Immunotherapy in Corticotroph and Lactotroph Aggressive Tumors and Carcinomas: Two Case Reports and a Review of the Literature

Abstract

Once temozolomide has failed, no other treatment is recommended for pituitary carcinomas and aggressive pituitary tumors. Recently, the use of immune checkpoint inhibitors (ICIs) has raised hope, but so far, only one corticotroph carcinoma and one aggressive corticotroph tumor treated with immunotherapies have been reported in the literature. Here, we present two cases, one corticotroph carcinoma and one aggressive prolactinoma (the first one reported in the literature) treated with ipilimumab (1 mg/kg) and nivolumab (3 mg/kg) every three weeks, followed by maintenance treatment with nivolumab (3 mg/kg every 2 weeks) in the case of the corticotroph carcinoma, and we compare them with the two previously reported cases. Patient #1 presented a biochemical partial response (plasma ACTH decreased from 13,813 to 841 pg/mL) and dissociated radiological response to the combined ipilimumab and nivolumab-the pituitary mass decreased from 37 × 32 × 41 to 29 × 23 × 42 mm, and the pre-existing liver metastases decreased in size (the largest one from 45 to 14 mm) or disappeared, while a new 11-mm liver metastasis appeared. The maintenance nivolumab (21 cycles) resulted in a stable disease for the initial liver metastases, and in progressive disease for the newly appeared metastasis (effectively treated with radiofrequency ablation) and the pituitary mass. Patient #2 presented radiological and biochemical progressive disease after two cycles of ICIs-the pituitary mass increased from 38 × 42 × 26 to 53 × 57 × 44 mm, and the prolactin levels increased from 4410 to 9840 ng/mL. In conclusion, ICIs represent a promising therapeutic option for aggressive pituitary tumors and carcinomas. The identification of subgroups of responders will be key.

Keywords: Cushing’s disease; aggressive PitNET; aggressive pituitary adenoma; aggressive pituitary tumor; immune checkpoint inhibitors (ICIs); ipilimumab; nivolumab; pituitary carcinoma; prolactinoma.

Figure 1

18-year follow-up of a corticotroph carcinoma (patient #1), from diagnosis to the present day. (A) Evolution of morning plasma adrenocorticotropic hormone (ACTH) levels under the different treatments. Every dot represents an individual measurement. (B) Radiological evolution of the pituitary mass as seen on the magnetic resonance imaging until February 2018 (contrast-enhanced T1-weighted images) and on the pituitary computed tomography from November 2018. (C) Radiological and metabolic evolution of the liver metastases. An ¹⁸F-fluorodeoxyglucose (FDG)-PET/CT performed on 29 July 2016 shows the absence of liver metastases. The blue and yellow arrows indicate the two largest liver metastases that appeared in November 2018. The metastasis indicated by the yellow arrow is not visible at every time point in this figure, but was still present, measuring 30 mm in February 2019, 13 mm in April 2019, 11 mm in November 2019, and 8 mm in February 2020. The red arrow indicates the liver metastasis that appeared after four cycles of combined immunotherapy. Abbreviations: TSS—transsphenoidal surgery; RT—radiotherapy; TMZ—temozolomide; PAS—pasireotide; CAB—cabergoline; HU—hydroxyurea; IPI—ipilimumab; NIVO—nivolumab; CT—computed tomography; PET—positron emission tomography.

Figure 2

Eight-year follow-up of an aggressive prolactinoma (patient #2), from diagnosis to the present day. (A) Evolution of the prolactin levels under the different treatments. Every dot represents an individual measurement. * ≥4700 ng/mL (the upper limit of the respective prolactin assay). (B) Radiological evolution of the pituitary mass as seen on the magnetic resonance imaging. Abbreviations: CAB—cabergoline; TSS—transsphenoidal surgery; RT—radiotherapy; PAS—pasireotide; TMZ—temozolomide; IPI—ipilimumab; NIVO—nivolumab; BVZ—bevacizumab; T2—T2-weighted image; T1 GADO—contrast-enhanced T1-weighted image.