Efficacy of RET inhibitors in the management of advanced, RET mutated, pheochromocytoma. Pooled analysis of published cases with the addition of 2 new cases.

PURPOSE: Selective RET inhibitors are approved for treatment of RET-mutant lung and thyroid cancers. RET mutation is a druggable molecular driver of malignant pheochromocytomas/paragangliomas (PPGLs), but few data have been published regarding the efficacy of RET inhibitors in this clinical setting. METHODS: We performed a pooled analysis of RET-mutated PPGLs treated with RET-inhibitors, including both literature published case reports and patients treated at our Institution. RESULTS: Nine patients with advanced pheochromocytoma were collected (7 published cases and 2 patients followed in our department). Eight patients had metastatic disease and 6 of them were pretreated. Eight patients received selpercatinib and one patient received pralsetinib. All patients obtained clinical benefit, 5 of them reached a partial response, 2 a durable stable disease and 2 a complete response. Median progression free survival ranged between 5.5 – 56.3 months. Urinary catecholamine and metanephrine levels improved or normalized in 7 cases. The treatment was well tolerated but in 2 patients a dose reduction was needed, due to G3 adverse events. CONCLUSION: RET inhibitors are efficacious in patients affected by PPGL with RET mutation or fusion. Based on these findings, these drugs represent a promising strategy and these data support the development of prospective clinical trials in this setting.