Evaluation of the use of targeted therapy for BRAF mutated and MSI digestive neuroendocrine carcinoma (NEC) or treated with other targeted therapy

TargetNEC

Level

: Level 2

Launch date

: 1 September 2026

Principle investigators

: Anna Pellat, MD, PhD, Cochin Hospital, Paris, France

Project description

Coordinating center:

Hôpital Cochin, APHP, Université Paris Cité, Paris, France

Study protocol group members:

• Julian Hadoux, Gustave Roussy, Paris, France.
• Halfdan Sorbye, Bergen, Norway.
• Thomas Walter, Lyon, France.
  
  

Ethical Approval:

The study has been approved by the scientific committee of the GTE (French neuroendocrine tumor group)

Registration of the study ongoing

Approval will be according to local ethics committee for each centre.

Type of research:

Retrospective study

Background:

Digestive neuroendocrine carcinomas are rare aggressive tumors with a poor prognosis, particularly at the metastatic stage. Some chemotherapy regimens have demonstrated efficacy in this disease (platinum-etoposide in the first line, FOLFIRI in the second line), but the number of therapeutic options for patients remains limited. Some studies have shown that molecular anomalies can be found in up to 75% of patients with NEC (Boilève et al. PMID: 34647903), with 5%, 20%, 23%, and 27% classified as ESCAT I, III, IV, and X respectively in one work conducted on 38 patients. Certain tumor locations are more frequently associated with specific molecular anomalies, such as the BRAF mutation in 65% of patients with NEC of the right colon (Elvebakken, J Neuroendocrinology, 2023). MSI seems to be present in around 5% of metastatic digestive NEC (Venizelos, ERC, 2021). BRAF inhibitors are approved for BRAF V600 mutated metastatic colorectal cancer not limited to adenocarcinoma cases. Immune check inhibitors have an agnostic approval for MSI/dMMR cases. Up to now only a handful of digestive NEC cases treated with targeted therapy have been reported and more concise data are needed to evaluate the possible role and benefit of targeted therapy for digestive NEC.

As we are in urgent need to find new therapeutics for these patients, evaluating the role of targeted therapies in patients with actionable molecular alterations is important.

Objectives

Primary:

Assess the clinical impact of targeted therapeutic management (treatment of actionable molecular alterations) in real-world settings within a population of patients with advanced digestive NEC and MiNEN.

Secondary:

• Describe overall survival, response rates, and real-world progression-free survival in real-world settings.
• Compare survival with a similar population receiving non-targeted therapeutic management despite having actionable targets (Nordic NEC 2) or with a synthetic arm  (cohort from the FFCD (Fédération Francophone de Cancérologie Digestive) with NEC in the second or more -line setting, without information on molecular anomalies (matched on other prognostic criteria) or historical control)

Population:

Inclusion criteria:

• Patients treated from 2015 to 2025
• Advanced Neuroendocrine carcinoma (NEC) or mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN*)
• All digestive primary tumor locations included
• If a molecular anomaly has been identified** using any panel in specific programs or during routine care
• All types of treatments received (including patients who received targeted treatment adapted to the detected molecular anomaly***)

*NB1 : Only MiNEN with a NEC component are eligible, and the molecular target must related to the NE component.

**NB2: Molecular anomaly identified in tissue or "liquid biopsy".  

Anonymized molecular report uploading as anonymized PDF in Database.

***NB3: For patients with a retained molecular anomaly and corresponding type of treatment (examples):

• • dMMR/MSI => immunotherapy
  • TMB>10 => immunotherapy
  • BRAF V600E => encorafenib-cetuximab or Dabrafenib- tremetinib or other BRAF inhibitor
  • Fusion NTRK=> larotrectinib
  • HER2 2+/FISH positive or 3+=> trastuzumab-based (with lapatinib, tucanib, pertuzumab, or traztu-deruxtecan…)
  • mutation Kit exon 11 => imatinib, regorafénib or sunitinib
  • Fusion ALK, ROS, RET, NRG1…
    
    

Exclusion criteria:

• Histology: NET including G3
• Patients with localised disease
• Other primary site than digestive

Methods

Recruitment through involved centers, regulations depending on each country

Data will be collected by local investigators and filled into the ENETS database (dedicated eCRF), extended version (200 items)

• Clinical characteristics (age, sex, OMS)
• Date of diagnosis and method
• Location of primary tumor and metastatic sites
• Ki-67% value
• Type of molecular alteration
• First line treatment: type, response, start and stop dates of treatment
• Second and further line treatment: type, response, PFS,
• Date of last follow up or death

Primary outcome:

Growth modulation index (GMI) > 1.3

GMI is defined as the ratio of time to progression (TTP) under the MMT (TTPn, e.g. oriented treatment line) to TTP under the treatment received prior to MMT (TTPn-1). A GMI ≥ 1.3 is considered as relevant clinical benefit, meaning TTPn is at least superior by 30% as compared to TTPn-1

Secondary outcomes:

Clinical efficacy and survival: real-world response rates, real-world progression free survival, overall survival

Statistical analysis plan:

• Descriptive cohort.
• Separate analyses for NEC and MINEC
• Survival curves: Kaplan Meier.
• Univariable/multivariable analysis of clinically relevant pre-defined characteristics and their influence on recurrence and OS (Cox model).
• Comparison of the population treated with targeted therapy vs the population treated according to standard care (ideally with propensity score) as secondary objective

References:

• Impact of KRAS and BRAF mutations on treatment efficacy and survival in high-grade gastroenteropancreatic neuroendocrine neoplasms. Elvebakken et al, J neuroendocrinology, 2023
• Molecular profiling and target actionability for precision medicine in neuroendocrine neoplasms: real-world data. Boilève et al. European Journal of cancer, 2023
• Phase II Study of Dabrafenib and Trametinib in Patients With Tumors With BRAF V600E Mutations: Updated Results From NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol H. Salama et al. Precision medicine 2026

Publication policy:

The ENETS DB publication policy will be adopted.

Study timelines:

• September 2026 - May 2027: Inclusion of patients into the ENETS database.
• June 2027 – January 2028: Quality check of entered cases.
• Nov 2027: Abstract with preliminary data for ENETS 2028
• January- May 2028: Final data analyses and manuscript preparation
• June 2028: Manuscript submittance
  
  

Introduction video – REDCap data entry (TargetNEC)

The following video tutorial provides step-by-step guidance on how to enter data in REDCap, including key study-specific requirements.
Watch the video tutorial (.mp4, 27 MB)