Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET (NETTER-2)

A Phase III Multi-center, Randomized, Open-label Study to Evaluate the Efficacy and Safety of Lutathera in Patients With Grade 2 and Grade 3 Advanced GEP-NET

The aim of NETTER-2 was to determine if Lutathera in combination with long-acting octreotide prolongs progression free survival (PFS) in gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients with high proliferation rate tumors (G2 and G3), when given as a first line treatment compared to treatment with high dose (60 mg) long-acting octreotide. Somatostatin analog (SSA) naive patients were eligible, as well as patients previously treated with SSAs in the absence of progression.

Study Overview

• Status: Active, not recruiting
• Conditions: Gastro-enteropancreatic Neuroendocrine Tumor
• Intervention / Treatment: Drug: Lutathera; Drug: 30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot); Drug: 2.5% Lys-Arg sterile amino acid solution; Drug: High dose 60 mg octreotide long-acting repeatable

Detailed Description

The study consisted of a screening phase, a treatment phase, an optional cross-over phase for subjects assigned to the control arm, optional re-treatment phase for subjects assigned to the Lutathera arm, and a follow-up phase. This study compared treatment with Lutathera (7.4 GBq/200 mCi 4 × administrations every 8 weeks ± 1 week; cumulative dose: 29.6 GBq/800mCi) plus octreotide long-acting release (LAR) (30 mg every 8 weeks during Lutathera treatment and every 4 weeks after last Lutathera treatment) and high dose octreotide LAR (60 mg every 4 weeks).

• Study Type: Interventional
• Enrollment (Actual): 226
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • London, Canada
    • London Health Sciences Centre, University of Western Ontario - Oncology
  • Québec, Canada
    • Centre Hospitalier Universitaire de Quebec
  • Toronto, Canada
    • Sunnybrook Health Sciences Centre
  • Vancouver, Canada
    • BC Cancer Agency
• France
  • Clichy, France
    • CHU Paris Nord-Val de Seine
  • Lyon, France
    • Hospices Civils de Lyon (HCL) - Hopital Edouard Herriot
  • Montpellier, France
    • Institut du Cancer de Montpellier - Oncology
  • Nantes, France
    • CHU-Hôtel Dieu Service de Médecine Nucléaire
  • Villejuif, France
    • Institut Gustave Roussy
• Germany
  • Erlangen, Germany
    • Universitätsklinikum Erlangen
  • Essen, Germany
    • Universitätsklinikum Essen - Klinik für Nuklearmedizin
• Italy
  • Bologna, Italy
    • A.O.di Bologna Policl.S.Orsola
  • Genova, Italy
    • University of Genova - Oncology
  • Meldola, Italy
    • Istituto Oncologico Romagnolo
  • Milan, Italy
    • Ieo, Irccs
  • Milan, Italy
    • Fondazione IRCCS Istituto Nazionale Tumori
  • Napoli, Italy
    • IRCCS fondazione Pascale - Oncology
  • Reggio Emilia, Italy
    • Arcispedale Santa Maria Nuova, Reggio Emilia - Oncology
  • Roma, Italy
    • Azienda Ospedaliera Sant'Andrea - Università La Sapienza U.O.C. Mal App. Digerente e - Oncology
• Netherlands
  • Rotterdam, Netherlands
    • Erasmus Medisch Centrum
  • Utrecht, Netherlands
    • UMC Utrecht - Oncology
• South Korea
  • Seongnam-si, South Korea
    • Seoul National University Bundang Hospital
  • Seoul, South Korea
    • Asan Medical Center - Oncology
  • Seoul, South Korea
    • Seoul National University Hospital - Department of Internal Medicine
  • Seoul, South Korea
    • Severance Hospital, Yonsei University Health System - Medical Oncology
• Spain
  • Barcelona, Spain
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain
    • Hospital General Universitario Gregorio Marañón
  • Madrid, Spain
    • Hospital Universitario Ramon y Cajal
  • Valencia, Spain
    • Hospital Universitari i Politècnic La Fe
• United Kingdom
  • Bristol, United Kingdom
    • Bristol Haematology and Oncology Centre
  • London, United Kingdom
    • Guys and St Thomas Hospital
  • London, United Kingdom
    • Kings College Hospital - Oncology
  • London, United Kingdom
    • Royal Free Hospital, London
  • Sheffield, United Kingdom
    • Weston Park Hospital
• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale Cancer Center
  • Florida
    • Tampa, Florida, United States, 33612
      • USF - H. Lee Moffitt Cancer Center and Research Institute
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics - Oncology
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky UK Markey Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic - Oncology
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Presence of metastasized or locally advanced, inoperable (curative intent) histologically proven, well differentiated Grade 2 or Grade 3 gastroenteropancreatic neuroendocrine (GEP-NET) tumor diagnosed within 6 months prior to screening.
• Ki67 index ≥10 and ≤ 55%
• Patients ≥ 15 years of age and a body weight of > 40 kg at screening
• Expression of somatostatin receptors on all target lesions documented by CT/MRI scans, assessed by any of the following somatostatin receptor imaging (SRI) modalities within 3 months prior to randomization: [68Ga]-DOTA-TOC (e.g. Somakit-TOC®) PET/CT (or MRI when applicable based on target lesions) imaging, [68Ga]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) imaging (e.g. NETSPOT®), Somatostatin Receptor scintigraphy (SRS) with [111In]-pentetreotide (Octreoscan® SPECT/CT), SRS with [99mTc]-Tektrotyd, [64Cu]-DOTA-TATE PET/CT (or MRI when applicable based on target lesions) imaging.
• The tumor uptake observed in the target lesions must be > normal liver uptake.
• Karnofsky Performance Score (KPS) ≥ 60
• Presence of at least 1 measurable site of disease
• Patients who have provided a signed informed consent form to participate in the study, obtained prior to the start of any protocol related activities

Exclusion Criteria:

• Creatinine clearance < 40 mL/min calculated by the Cockroft Gault method
• Hb concentration < 5.0 mmol/L (<8.0 g/dL); WBC < 2x10E9/L (2000/mm3); platelets < 75x10E9/L (75x10E3/mm3)
• Total bilirubin > 3 x ULN
• Serum albumin < 3.0 g/dL unless prothrombin time is within the normal range
• Pregnancy or lactation
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study UNLESS they are using highly effective methods of contraception throughout the study treatment period (including cross-over and re-treatment, if applicable) and for 7 months after study drug discontinuation
• Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study.
• Documented RECIST progression to previous treatments for the current GEP-NET at any time prior to randomization
• Patients for whom in the opinion of the investigator other therapeutic options (eg chemo-, targeted therapy) are considered more appropriate than therapy offered in the study, based on patient and disease characteristics
• Any previous therapy with Interferons, Everolimus (mTOR-inhibitors), chemotherapy or other systemic therapies for GEP-NET administered for more than 1 month or within 12 weeks prior to randomization in the study.
• Any previous radioembolization, chemoembolization and radiofrequency ablation for GEP-NET
• Any surgery within 12 weeks prior to randomization in the study
• Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to screening in the study. Patients with a history of brain metastases must have a head CT or MRI with contrast to document stable disease prior to randomization in the study.
• Uncontrolled congestive heart failure (NYHA II, III, IV). Patients with history of congestive heart failure who do not violate this exclusion criterion will undergo an evaluation of their cardiac ejection fraction prior to randomization via echocardiography. The results from an earlier assessment (not exceeding 30 days prior to randomization) may substitute the evaluation at the discretion of the Investigator, if no clinical worsening is noted. The patient's measured cardiac ejection fraction in these patients must be ≥40% before randomization.
• QTcF > 470 msec for females and QTcF > 450 msec for males or congenital long QT syndrome
• Uncontrolled diabetes mellitus as defined by hemoglobin A1c value > 7.5%
• Hyperkaleamia > 6.0 mmol/L (CTCAE Grade 3) which is not corrected prior to study enrolment
• Any patient receiving treatment with short-acting octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of Lutathera, or any patient receiving treatment with SSAs (e.g. octreotide long-acting), which cannot be interrupted for at least 6 weeks before the administration of Lutathera.
• Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.
• Prior external beam radiation therapy to more than 25% of the bone marrow.
• Current spontaneous urinary incontinence
• Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years
• Patient with known incompatibility to CT Scans with IV contrast due to allergic reaction or renal insufficiency. If such a patient can be imaged with MRI, then the patient would not be excluded.
• Hypersensitivity to any somatostatin analogues, the IMPs active substance or to any of the excipients.
• Patients who have participated in any therapeutic clinical study/received any investigational agent within the last 30 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lutathera® plus Octreotide LAR 30 mg (Investigational arm); Lutathera treatment consisted of a cumulative administered radioactivity of 29.6 GBq (800mCi) (7.4 GBq/200 mCi x 4 administrations every 8 +/- 1 week). Participants in the Lutathera arm were concomitantly administered with octreotide LAR 30 mg (Sandostatin LAR Depot) the day after each administration of Lutathera and no earlier than 4 hours after completion of the Lutathera infusion. Once Lutathera treatment completed, participants continued the 4-week interval administrations of 30 mg octreotide LAR until the completion of the Treatment Phase. Concomitantly with Lutathera, sterile amino acid solution was administered to minimize renal radiation exposure during Lutathera treatment.	Drug: Lutathera; Lutathera is a sterile radiopharmaceutical supplied as a ready-to-use solution for infusion containing 177Lu-DOTA0-Tyr3-octreotate as a drug substance with a volumetric activity of 370 MBq/mL at reference date and time (calibration time). Each Lutathera infusion continued for 30 min.; Other Names: AAA601; Drug: 30 mg Octreotide long acting repeatable (LAR) (Sandostatin LAR Depot); Sandostatin® LAR Depot (octreotide LAR) is a pharmaceutical that was available in single-use kits containing a 6-mL vial of 10 mg, 20 mg, or 30 mg strength for intramuscular injection, a syringe containing 2.5 mL of diluent, two sterile 1½" 19-gauge needles, and two alcohol wipes.; Other Names: SOM230; Drug: 2.5% Lys-Arg sterile amino acid solution; Participants who received Lutathera were administered a concomitant 2.5% Lys-Arg solution for kidney protection, with each Lutathera dose. The 2.5% Lys-Arg solution was administered intravenously for 4 hours (infusion rate: 250 ml/h); the infusion was to start 30 minutes prior to the start of the Lutathera infusion and continue during (30 min) and up to at least 3 hours after the Lutathera infusion.
Active Comparator: Octreotide LAR 60 mg (Control arm); Participants were administered with octreotide LAR 60 mg (Sandostatin LAR Depot) at 4-week intervals until the completion of the Treatment Phase.	Drug: High dose 60 mg octreotide long-acting repeatable; Sandostatin® LAR Depot (octreotide LAR) is a pharmaceutical that was available in single-use kits containing a 6-mL vial of 10 mg, 20 mg, or 30 mg strength for intramuscular injection, a syringe containing 2.5 mL of diluent, two sterile 1½" 19-gauge needles, and two alcohol wipes.
Experimental: Optional post-progression re-treatment with Lutathera; Participants who received Lutathera in experimental arm and who progressed and met re-treatment eligibility criteria received additional 2 - 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles)	Drug: Lutathera; Lutathera is a sterile radiopharmaceutical supplied as a ready-to-use solution for infusion containing 177Lu-DOTA0-Tyr3-octreotate as a drug substance with a volumetric activity of 370 MBq/mL at reference date and time (calibration time). Each Lutathera infusion continued for 30 min.; Other Names: AAA601
Active Comparator: Optional post-progression cross-over to Lutathera; Participants who received Octreotide LAR in Active comparator arm and who progressed and met cross-over eligibility criteria received maximum 4 cycles of Lutaathera (7.4 GBq/200 mCi x 4 cycles) plus octreotide long-acting (30 mg every 8 weeks).	Drug: Lutathera; Lutathera is a sterile radiopharmaceutical supplied as a ready-to-use solution for infusion containing 177Lu-DOTA0-Tyr3-octreotate as a drug substance with a volumetric activity of 370 MBq/mL at reference date and time (calibration time). Each Lutathera infusion continued for 30 min.; Other Names: AAA601
Active Comparator: Optional post-progression re-treatment with Lutathera after cross-over; Participants who received Octreotide LAR in Active comparator arm subsequently entered cross-over, received Lutathera in cross-over, progressed for the second time and met re-treatment eligibility criteria could receive additional 2 - 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles).	Drug: Lutathera; Lutathera is a sterile radiopharmaceutical supplied as a ready-to-use solution for infusion containing 177Lu-DOTA0-Tyr3-octreotate as a drug substance with a volumetric activity of 370 MBq/mL at reference date and time (calibration time). Each Lutathera infusion continued for 30 min.; Other Names: AAA601; Drug: High dose 60 mg octreotide long-acting repeatable; Sandostatin® LAR Depot (octreotide LAR) is a pharmaceutical that was available in single-use kits containing a 6-mL vial of 10 mg, 20 mg, or 30 mg strength for intramuscular injection, a syringe containing 2.5 mL of diluent, two sterile 1½" 19-gauge needles, and two alcohol wipes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) Per Central Assessment	PFS is the time from randomization to the first line progression (centrally assessed according to RECIST 1.1) or death due to any cause. Progression is defined using Response Evaluation Criteria in Solid Tumor Criteria (RECIST 1.1) as a 20% increase in the sum of diameters of all measured target lesions or unequivocal progression of non-target lesions or appearance of a new lesion.	from randomization to the first line progression or death due to any cause, up to approx. 42 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) Per Central Assessment (Key Secondary)	ORR is defined as the percentage of patients with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.	Up to approx. 42 months
Time to Deteriration (TTD) Global Health Status, Diarrhea, Fatigue, Pain (EORTC QLQ-C30) (Key Secondary)	TTD is defined as the first deterioration of at least 10 points from baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30): global health status, diarrhea, fatigue, and pain. The Quality of Life Questionnaire C30 (QLQ-C30) was developed by the European Organization for Research and Treatment of Cancer (EORTC) to assess quality of life in cancer patients. It includes five function domains (physical, emotional, social, role, cognitive), eight symptoms (fatigue, pain, nausea/vomiting, constipation, diarrhea, insomnia, dyspnea, and appetite loss), as well as global health/quality-of-life and financial impact. Subjects respond on a four-point scale from "not at all" to "very much" for most items. Raw scores are linearly transformed so each score ranged a 0-100, where higher scores indicate worse symptoms (e.g., more severe/worsened) and lower scores indicate less symptoms (e.g., less severe/improvement).	Up to approx. 42 months
Disease Control Rate (DCR) Per Central Assessment	Disease Control Rate is the percentage of participants with a best overall response of complete response (CR), partial response (PR) or stable disease (SD) (centrally assessed according to RECIST 1.1). CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD).	Up to approx. 42 months
Duration of Response (DOR) Per Central Assessment	Duration of Response defined as time from first complete or partial response to progression or death due to underlying cancer according to RECIST 1.1.	Up to approx. 42 months
Rate of Adverse Events	Rate of adverse events scored according to CTCAE grade	from FPFV until end of study (about 94 months)
Rate of Laboratory Toxicities	Rate of laboratory toxicities scored according to CTCAE grade	from FPFV until end of study (about 94 months)
Overall Survival (OS)	OS is the time from randomization date until day of death due to any cause.	from FPFV until end of study (about 94 months)

Collaborators and Investigators

• Sponsor: Advanced Accelerator Applications
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Jungels C, Deleporte A. State of the art and future directions in the systemic treatment of neuroendocrine neoplasms. Curr Opin Oncol. 2021 Jul 1;33(4):378-385. doi: 10.1097/CCO.0000000000000740.
• Singh S, Halperin D, Myrehaug S, Herrmann K, Pavel M, Kunz PL, Chasen B, Tafuto S, Lastoria S, Capdevila J, Garcia-Burillo A, Oh DY, Yoo C, Halfdanarson TR, Falk S, Folitar I, Zhang Y, Aimone P, de Herder WW, Ferone D; all the NETTER-2 Trial Investigators. [177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high-dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet. 2024 Jun 29;403(10446):2807-2817. doi: 10.1016/S0140-6736(24)00701-3. Epub 2024 Jun 5.
• Bahri N, Crook C, Daneng Li. Casting a Wide NET: When Is the Optimal Time for 177Lu-Dotatate Treatment? Oncology (Williston Park). 2024 Nov 5;38(11):442-443. doi: 10.46883/2024.25921029.

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2020
• Primary Completion (Actual): July 20, 2023
• Study Completion (Estimated): October 29, 2027

Study Registration Dates

• First Submitted: May 24, 2019
• First Submitted That Met QC Criteria: May 31, 2019
• First Posted (Actual): June 3, 2019

Study Record Updates

• Last Update Posted (Actual): January 21, 2026
• Last Update Submitted That Met QC Criteria: January 4, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Lutathera; GEP-NET; NETTER-2; 177Lu-DOTA0-TATE; Lutetium oxodotreotide; Lutetium dotatate; AAA601
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Gastro-enteropancreatic neuroendocrine tumor; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Polycyclic Compounds; Hydrolases; Enzymes; Enzymes and Coenzymes; Macrocyclic Compounds; Peptides, Cyclic; Intracellular Signaling Peptides and Proteins; Esterases; Receptor-Like Protein Tyrosine Phosphatases; Protein Tyrosine Phosphatases; Phosphoric Monoester Hydrolases; Octreotide; lutetium Lu 177 dotatate; pasireotide; Receptor-Like Protein Tyrosine Phosphatases, Class 2
• Other Study ID Numbers: CAAA601A22301; 2023-507443-10-00 (Other Identifier: EU CTIS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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 is 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No