Abstract: Background: Angiogenesis plays a key role in development and progression of endocrine neoplasms and synergism has been observed when combined with immune-checkpoint inhibitors in other tumors. We aimed to demonstrate the activity and safety of cabozantinib (cabo) plus atezolizumab (atezo) in different endocrine neoplasms refractory to standard therapies. Methods: This is a prospective, multi-center, open-label, phase II study including patients (pts) with advanced and refractory endocrine tumors in 6 independent cohorts (C): (1) well-differentiated neuroendocrine tumors of the lung (LungNET), (2) anaplastic thyroid cancer (ATC), (3) adrenocortical carcinoma (ACC), (4) pheochromocytoma/ paraganglioma (PPGL), (5) well-differentiated gastroenteropancreatic NET (GEPNET), (6) grade 3 extrapulmonary neuroendocrine neoplasms (G3 EP-NEN). All pts received atezo Results: 93 pts were enrolled. Cabo and atezo were administered for a median of 5.8 m (95% CI: 3.4-7.5) and 6.3 m (95% CI: 3.5-7.7), respectively. Most frequent grade ?3 toxicities were fatigue (7.5%), neutropenia (6.5%) and liver enzyme increase (6.5%). 2 pts died due to drug-related ischemic stroke and pancreatitis. Due to AE?s, cabo and atezo treatment was interrupted in 67.7% and 35.5% of pts, and discontinued in 16.1% and 14% of pts, respectively. Cabo was reduced to 20 mg/day in 41.9% of pts. Conclusions: Cabo plus atezo showed limited activity in progressive / refractory endocrine malignancies, surpassing the futility threshold in ATC. Atezo does not improve the outcomes of cabo as a single agent in NEN.

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