Clinical outcomes and treatment sequencing effects in well-differentiated grade 3 gastroenteropancreatic neuroendocrine tumors.

Abstract

e16311 Background: Following the 2017 WHO reclassification, well-differentiated grade 3 neuroendocrine tumors (WDG3 NETs) were recognized as distinct from neuroendocrine carcinomas due to their unique biology. Given this recent change, outcomes data for WDG3 NETs remain limited. This study analyzes clinical outcomes and impact of treatment sequencing in WDG3 NETs. Methods: We included WDG3 gastroenteropancreatic (GEP) NET patients treated at our multidisciplinary NET clinic from 2014–2025. Median progression-free survival (mPFS) and overall survival (OS; from date of biopsy) were estimated using Kaplan–Meier methods with p-values derived from Cox regression analysis. Objective response rate (ORR) was assessed using RECIST v1.1. Subgroup analyses evaluated patients receiving multiple systemic therapy lines. Lines of treatment were categorized as first-line (1L) or second line and beyond (2L). All patients were initially treated with somatostatin analogue therapy (SSA) thus lines of treatment were counted following progression on initial SSA. Results: We analyzed 35 WDG3 GEP NET patients (primary sites: pancreas n = 27; small bowel n = 4; rectum n = 2; gastric n = 2). Median PFS by treatment was Peptide Receptor Radionuclide Therapy (PRRT) (n = 14, 11.53 months [m]), Capecitabine/Temozolomide (CAPTEM) (n = 20, 8.72 m), surgical debulking of liver metastases (surgery) (n = 11, 6.30 m), and non-CAPTEM chemotherapy (n = 10, 7.10 m). ORR was 12.5% for PRRT, 16.7% for CAPTEM, and 10% for non-CAPTEM chemotherapy. First-line PRRT (1L = 16.97 m vs 2L = 3.73 m, p = 0.04) and CAPTEM (1L = 16.27 m vs 2L = 7.20 m, p = 0.01) had significantly longer mPFS compared to later-line use. Timing of surgery did not impact mPFS (before systemic therapy = 6.30 m vs after = 6.10 m, p = 0.57). OS was not significant across treatment groups. Compared to first line non-CAPTEM chemotherapy, first line CAPTEM had longer mPFS (CAPTEM = 9.32 m vs non-CAPTEM = 5.36 m, p = 0.03), with a trend toward longer OS (CAPTEM = 31.70 m vs non-CAPTEM = 18.47 m, p = 0.09). Conclusions: In patients diagnosed with WDG3 GEP NETS receiving multiple lines of systemic therapy, treatment sequencing may be important with those receiving first-line CAPTEM or PRRT prior to other systemic therapies experiencing a longer progression free survival. mPFS (months) OS (months) ORR PRRT (n = 14) 11.53 (3.73-17.96) 35.45 (28.96-NA) 12.5% (1/8) CAPTEM (n = 20) 8.72 (4.63-16.64) 29.80 (23.83-53.67) 16.7% (3/18) Surgery (n = 11) 6.30 (5.17-NA) 45.30 (15.40-NA) - Non-CAPTEM chemotherapy (n = 10) 7.10 (5.67-NA) 27.77 (18.46-NA) 10% (1/10) 1L (n = 3) vs 2L (n = 9) PRRT 16.97 vs 3.73 p = 0.04 53.66 vs 38.86 p = 0.12 - 1L (n = 8) vs 2L (n = 8) CAPTEM 16.27 vs 7.20 p = 0.01 36.45 vs 27.30 p = 0.23 - Surgery before systemic therapy (n = 3) vs after systemic therapy (n = 5) 6.30 vs 6.10 p = 0.57 28.96 vs 45.30 p = 0.62 - CAPTEM (n = 16) vs non-CAPTEM chemotherapy (n = 7) 9.32 vs 5.36 p = 0.03 31.70 vs 18.47 p = 0.09 -