Distinct Patterns of Pituitary Dysfunction in Combination Immunotherapy with Nivolumab and Ipilimumab

ContextImmune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but are associated with immune-related adverse events (irAEs), including pituitary dysfunction. Combination immunotherapy with PD-1 and CTLA-4 inhibitors increases the risk of pituitary irAEs compared to PD-1 monotherapy; however, their detailed clinical characteristics remain unclear. ObjectiveTo clarify the clinical features of pituitary irAEs induced by combination immunotherapy. MethodsIn this retrospective cohort study, we compared patients treated with combination therapy of nivolumab and ipilimumab (Nivo/Ipi) to those receiving nivolumab monotherapy (Nivo). We analyzed clinical data including presenting symptoms, laboratory findings, pituitary MRI results, and coexisting irAEs. ResultsPituitary irAEs were more frequent in the Nivo/Ipi group (17.4%) than in the Nivo group (2.7%) and developed earlier (median onset: 63 vs. 153 days, respectively). All 15 patients in the Nivo group presented with isolated ACTH deficiency (IAD), whereas the Nivo/Ipi group included 8 cases of IAD and 8 cases of combined pituitary hormone deficiency (CPHD). In the Nivo/Ipi group, CPHD occurred significantly earlier than IAD (median onset: 40 vs. 84 days) and was associated with a higher incidence of headache and pituitary swelling on MRI. Furthermore, 75% of patients with CPHD also experienced non-endocrine irAEs. Two CPHD patients experienced worsening of symptoms and pituitary dysfunction following re-administration of Nivo/Ipi. ConclusionPituitary irAEs are more frequent and develop earlier in patients receiving Nivo/Ipi. CPHD and IAD, induced by this combination immunotherapy, exhibit distinct clinical courses. Recognizing these differences is crucial for the optimal management of pituitary irAEs during combination immunotherapy.