Chia-Jui Yen

Background Highly vascularised neuroendocrine tumours (NETs) are attractive targets for foslinanib (CVM-1118), which disrupts vasculogenic mimicry and induces apoptosis via tumour necrosis factor receptor-associated protein 1. We evaluated the efficacy and safety of CVM-1118 in advanced NETs. Methods Patients with grades 1–2, well-differentiated lung, gastrointestinal, or pancreatic NETs, refractory or intolerant to one or more standard therapies and progressing within 6 months, received CVM-1118 (200–300 mg orally twice daily) in 28-day cycles. Primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results Of 43 enroled participants, 35 were efficacy-evaluable; most had grade 2 pancreatic (63%) or gastrointestinal (34%) NETs with two prior therapies. Median PFS was 10.5 months (95% CI, 5.6–22.3). ORR was 3%, DCR was 77%, and median OS was not reached (95% CI, 23.8–NR). Sensitivity analysis in the full analysis set (N = 43) showed a PFS estimate broadly aligned with the primary analysis (median, 8.4 months); patients with prior everolimus, sunitinib, or peptide receptor radionuclide therapy (N = 22; median, 8.3 months) showed similar findings. Treatment-related adverse events occurred in 44%, mostly grades 1–2, with no serious events. Conclusions CVM-1118 demonstrates favourable efficacy and safety in advanced NETs. Clinical Trial Registration ClinicalTrials.gov identifier, NCT03600233.

Purpose:Carbohydrate antigen 19-9 (CA19-9) has limited utility in the ∼10% of patients with pancreatic ductal adenocarcinoma (PDAC) who are Lewis-negative CA19-9 “nonproducers” (FUT3-null). This study aims to define the prognosis of FUT3-null PDAC and establish a CA19-9 cutoff that can help identify this subgroup in clinical practice.Experimental Design:Germline whole-exome sequencing was performed in a multicenter cohort of 615 patients with PDAC to determine FUT2/FUT3 genotypes. Receiver operating characteristic (ROC) analysis identified the optimal CA19-9 cutoff for FUT3-null status. Maximally selected rank statistics were used to derive CA19-9 cutoffs that best stratified overall survival (OS) in a training set (n = 307) and were tested in a validation set (n = 308).Results:FUT3-null patients had similar demographics except for a lower median baseline CA19-9 level (2.4 vs. 496 U/mL in FUT3-intact patients) and a comparable median OS (13.5 months) to FUT3-intact patients with CA19-9 >200 U/mL (12.9 months). ROC analysis identified 7 U/mL as the optimal CA19-9 cutoff for FUT3-null (positive predictive value 95.1%; accuracy 87.9%). Using CA19-9 cutoffs of 7 and 200 U/mL (without genotyping), patients were stratified into four prognostic groups: >7 to 37 U/mL (median OS, 23.2 months), >37 to 200 U/mL (median OS, 22 months), >200 U/mL (median OS, 12.8 months), and ≤7 U/mL (likely FUT3-null; median OS, 13.5 months; P < 0.001). Findings were consistent in multivariable Cox models.Conclusions:CA19-9 nonproducers whose outcomes are comparable with those with CA19-9 >200 U/mL represent a high-risk subgroup. CA19-9 ≤7 U/mL is a practical surrogate for identifying these patients. When genotyping is unavailable, a dual-threshold model (≤7 and >200 U/mL) improves risk stratification.

Purpose: Carbohydrate antigen 19-9 (CA19-9) has limited utility in the ∼10% of patients with pancreatic ductal adenocarcinoma (PDAC) who are Lewis-negative CA19-9 “nonproducers” (FUT3-null). This study aims to define the prognosis of FUT3-null PDAC and establish a CA19-9 cutoff that can help identify this subgroup in clinical practice. Experimental Design: Germline whole-exome sequencing was performed in a multicenter cohort of 615 patients with PDAC to determine FUT2/FUT3 genotypes. Receiver operating characteristic (ROC) analysis identified the optimal CA19-9 cutoff for FUT3-null status. Maximally selected rank statistics were used to derive CA19-9 cutoffs that best stratified overall survival (OS) in a training set (n = 307) and were tested in a validation set (n = 308). Results: FUT3-null patients had similar demographics except for a lower median baseline CA19-9 level (2.4 vs. 496 U/mL in FUT3-intact patients) and a comparable median OS (13.5 months) to FUT3-intact patients with CA19-9 >200 U/mL (12.9 months). ROC analysis identified 7 U/mL as the optimal CA19-9 cutoff for FUT3-null (positive predictive value 95.1%; accuracy 87.9%). Using CA19-9 cutoffs of 7 and 200 U/mL (without genotyping), patients were stratified into four prognostic groups: >7 to 37 U/mL (median OS, 23.2 months), >37 to 200 U/mL (median OS, 22 months), >200 U/mL (median OS, 12.8 months), and ≤7 U/mL (likely FUT3-null; median OS, 13.5 months; P < 0.001). Findings were consistent in multivariable Cox models. Conclusions: CA19-9 nonproducers whose outcomes are comparable with those with CA19-9 >200 U/mL represent a high-risk subgroup. CA19-9 ≤7 U/mL is a practical surrogate for identifying these patients. When genotyping is unavailable, a dual-threshold model (≤7 and >200 U/mL) improves risk stratification.