. 2025 Apr 4;25(1):613.

doi: 10.1186/s12885-025-13941-3.

A Randomized clinical trial evaluating the impact on survival and quality of life of ¹⁷⁷Lutetium[Lu]-edotreotide versus everolimus in patients with neuroendocrine tumors of the lung and thymus: the LEVEL study (GETNE T-2217)

Jaume Capdevila¹, Virginia Pubul², Urbano Anido³, Thomas Walter⁴, Javier Molina-Cerrillo⁵, Teresa Alonso-Gordoa⁵, Rocio Garcia-Carbonero^{6

7

8}, Maria San-Roman-Gil⁶, Belen Llana⁹, Paula Jimenez-Fonseca¹⁰, Marta Benavent Viñuales¹¹, Catherine Ansquer¹², Eric Baudin¹³, Come Lepage¹⁴, Maribel Del Olmo-García^{15

16}, José Carlos Ruffinelli¹⁷, Amandine Beron¹⁸, Magalie Haissaguerre¹⁹, Emmanuel Deshayes²⁰, David Taïeb²¹, Sergio Baldari²², Maddalena Sansovini²³, Sara Cingarlini²⁴, Angelina Filice²⁵, Francesco Panzuto²⁶, Rosa Álvarez-Álvarez²⁷, Laurence Lousberg²⁸, Frank Aboubakar Nana^{29

30}, Jorge Hernando³¹, Alejando García-Álvarez³¹, Amparo García-Burillo³¹, Guillermo Villacampa³², Timon Vandamme^{33

34}, Nicola Fazio³⁵, Alice Durand⁴

Affiliations

¹ Medical Oncology Department. Vall, Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain. jcapdevila@vhio.net.
² Department of Nuclear Medicine, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.
³ Molecular Imaging Research Group, Nuclear Medicine Department, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain.
⁴ Medical Oncology Department, Edouard Herriot Hospital, Lyon, France.
⁵ Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.
⁶ Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
⁷ Center of Experimental Oncology. Gastrointestinal and Neuroendrocrine Tumors Research Group. Hospital 12 de Octubre Research Institute (Imas12), Madrid, Spain.
⁸ Facultad de Medicina, Departamento de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain.
⁹ Nuclear Medicine Department, Hospital Universitario Central de Asturias, Oviedo, Spain.
¹⁰ Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain.
¹¹ Medical Oncology Department, University Hospital Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), Seville, Spain.
¹² Service de Médecine Nucléaire, CHU de Nantes, Nantes Université, Nantes, France.
¹³ Department of Endocrine Oncology and Nuclear Medicine, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France.
¹⁴ Department of Digestive Oncology, University Hospital Dijon, University of Burgundy and Franche Comté, Dijon, France.
¹⁵ Endocrinology and Nutrition Department, Endocrinology, Nutrition and Diet Therapy Research Unit, University and Polytechnic Hospital La Fe, Valencia, Spain.
¹⁶ Departamento de Medicina, Universidad de Valencia, Valencia, Spain.
¹⁷ Medical Oncology Department, Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain.
¹⁸ Service de Médecine Nucléaire, Hôpital Claude Huriez, CHU Lille, Lille, France.
¹⁹ Department of Endocrinology, University of Bordeaux, Bordeaux, France.
²⁰ Department of Nuclear Medicine, Institut du Cancer de Montpellier, Université de Montpellier, Cedex 5, Montpellier, France.
²¹ Department of Nuclear Medicine, Aix-Marseille University, La Timone University Hospital, Marseille, France.
²² Nuclear Medicine Unit, Department of Biomedical and Dental Sciences and of Morpho-Functional Imaging, University of Messina, Messina, Italy.
²³ Therapeutic Nuclear Medicine, IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori (IRST) ''Dino Amadori'', Meldola, Italy.
²⁴ Medical Oncology, University and Hospital Trust of Verona, Verona, Italy.
²⁵ Servizio Di Medicina Nucleare, Azienda USL-IRCCS Di Reggio Emilia, Reggio Emilia, Italy.
²⁶ Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, Digestive Disease Unit, ENETS Center of Excellence, Sant'Andrea University Hospital, Rome, Italy.
²⁷ Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
²⁸ Service d'Oncologie Médicale CHU Liège, Liège, Belgium.
²⁹ Department of Pulmonology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1200, Brussels, Belgium.
³⁰ Institut de Recherche Expérimentale Et Clinique (IREC), Université Catholique de Louvain, 1200, Brussels, Belgium.
³¹ Medical Oncology Department. Vall, Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain.
³² Statistics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
³³ Department of Oncology and Netwerk, University Hospital Antwerp, Edegem, Belgium.
³⁴ Center for Oncological Research, Integrated Personalized &Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium.
³⁵ Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy.

PMID: 40186126
PMCID: PMC11971812
DOI: 10.1186/s12885-025-13941-3

A Randomized clinical trial evaluating the impact on survival and quality of life of ¹⁷⁷Lutetium[Lu]-edotreotide versus everolimus in patients with neuroendocrine tumors of the lung and thymus: the LEVEL study (GETNE T-2217)

Jaume Capdevila et al. BMC Cancer. 2025.

. 2025 Apr 4;25(1):613.

doi: 10.1186/s12885-025-13941-3.

Authors

Affiliations

¹ Medical Oncology Department. Vall, Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain. jcapdevila@vhio.net.
² Department of Nuclear Medicine, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain.
³ Molecular Imaging Research Group, Nuclear Medicine Department, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain.
⁴ Medical Oncology Department, Edouard Herriot Hospital, Lyon, France.
⁵ Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.
⁶ Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.
⁷ Center of Experimental Oncology. Gastrointestinal and Neuroendrocrine Tumors Research Group. Hospital 12 de Octubre Research Institute (Imas12), Madrid, Spain.
⁸ Facultad de Medicina, Departamento de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain.
⁹ Nuclear Medicine Department, Hospital Universitario Central de Asturias, Oviedo, Spain.
¹⁰ Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain.
¹¹ Medical Oncology Department, University Hospital Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), Seville, Spain.
¹² Service de Médecine Nucléaire, CHU de Nantes, Nantes Université, Nantes, France.
¹³ Department of Endocrine Oncology and Nuclear Medicine, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France.
¹⁴ Department of Digestive Oncology, University Hospital Dijon, University of Burgundy and Franche Comté, Dijon, France.
¹⁵ Endocrinology and Nutrition Department, Endocrinology, Nutrition and Diet Therapy Research Unit, University and Polytechnic Hospital La Fe, Valencia, Spain.
¹⁶ Departamento de Medicina, Universidad de Valencia, Valencia, Spain.
¹⁷ Medical Oncology Department, Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain.
¹⁸ Service de Médecine Nucléaire, Hôpital Claude Huriez, CHU Lille, Lille, France.
¹⁹ Department of Endocrinology, University of Bordeaux, Bordeaux, France.
²⁰ Department of Nuclear Medicine, Institut du Cancer de Montpellier, Université de Montpellier, Cedex 5, Montpellier, France.
²¹ Department of Nuclear Medicine, Aix-Marseille University, La Timone University Hospital, Marseille, France.
²² Nuclear Medicine Unit, Department of Biomedical and Dental Sciences and of Morpho-Functional Imaging, University of Messina, Messina, Italy.
²³ Therapeutic Nuclear Medicine, IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori (IRST) ''Dino Amadori'', Meldola, Italy.
²⁴ Medical Oncology, University and Hospital Trust of Verona, Verona, Italy.
²⁵ Servizio Di Medicina Nucleare, Azienda USL-IRCCS Di Reggio Emilia, Reggio Emilia, Italy.
²⁶ Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, Digestive Disease Unit, ENETS Center of Excellence, Sant'Andrea University Hospital, Rome, Italy.
²⁷ Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
²⁸ Service d'Oncologie Médicale CHU Liège, Liège, Belgium.
²⁹ Department of Pulmonology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1200, Brussels, Belgium.
³⁰ Institut de Recherche Expérimentale Et Clinique (IREC), Université Catholique de Louvain, 1200, Brussels, Belgium.
³¹ Medical Oncology Department. Vall, Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain.
³² Statistics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
³³ Department of Oncology and Netwerk, University Hospital Antwerp, Edegem, Belgium.
³⁴ Center for Oncological Research, Integrated Personalized &Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium.
³⁵ Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy.

PMID: 40186126
PMCID: PMC11971812
DOI: 10.1186/s12885-025-13941-3

Abstract

Background: Everolimus is the only approved therapy for patients with advanced neuroendocrine tumors (NET) of lung and thymus and new treatment options are urgently needed. Expression of somatostatin receptor 2 (SSTR2) is frequently seen in functional imaging in lung-NETs opening the opportunity to treat SSTR2 positive patients with radioligand therapies (RLT). Retrospective data suggest a potential meaningful benefit of RLT directed to SSTR2 in lung-NET patients.

Methods: The LEVEL trial is a randomized, open-label, phase III international trial of ¹⁷⁷Lu-edotreotide versus everolimus in patients with progressive, locally advanced or metastatic, and well/moderately differentiated NETs of lung (typical/atypical) or thymic origin. Patients could be treatment-naïve or have progressed (PD) on somatostatin analogues or ≤ 2 additional systemic treatments. Prior RLT or mTOR inhibitors are not permitted. Eligible patients are randomly assigned 3:2 to 6 cycles of ¹⁷⁷Lu-edotreotide (total administered activity 7.5 ± 0.7 GBq / cycle) or to oral everolimus 10 mg once daily until PD or unacceptable toxicity. Only patients with positivity in somatostatin receptor imaging will be included. CT or MRI scans are performed every 12 weeks until PD. Blood samples are analyzed at baseline, at 1^st tumor assessment, and at PD for pharmacodynamic endpoints. Archival tumor tissue samples will be analyzed for ancillary studies. The primary endpoint is progression-free survival (PFS) according to RECIST v1.1 based on local investigator assessment. Secondary endpoints include overall survival, overall response rate, safety, and quality of life (EORTC QLQ-C30). The expected sample size is 120 patients to demonstrate statistical significant risk reduction of 46.4% (HR = 0.536) in PFS with the experimental treatment using an overall 5% two-sided alpha error with 80% power. An interim PFS analysis was included using the Lan-DeMets with O'Brian-Fleming-like boundaries.

Discussion: The LEVEL trial will investigate if ¹⁷⁷Lu-edotreotide has the potential to be incorporated as a standard treatment option for patients with NETs from the lung and Thymus.

Trial registration: EU CT: 2022-502154-13-00 / www.

Clinicaltrials: gov : NCT05918302 (June 23^rd, 2023).

Keywords: 177Lu-edotreotide; Everolimus; Lung and Thymus; Neuroendocrine tumors; Targeted Radioligand Therapy.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study is being conducted in accordance with the principles of the Declaration of Helsinki, the International Council for Harmonisation Guidelines for Good Clinical Practice and the local regulations. The study protocol was approved by the IEC of Hospital Universitari Vall D'Hebron on June 19th, 2023 (Ref: 2023/578) and the competent authorities of the European member states concerned (Spain: July 14th, 2023, France: October 10th, 2023, Italy: November 8th, 2023). All patients are providing written informed consent. Consent for publication: Not applicable. Competing interests: RGC has received honoraria for speaker engagements, advisory roles or funding for continuous medical education from: AAA-Novartis, Advanz Pharma, Astellas, Bayer, BMS, Boehringer, Esteve, GSK, Hutchmed, Ipsen, ITM, MSD, PharmaMar, Pierre Fabre, Sanofi, Servier, Takeda.PJF has received honoraria for speaker engagements, advisory roles or funding for continuous medical education from: Astellas, AstraZeneca, Bristol-Myers Squibb (BMS), Esteve, Merck Sharp & Dohme (MSD), Novartis, Nutricia, Pfizer, Rovi, Takeda, Viatris.TW has received honoraria for speaker engagements, advisory roles or funding for continuous medical education from: Novartis, MSD, Esteve, Ipsen, ITM, Terumo, Pierre Fabre, Sanofi, OranoMed, Sirtex.CL has received honoraria for speaker engagements, advisory roles or funding for continuous medical education from: Pierre Fabre, AMGEN, Takeda, Ipsen, AAA.ED has received fees from AAA-Novartis, Janssen and GE.JCR has received honoraria for speaker engagements, advisory roles or funding for continuous medical education from: AMGEN, MSD, AAA.TV has received honoraria for speaker engagements, advisory roles or funding for continuous medical education from from AstraZeneca, Astellas, Bayer, Bristol Myers Squibb, Eisai, Elmedix, Ipsen, MyNeoTx, Nordic Pharma, Novartis, Roche, Sirtex, Servier, Takeda. TV is a senior clinical investigator at the Research Foundation-Flanders (FWO), project number 1803723N.The remaining authors declare that they have no competing interests.GV has received a speaker’s fee from Pfizer, MSD, GSK and Pierre Fabrer, has held an advisory role with AstraZeneca and received consultant fees from Reveal Genomics.TAG reports Advisory role or speaker & fee from Lilly, Bayer, Johnson & Johnson, Astellas, Eisai, Roche, Ipsen, MSD and Adacap. Research Grant from Johnson & Johnson and IPSEN.All the other co-authors confirmed that they had no competing interests to be declared.

Figures

**Fig. 1**
The LEVEL study protocol design

See this image and copyright information in PMC

References

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A Randomized clinical trial evaluating the impact on survival and quality of life of ¹⁷⁷Lutetium[Lu]-edotreotide versus everolimus in patients with neuroendocrine tumors of the lung and thymus: the LEVEL study (GETNE T-2217)

Affiliations

A Randomized clinical trial evaluating the impact on survival and quality of life of ¹⁷⁷Lutetium[Lu]-edotreotide versus everolimus in patients with neuroendocrine tumors of the lung and thymus: the LEVEL study (GETNE T-2217)

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous