A systematic literature review of studies assessing first-line (1L) treatments in patients with advanced, grade 2/3 (G2/G3) gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
Authors: Capdevila Jaume , Deshayes Emmanuel , Navalkissoor Shaunak , Srirajaskanthan Raj , Folitar Ilya , Lovelle Marcos , Soni Deepali , Lakkakula Udaya Sri , Joshi Parth , Pathak Purnima 
Published: January 2025

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Background:
There is no universally accepted standard of care for newly diagnosed patients with G2/G3 advanced GEP-NETs. The phase 3 NETTER-2 trial showed that [
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Lu]Lu-DOTA-TATE plus long-acting octreotide demonstrated a significant improvement in progression-free survival (PFS) vs. high-dose long-acting octreotide alone in this patient population. We conducted a comprehensive review of the published literature to summarize the available evidence on other 1L treatments assessed in advanced, well-differentiated, G2/G3 GEP-NETs.
Methods:
Embase, MEDLINE, and CENTRAL were systematically searched (until Jan 2024) to identify relevant clinical trials and observational studies assessing 1L systemic therapies among adults with advanced, well-differentiated, G2/G3 GEP-NETs. Key conferences from the past three years were also reviewed. Comparators of interest included somatostatin analogues (SSAs; octreotide and lanreotide), targeted therapies (sunitinib and everolimus), and chemotherapies (CAPTEM, STZ+5-FU, FOLFIRI, and platinum-based therapies). Studies with mixed patient populations were also included if ≥80% of the study participants matched the eligibility criteria. The 2022 WHO classification system was applied in studies with available Ki-67 index data but lacking grade information.
Results:
A total of 31 studies met the review eligibility criteria (three randomized controlled trials, one open-label extension study, three single-arm trials, and 24 observational studies). None of the included studies entirely matched the NETTER-2 population but provided data only for specific sub-populations. The included studies were categorized either by overall GEP-NET (n=16) or pancreatic-NET only population (n=15) with no study exclusively assessing gastrointestinal-NET patients. Majority of the comparator studies assessed chemotherapies (n=14), followed by SSAs (n=10), targeted therapies (n=3), a combination of targeted therapy and chemotherapy (n=1), and mixed treatments (n=2). Heterogeneity was also observed in terms of patient characteristics (data reported only in 12 studies), sample size (<50 patients in 20 studies), and disease grade (G2/G3: nine studies, G2 only: 12 studies, and G3 only: 10 studies). Grading was derived using Ki-67 index in two studies. Majority of the studies reported PFS data (n=22), with nine studies providing data for both PFS and overall survival (OS); Kaplan-Meier curves for PFS and OS were reported for only 13 and four studies, respectively.
Conclusions:
This systematic literature review highlights a substantial evidence gap and an unmet need in 1L treatment of G2/G3 GEP-NETs. Robust quantitative comparison of NETTER-2 data with published evidence on other 1L treatments was largely restricted by low sample sizes and the aforementioned heterogeneity.