BACKGROUND: Pituitary neuroendocrine tumors (PitNETs) that progress following surgery and radiotherapy are in need of additional treatment options. Responses to immune checkpoint inhibitors (ICIs) have been described; however, the feasibility of ICI therapy and biomarkers of response have not been formally assessed. METHODS: We performed a single center, prospective, phase 2 trial investigating the activity of ipilimumab and nivolumab in PitNET patients. The primary endpoint was objective response using the iRANO response criteria. We then explored genetic biomarkers of response to ICI in 13 patients with PitNETs, who were treated with ICI, on or outside of the trial. RESULTS: 10 patients with a PitNET were enrolled, including 5 corticotroph, 4 lactotroph, and 1 somatotroph tumor; of which 9/10 (4 metastatic and 5 non-metastatic) patients were evaluable for the primary endpoint. While no objective responses were observed, tumor shrinkage was seen in 2/9 patients. In a biomarker discovery cohort, comprised of 7 tumors treated on trial and 6 tumors treated off trial, temozolomide hypermutation and mismatch repair deficiency (MMRd) were associated with immunological response. In 3 tumors sequenced pre- and post-ICI treatment, we identified evidence of immunoediting, characterized by loss of MMRd and/or a decrease in tumor mutational burden. CONCLUSION: This study demonstrates the safety and feasibility of ICI treatment in aggressive PitNETs. We also identified MMRd and temozolomide hypermutation as potential biomarkers of response to ICI. Overall, our data suggests that ICIs might provide an additional treatment option for PitNET; this should be evaluated more broadly in future studies.
