Background: Well-differentiated (WD) NETs are a group of rare neoplasms with limited therapeutic options. New combinations of somatostatin analogs (SSAs) and investigational drugs are warranted to improve clinical outcomes. Cabozantinib (CAB) is an orally administered inhibitor of multiple tyrosine kinases, including c-MET and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), with a pivotal role in NET pathogenesis. The biological rationale of the synergistic effects of CAB plus SSAs lies in the concomitant modulation of the RAS/MAPK and PI3K/Akt/mTOR pathways both at the level of cancer cells and tumor stroma, leading to enhanced anti-proliferative and anti-angiogenic effects. CAB exhibited encouraging activity in a recent phase II trial of patients with progressive carcinoids and pancreatic (p)NETs (Chan JA et al. JCO 2017; 35:4_suppl, 228-228). The LOLA trial is the first prospective phase II study aiming to assess the safety and activity of CAB in combination with lanreotide (LAN) in WD NETs of GEP, thoracic and of unknown origin. Clinical trial information: NCT04427787. Methods: This is a multicenter, open-label, double-cohort, non comparative, non-randomized, three-stage phase II trial. Eligible patients have to meet the following inclusion criteria: diagnosis of advanced or metastatic, progressive, non-functioning WD thoracic NETs, GEP-NETs or NETs of unknown origin with Ki67 ≥10%; positive 68Ga-PET uptake or somatostatin receptor 2 immunohistochemical (IHC) stain; maximum 1 prior systemic regimen for metastatic disease. Two cohorts will be considered: pNETs and carcinoids. In the stage I, the primary objective is to find the optimal dose of CAB in combination with LAN and to evaluate the safety of the combination (defined as the percentage of patients experiencing grade 3-5 toxicities according to NCI-CTCAE v5.0). Starting dose of CAB is 60 mg/day continuously, plus LAN 120 mg every 28 days. In stage II and III, co-primary endpoints are safety and overall response rate (ORR) according to RECIST v1.1. The useful antitumor activity to be detected is fixed in ORR > 20%. Secondary endpoints are progression-free survival and overall survival. Exploratory objectives include the assessment of IHC expression of c-MET, AXL and VEGFR2, with the aim to identify predictive or prognostic tissue biomarkers. Enrolment started in July 2020, with an expected trial duration of 42 months comprehensive of accrual, treatment and follow-up. Considering a drop out rate of 5%, the maximum number of enrolled patients will be 69. Supported by a solid rationale, the trial has the potential to generate milestone data about the synergistic effects of CAB plus LAN in a group of NET patients with relatively aggressive disease and limited therapeutic options, for whom optimal treatment sequencing is not yet defined. Clinical trial information: NCT04427787