Morken, SirenSirenMorkenLanger, Seppo WSeppo WLangerSundlöv, AnnaAnnaSundlövVestermark, Lene WeberLene WeberVestermarkLadekarl, MortenMortenLadekarlHjortland, Geir OlavGeir OlavHjortlandSvensson, Johanna BJohanna BSvenssonTabaksblat, Elizaveta MitkinaElizaveta MitkinaTabaksblatHaslerud, Torjan MagneTorjan MagneHaslerudAssmus, JörgJörgAssmusDetlefsen, SönkeSönkeDetlefsenCouvelard, AnneAnneCouvelardPerren, AurelAurelPerren0000-0002-6819-6092Sorbye, HalfdanHalfdanSorbye2024-10-252024-10-252023-12https://boris-portal.unibe.ch/handle/20.500.12422/170840BACKGROUND The optimal treatment for metastatic high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms when Ki-67 ≤55% is unknown. A prospective multi-centre phase 2 study was performed to evaluate the efficacy and safety of everolimus and temozolomide as first-line treatment for these patients. METHODS Patients received everolimus 10 mg daily continuously and temozolomide 150 mg/m2 for 7 days every 2 weeks. Endpoints included response, survival, safety and quality of life (QoL). Histopathological re-evaluation according to the 2019 WHO classification was performed. RESULTS For 37 eligible patients, the primary endpoint with 65% disease control rate (DCR) at 6 months (m) was reached. The response rate was 30%, the median progression-free survival (PFS) 10.2 months and the median overall survival (OS) 26.4 months. Considering 26 NET G3 patients, 6 months DCR was 77% vs. 22% among nine NEC patients (p = 0.006). PFS was superior for NET G3 vs. NEC (12.6 months vs. 3.4 months, Log-rank-test: p = 0.133, Breslow-test: p < 0.001). OS was significantly better for NET G3 (31.4 months vs. 7.8 months, p = 0.003). Grade 3 and 4 toxicities were reported in 43% and 38%. QoL remained stable during treatment. CONCLUSION Everolimus and temozolomide may be a treatment option for selected GEP-NET G3 patients including careful monitoring. Toxicity did not compromise QoL. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov (NTC02248012).en500 - Science::570 - Life sciences; biology600 - Technology::610 - Medicine & healtharticle10.48350/1873983787240510.1038/s41416-023-02462-0