≥ 3) reported in 2/11 patients (18%), which were all considered unrelated to ¹⁷⁷Lu-DOTATATE by investigators. One patient (GEP-NET) experienced SAEs of lower GI haemorrhage during Cycle 1 and hypercalcaemia during treatment (pre-existing hypercalcaemia due to disease was evident at enrolment). Another patient (PPGL) had an SAE of device (catheter)-related infection during treatment that resolved within 2 days.

During Cycle 1, laboratory haematologic abnormalities included lymphocyte count decreased (all grades, 10/11 patients [91%]; Grade ≥ 3, 3/11 [27%]); anaemia (all grades, 8/11 [73%]); white blood cell count decreased (all grades, 6/11 [55%]); neutrophil count decreased (all grades, 4/11 [36%]; Grade ≥ 3, 1/11 [9%]); and eosinophilia (all grades, 1/11 [9%]). Biochemistry abnormalities observed in ≥ 2 patients during Cycle 1 included creatinine increased (3/11 [27%]) and blood bilirubin increased, blood lactate dehydrogenase increased and hypomagnesaemia (all 2/11 [18%]). No Grade ≥ 3 biochemistry abnormalities were observed during Cycle 1.

During the treatment period, Grade ≥ 3 laboratory haematologic abnormalities included lymphocyte count decreased (7/11 [64%]), neutrophil count decreased (3/11 [27%]) and white blood cell count decreased (3/11 [27%]) (Table 4). The most frequent biochemistry abnormality during the treatment period was hypomagnesaemia (6/11 [55%]) and only one Grade ≥ 3 event was reported (hypercalcaemia, as described above).

Table 4.

Worst post-baseline laboratory abnormalities during treatment (safety set)

	GEP-NET cohort N = 4		PPGL cohort N = 7		All patients N = 11
	All grades	Grade ≥ 3	All grades	Grade ≥ 3	All grades	Grade ≥ 3
Haematology abnormalities
Anaemia	4 (100.0)	0	6 (85.7)	0	10 (90.9)	0
Eosinophilia	0	0	1 (14.3)	0	1 (9.1)	0
Lymphocyte count decreased	4 (100.0)	2 (50.0)	7 (100.0)	5 (71.4)	11 (100.0)	7 (63.6)
Neutrophil count decreased	2 (50.0)	1 (25.0)	4 (57.1)	2 (28.6)	6 (54.5)	3 (27.3)
Platelet count decreased	2 (50.0)	0	0	0	2 (18.2)	0
WBC count decreased	4 (100.0)	1 (25.0)	5 (71.4)	2 (28.6)	9 (81.8)	3 (27.3)
Biochemistry abnormalities
ALP increased	2 (50.0)	0	0	0	2 (18.2)	0
AST increased	1 (25.0)	0	0	0	1 (9.1)	0
Blood bilirubin increased	1 (25.0)	0	2 (28.6)	0	3 (27.3)	0
Blood LDH increased	1 (25.0)	0	1 (14.3)	0	2 (18.2)	0
Creatinine increased	2 (50.0)	0	2 (28.6)	0	4 (36.4)	0
GGT increased	1 (25.0)	0	0	0	1 (9.1)	0
Hypercalcaemia	1 (25.0)	1 (25.0)	0	0	1 (9.1)	1 (9.1)
Hyperkalaemia	1 (25.0)	0	2 (28.6)	0	3 (27.3)	0
Hypoalbuminaemia	1 (25.0)	0	0	0	1 (9.1)	0
Hypocalcaemia	1 (25.0)	0	2 (28.6)	0	3 (27.3)	0
Hypokalaemia	1 (25.0)	0	1 (14.3)	0	2 (18.2)	0
Hypomagnesaemia	4 (100.0)	0	2 (28.6)	0	6 (54.5)	0
Hyponatraemia	2 (50.0)	0	0	0	2 (18.2)	0

Data are presented as n (%)

ALP alkaline phosphatase, AST aspartate aminotransferase, GEP-NET gastroenteropancreatic neuroendocrine tumour, GGT gamma-glutamyl transferase, LDH lactate dehydrogenase, PPGL pheochromocytoma and paraganglioma, WBC white blood cell

There were no clinically meaningful observations for post-baseline abnormalities in other safety parameters (including safety biomarkers of growth and development). By data cutoff, no deaths had been reported. All safety data were consistent across both disease cohorts.

Dosimetry

Overall, the mean ± standard deviation (SD) and median (range) absorbed dose coefficient of ¹⁷⁷Lu-DOTATATE was 0.78 ± 0.28 and 0.71 (0.46–1.3) Gy/GBq in the kidneys and 0.026 ± 0.0050 and 0.026 (0.019–0.035) Gy/GBq in the red marrow (estimated using blood data) (Table 5). For a planned cumulative administered activity of 29.6 GBq (based on four administrations of ¹⁷⁷Lu-DOTATATE), the organs receiving the largest projected cumulative absorbed doses (mean ± SD and median [range]) were the pituitary glands (33 ± 13 and 30 [18–56] Gy) and kidneys (23 ± 8.3 and 21 [14–40] Gy). The projected cumulative absorbed dose in the red marrow by blood was 0.78 ± 0.15 and 0.76 (0.55–1.0) Gy (Table 5). Target organ dosimetry values were comparable between the GEP-NET and PPGL cohorts. The mean cumulative absorbed dose received by the tumour lesions based on dosimetric calculations was high in both disease cohorts compared with organs (Table 5; Table S4). Mean ± SD and median (range) projected cumulative absorbed doses in tumour lesions were 76 ± 35 and 69 (41–150) in the GEP-NET cohort (8 lesions) versus 44 ± 34 and 36 (4.9–98) Gy in the PPGL cohort (10 lesions).

Table 5.

Mean organ and tumour dosimetry parameters following ¹⁷⁷Lu-DOTATATE administration (dosimetry analysis set)

	GEP-NET cohort N = 4		PPGL cohorta N=6		All patients N = 10
	Absorbed dose coefficient (Gy/GBq)	Projected CAD (Gy)	Absorbed dose coefficient (Gy/GBq)	Projected CAD (Gy)	Absorbed dose coefficient (Gy/GBq)	Projected CAD (Gy)
Kidneys, n  Mean (SD)  Median (range)	4 0.71 (0.25) 0.71 (0.46–0.96)	4 21 (7.3) 21 (14–28)	6 0.82 (0.32) 0.71 (0.55–1.3)	6 24 (9.3) 21 (16–40)	10 0.78 (0.28) 0.71 (0.46–1.3)	10 23 (8.3) 21 (14–40)
Pituitary, n  Mean (SD)  Median (range)	3 1.2 (0.43) 1.1 (0.93–1.7)	3 37 (13) 32 (28–51)	6 1.0 (0.45) 0.93 (0.61–1.9)	6 31 (13) 28 (18–56)	9 1.1 (0.43) 1.0 (0.61–1.9)	9 33 (13) 30 (18–56)
Red marrow (blood), n  Mean (SD)  Median (range)	4 0.024 (0.0035) 0.024 (0.019–0.027)	4 0.70 (0.10) 0.72 (0.55–0.79)	6 0.028 (0.0052) 0.029 (0.022–0.035)	6 0.83 (0.16) 0.87 (0.64–1.0)	10 0.026 (0.0050) 0.026 (0.019–0.035)	10 0.78 (0.15) 0.76 (0.55–1.0)
Spleen, n  Mean (SD)  Median (range)	4 0.63 (0.39) 0.55 (0.28–1.1)	4 19 (12) 16 (8.3–34)	6 0.82 (0.17) 0.81 (0.64–1.1)	6 24 (5.0) 24 (19–31)	10 0.74 (0.27) 0.72 (0.28–1.1)	10 22 (8.1) 21 (8.3–34)
Urinary bladder wall, n  Mean (SD)  Median (range)	4 0.50 (0.034) 0.49 (0.47–0.54)	4 15 (1.0) 14 (14–16)	6 0.59 (0.096) 0.63 (0.47–0.68)	6 17 (2.8) 19 (14–20)	10 0.55 (0.089) 0.52 (0.47–0.68)	10 16 (2.6) 15 (14–20)
Total body, n  Mean (SD)  Median (range)	4 0.040 (0.013) 0.040 (0.022–0.055)	4 1.2 (0.40) 1.2 (0.66–1.6)	6 0.041 (0.0073) 0.0040 (0.033–0.052)	6 1.2 (0.21) 1.2 (0.97–1.5)	10 0.040 (0.0095) 0.0040 (0.022–0.055)	10 1.2 (0.28) 1.2 (0.66–1.6)
Tumour, n  Mean (SD)  Median (range)	8 2.6 (1.2) 2.3 (1.4–5.1)	8 76 (35) 69 (41–150)	10 1.5 (1.1) 1.2 (0.17–3.3)	10 44 (34) 36 (4.9–98)	18 2.0 (1.2) 1.9 (0.17–5.1)	18 58 (37) 55 (4.9–150)

Projected CAD (Gy) is defined as absorbed dose coefficient (Gy/GBq) × 4 × 7.4

CAD cumulative absorbed dose, GEP-NET gastroenteropancreatic neuroendocrine tumour, PPGL pheochromocytoma and paraganglioma, SD standard deviation

^a Due to SPECT/CT imaging issues, one patient from the PPGL cohort was excluded from the dosimetry analysis set. Additionally, one patient from the PPGL cohort had dosimetry assessed at Cycle 2 due to technical issues with the imaging equipment

The dosimetry extrapolation model (which compared median dosimetry values with 5th and 95th percentiles) showed that neither kidney nor bone marrow estimates from adults with GEP-NET were affected by the addition of pooled adolescent data, confirming similar dosimetry estimates, and the same empirical model could be used for both patient populations. The observed probabilities of exceeding 29 Gy for kidneys and 2 Gy for bone marrow after four cycles of ¹⁷⁷Lu-DOTATATE did not exceed 20% – which is considered to be the acceptable safety limit – for either adolescents (pooled cohorts; kidneys: 20%; bone marrow: 0%) or adults (kidneys: 13%; bone marrow: 6%) (Table 6).

Table 6.

Comparative assessment of ¹⁷⁷Lu-DOTATATE dosimetry in kidneys and bone marrow of adolescents and adults (dosimetry analysis set)

Scenario	N	Kidneys Probability (%) >29 Gy	Bone marrow Probability (%) >2 Gy
Observed
Adult GEP-NET	47	12.8	6.4
Adolescent GEP-NET and PPGL	10	20.0	0.0
Pooled adult GEP-NET and adolescent GEP-NET and PPGL	57	14.0	5.3
Predicteda
Adult GEP-NET		10.0 (7.8, 12.2)	11.0 (8.8, 13.4)
Adolescent GEP-NET and PPGL		20.9 (7.7, 36.7)	2.4 (0.0, 6.8)
Pooled adult GEP-NET and adolescent GEP-NET and PPGL		11.8 (6.4, 17.6)	9.2 (4.8, 13.6)

GEP-NET gastroenteropancreatic neuroendocrine tumour, PPGL pheochromocytoma and paraganglioma

^a Predicted probability median (5th, 95th percentile)

Pharmacokinetics

The pharmacokinetic analysis set included all 11 patients. ¹⁷⁷Lu-DOTATATE concentration–time profiles following one administration were comparable for both cohorts (Supplementary Fig. S1). The concentrations declined following a bi-exponential phase, with a quick first phase until 24 h and a slower second phase until 72 h post administration. ¹⁷⁷Lu-DOTATATE exposure was similar for both cohorts and the overall mean ± SD for C_max was 10.33 ± 0.54 ng/mL, AUC_inf was 35.84 ± 4.49 ng.h/mL and clearance was 5.98 ± 0.69 L/h; median (range) T_max was 0.5 (0.5–0.7) hours. The population values of T_½α and T_½β were 1.4 and 36.9 h, respectively.

Population pharmacokinetic models demonstrated similar exposure metrics (observed and predicted) between adolescents (pooled cohorts) and adults with GEP-NET, indicating that the model developed for this study predicted the pharmacokinetics of ¹⁷⁷Lu-DOTATATE reasonably well (Table 7). T_½α data were also similar between adolescents and adults (for adults, T_½α was 1.5 h, whereas T_½β was 59.1 h).

Table 7.

Comparative assessment of pharmacokinetics of ¹⁷⁷Lu-DOTATATE in adolescents and adults (pharmacokinetics analysis set)

Scenario	N	AUClast (ng.h/mL)a	Cmax (ng/mL)a	Tmax (hours)b
Observed
Adult GEP-NET	20	30.08 (50.38)	8.98 (73.28)	0.47 (0.25–1.17)
Adolescent GEP-NET and PPGL	11	41.00 (24.15)	11.17 (33.04)	0.58 (0.50–0.77)
Pooled adult GEP-NET and adolescent GEP-NET and PPGL	31	33.57 (45.07)	9.7 (61.18)	0.50 (0.25–1.17)
Predicted
Adult GEP-NET	20	31.01 (40.95)	6.80 (49.04)	0.50 (0.30–0.80)
Adolescent GEP-NET and PPGL	11	32.34 (10.43)	10.31 (5.22)	0.50 (0.50–0.70)
Pooled adult GEP-NET and adolescent GEP-NET and PPGL	31	31.48 (32.81)	7.89 (44.19)	0.50 (0.30–0.80)

AUC_last area under the concentration–time curve from dosing (time 0) to the time of last measured concentration, C_max maximum blood concentration, CV coefficient of variation, GEP-NET gastroenteropancreatic neuroendocrine tumour, PPGL pheochromocytoma and paraganglioma, T_max time at which C_max is reached

^a Geometric mean (geometric CV%); ^bMedian (range)

Efficacy

At data cutoff, PFS and OS data were immature. In the nine patients (GEP-NET, 3/4; PPGL, 6/7) with post-baseline tumour assessments, stable disease was the best overall response. Two patients were not evaluable; one patient (PPGL) discontinued after Cycle 1 and had no post-baseline assessment and one patient (GEP-NET) was no longer evaluable by MRI due to the introduction of metallic implants during partial resection (the remaining lesions could not be individualised on a CT scan). One patient (GEP-NET) had disease progression at 8.6 months and was subsequently withdrawn from the study (physician decision).

Discussion

NETTER-P was the first study to prospectively evaluate ¹⁷⁷Lu-DOTATATE safety and dosimetry in an adolescent patient population. No new safety signals were identified in adolescents with advanced, SSTR-positive GEP-NET/PPGL, and the safety profile was consistent with that observed in adults [14–16]. Mean cumulative absorbed doses of ¹⁷⁷Lu-DOTATATE in the target organs at risk were below the threshold limits set for this study (≤ 29 Gy for kidneys and ≤ 2 Gy for bone marrow) and were comparable between the disease cohorts. However, predicted dosimetry estimates assume that the same dose is received by organs/tumour after each fraction and may not necessarily be accurate [35]. The extrapolation model showed that the observed probabilities of exceeding 29 Gy for kidneys and 2 Gy for bone marrow after four cycles of ¹⁷⁷Lu-DOTATATE (7.4 GBq) did not exceed 20% (i.e. the acceptable safety limit) for either adolescents or adults. Pharmacokinetic parameters were comparable between disease cohorts, and between adolescents and adults (population pharmacokinetic model). An exploratory analysis of efficacy showed that, as of data cutoff, the best overall response was stable disease in the nine evaluable patients. Ten patients remained in the study; one patient (GEP-NET) had disease progression and discontinued the study (physician decision).

The recommended administration schedule of ¹⁷⁷Lu-DOTATATE for the treatment of GEP-NET is four cycles administered 8 weeks apart [14, 15], which aligns with the treatment regimen used in the NETTER-1 study of adults with midgut NETs [16, 36]. Real-world data from the international NETTER-R study (110 patients with advanced pancreatic NET) have shown that most patients (70%) in clinical practice receive all four scheduled cycles [37]. The results from this NETTER-P study in patients aged 12 to < 18 years suggest that the same regimen is suitable for the adolescent patient population. The overall safety profile observed was similar to that observed in adults [16, 36]. The most common AEs observed during treatment were lymphopenia/lymphocyte count decreased and headache. However, headache is a common symptom of PPGL [7, 8]; therefore, among the PPGL cohort, headache may have been related to the underlying disease or may have been an exacerbation of symptoms due to treatment-associated tumour-directed cell death. The most common Grade ≥ 3 AEs relating to ¹⁷⁷Lu-DOTATATE during treatment were lymphopenia/lymphocyte count decreased and neutropenia/neutrophil count decreased. All AEs relating to ¹⁷⁷Lu-DOTATATE, except for one case of lymphopenia, had resolved by data cutoff. Such haematotoxicities have been reported previously in adults with GEP-NET and PPGL treated with ¹⁷⁷Lu-DOTATATE [16–18]. A retrospective analysis of long-term haematotoxicity in patients treated with ¹⁷⁷Lu-DOTATATE (n = 203) concluded that myelosuppression was almost invariably transient in nature and of minor clinical relevance [38]. Due to the limited reports of ¹⁷⁷Lu-DOTATATE use in paediatrics, safety data are scarce. Foster et al. described ¹⁷⁷Lu-DOTATATE treatment in two children (aged 8 and 13 years) with metastatic NETs and reported minimal side effects [22]. ¹⁷⁷Lu-DOTATATE has been evaluated as a treatment for high-risk neuroblastoma in children. Safety data from 26 children with relapsed/refractory neuroblastoma treated with ¹⁷⁷Lu-DOTATATE included observations of Grade ≥ 3 thrombocytopenia (transient in most cases), with no significant renal toxicities observed [39, 40]. Similarly, no treatment-related nephrotoxicity was observed in NETTER-P, which administered a 2.5% Lys-Arg amino-acid solution for renal protection (per the adult protocol with ¹⁷⁷Lu-DOTATATE). Of note, there were no clinically meaningful changes in any of the growth and development safety biomarkers evaluated. Long-term safety monitoring is ongoing, with a special focus on kidney function and secondary malignancies, in addition to safety biomarkers of growth and development, bone development, reproductive (gonadal) function and endocrine (pituitary) function. Long-term safety monitoring is critical for adolescents, who have a longer life expectancy than adults.

There were no clinically relevant differences in ¹⁷⁷Lu-DOTATATE organ dosimetry or pharmacokinetics in adolescents versus adult patients from NETTER-1 (plus Erasmus for dosimetry) [14]. Both the observed and the model-derived predicted dosimetry estimates revealed a low probability of exceeding the proposed radiation threshold limits in the kidneys and bone marrow (29 and 2 Gy, respectively) after four cycles of ¹⁷⁷Lu-DOTATATE. Of note, these radiation threshold limits were extrapolated from experience with external beam radiotherapy, as they have not been defined for PRRT [41–44]. Due to differences in how radiation is delivered by the two therapies, the clinical relevance of the limits to PRRT is debatable, with suggestions that they may be overly cautious [42–45]. Nevertheless, the low probability of exceeding these conservative limits in NETTER-P supports the safety profile of ¹⁷⁷Lu-DOTATATE in adolescents. Across the study, the only difference observed between the disease cohorts was in tumour dosimetry, which was higher for GEP-NET than for PPGL. Larger studies are needed to confirm if this finding is clinically meaningful, as lesion dosimetry after ¹⁷⁷Lu-DOTATATE treatment is associated with high variability [46] and our observation was based on a small sample size.

Preliminary efficacy data in all evaluable patients demonstrated stable disease as the best response – including among the PPGL cohort, who had a lower mean projected tumour cumulative absorbed dose – indicating that radiation exposure was sufficient for tumour control. We acknowledge that the small sample size of NETTER-P (due to the rarity of the indications) limits the efficacy data reported and that a larger trial is needed to determine efficacy more reliably. However, efficacy has been determined from larger adult studies [16, 36, 47] and, along with the similar pharmacokinetics and safety observed in adolescents in NETTER-P compared with adults, has resulted in FDA approval for ¹⁷⁷Lu-DOTATATE to treat SSTR-positive GEP-NET in children aged ≥ 12 years [31]. Treatment modalities for children with advanced PPGL are limited. A recent international consensus statement on the management of PPGL in children and adolescents recommends PRRT as an option for metastatic disease if the lesions express the relevant receptor and do not have rapid progression [20]. Most PPGL have high expression of SSTR [48], making ¹⁷⁷Lu-DOTATATE a potential therapeutic option.

Our study does have some limitations. Due to the rarity of GEP-NET and PPGL in the adolescent population, the study was non-randomised and open-label and the sample size was very small. Additionally, the follow-up time for this analysis was relatively short (median 10.2 months); however, long-term safety monitoring, including assessment of secondary malignancies and biomarkers of endocrine and gonadal function and bone development, is ongoing. Finally, when this study was designed, it was considered appropriate to conduct dosimetry assessments after a single cycle of ¹⁷⁷Lu-DOTATATE and use the resulting data to project the cumulative absorbed dose for four cycles. However, based on the latest developments in the field, we acknowledge it would have been preferable to conduct multicycle dosimetry assessments.

In conclusion, no new safety signals attributable to ¹⁷⁷Lu-DOTATATE were identified in adolescents with SSTR-positive GEP-NET/PPGL. Organ dosimetry values were predicted to be within safety thresholds for adolescents and adults, while pharmacokinetics were comparable in both populations. As such, the standard scheduled regimen of four cycles of ¹⁷⁷Lu-DOTATATE (7.4 GBq) every 8 weeks (cumulative administered activity: 29.6 GBq) appears suitable for use in the adolescent population. All adolescent results, except tumour dosimetry, were consistent between the GEP-NET and PPGL cohorts, but sample sizes were very small. Further clinical trials in a larger adolescent population are recommended.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Author contributions

RS, LJS, PA, KP, GK, FK and FB contributed to the conception or design of the study. MNG, DH-J, TWL, CS, SW, AC, AK-G, CG-C, REK, PA, KP, GK, LB and ALG contributed to data collection. MNG, DH-J, RH, TWL, RS, SW, AK-G, LJS, PA, KP, GK, FK, LB, FB and ALG contributed to data analysis or interpretation. All authors critically reviewed the manuscript, provided final approval of the version to be published and agree to be accountable for the accuracy and integrity of the manuscript.

Funding

This study was funded by Advanced Accelerator Applications, a Novartis Company. Dr Mark N. Gaze is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre and by the Radiation Research Unit at the Cancer Research UK City of London Centre Award [C7893/A28990]. Dr Simon Wan is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre.

Data availability

Novartis is committed to sharing with qualified external researchers access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Declarations

Ethics approval

The trial was performed in accordance with the principles of the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guidelines and all applicable regulations. This study was approved by the institutional review board or independent ethics committee at each participating centre (France: Comité de Protection des Personnes Ile-de-France; Poland: Komisja Bioetyczna przy Centrum Onkologii Instytut im. M. Skłodowskiej Curie; Spain: CEIC Hospital General Universitario Gregorio Marañon; UK: London – Westminster Research Ethics Committee Health Research Authority; USA: Cincinnati Children’s Hospital Medical Center IRB, CHOP Committees for the Protection of Human Subjects and University of Kentucky IRB).

Consent to participate

Written informed consent was obtained from the parent/legal guardian for adolescents or adolescents signed assent along with parental/legal guardian consent or co-signed consent with parent/legal guardian in accordance with local regulations, prior to participation in the study.

Competing interests

MNG, RH, CS, SW, AC, AK-G, CG-C, LJS and REK have no relevant competing interests to disclose. DH-J has received travel grants and lecture fees from Ipsen, Novartis and Sanofi, and has acted as a consultant and served on advisory boards for Novartis. TWL has received research funding from Bayer and Pfizer, and has acted as a consultant and served on advisory boards for Advanced Microbubbles, AI Therapeutics, Bayer, GSK, ITM Oncologics, Jazz Pharmaceuticals and Massive Bio. RS declares that Novartis paid CDE Dosimetry Services to perform the dosimetry analysis. PA is an employee of Novartis. KP and GK are employees of Advanced Accelerator Applications, a Novartis Company. FK was an employee of Novartis at the time of manuscript development. LB is an employee of and holds stock and share options in Novartis. FB is an employee of and holds share options in Advanced Accelerator Applications, a Novartis Company. A-LG has received lecture fees and consultancy fees from Advanced Accelerator Applications (a Novartis company) and Curium.