Therapeutical Usefulness of PD-1/PD-L1 Inhibitors in Aggressive or Metastatic Pituitary Tumours

Abstract

Therapeutic options for pituitary neuroendocrine tumours (PitNETs) refractory to temozolomide are scarce. Immune checkpoint inhibitors (ICIs), particularly inhibitors of the programmed cell death-1 (PD-1) pathway and its ligand (PD-L1), have been experimentally used in aggressive or metastatic PitNETs. We aimed to study the therapeutic usefulness of anti-PD-1 drugs in patients with aggressive or metastatic PitNETs. Published cases and case series involving patients with PitNETs treated with PD-1/PD-L1 inhibitors were reviewed. Demographic data, clinical-pathological features, previous therapies, drug dosage and posology, and the best radiological and biochemical responses, as well as survival data, were evaluated. We identified 29 cases of aggressive (n = 13) or metastatic (n = 16) PitNETs treated with PD-1/PD-L1 inhibitors. The hypersecretion of adrenocorticotropic hormone (ACTH) was documented in eighteen cases (62.1%), seven were prolactinomas (24.1%), and four were non-functioning PitNETs. All patients underwent various therapies prior to using ICIs. Overall, a positive radiological response (i.e., partial/complete radiological response and stable disease) was observed in eighteen of twenty-nine cases (62.1%), of which ten and four were ACTH- and prolactin-secreting PitNETs, respectively. Hormonal levels reduced or stabilised after using ICIs in 11 of the 17 functioning PitNET cases with available data (64.7%). The median survival of patients treated with ICIs was 13 months, with a maximum of 42 months in two ACTH-secreting tumours. Among 29 patients with PitNETs treated with PD-1/PD-L1 inhibitors, the positive radiological and biochemical response rates were 62.1% and 64.7%, respectively. Altogether, these data suggest a promising role of ICIs in patients with aggressive or metastatic PitNETs refractory to other treatment modalities.

Keywords: PD-1; PD-L1; immune checkpoint inhibitors; immunotherapy; ipilimumab; nivolumab; pembrolizumab; pituitary adenoma; pituitary tumour.

Figure 1

Stage, tumour subtypes, and response to treatment with PD-1 inhibitors in the cohort of 29 PitNETs. Data are presented regarding tumour stage as metastatic PitNET versus aggressive PitNET (a), PitNET subtypes (b), best radiological response (c), and best biochemical response (d). Results are presented as n (%). Regarding the best biochemical response (d), only 17 of the 25 functioning tumours had biochemical response data available. ACTH: adrenocorticotropic hormone-secreting PitNET; CR: complete response; DR: dissociated response (opposite effect of immune checkpoint inhibitors in primary tumour and metastases); NF: non-functioning PitNET; PD: progressive disease; PD-1: programmed cell death protein 1; PitNET: pituitary neuroendocrine tumour; PR: partial response; PRL: prolactin-secreting PitNET; SD: stable disease.

Figure 2

Remarkable response to anti-PD-1 treatment in 3 patients with metastatic PitNETs. CASE 1: Metastatic ACTH-PitNET with radiological and biochemical response to ipilimumab and nivolumab—brain and liver MRI before (a,b) and after ICI treatment (c,d). The yellow arrowheads point to the main tumour metastasis in the central nervous system and in the liver before and after ICI treatment. (Lin et al. 2018 [37], J Clin Endocrinol Metab (PMID: 30085142)). CASE 2: Metastatic ACTH-PitNET with radiological and biochemical response to pembrolizumab—MRI before (e) and after ICI treatment (f). The grey arrows point to tumour extension to the sphenoid sinus and posterior ethmoid air cells; white arrows indicate the tumour extension to the anterior and inferior aspects of the left temporal lobe. (Majd et al. 2020 [41], J Immunother Cancer (PMID: 33427689).) CASE 3: Metastatic NF-PitNET with radiological response to pembrolizumab, with >70% shrinkage in the main tumour and involution of spinal metastasis—MRI before (g,h) and after 1 year of ICI treatment (i,j). The yellow arrowheads show the primary PitNET before and after treatment, where a remarkable shrinkage of the tumour is visible; the yellow arrow with “m” letter depicts the spinal metastasis before ICI treatment, which involved following the treatment with pembrolizumab. (Feola et al. 2022 [11], Cancers (PMID: 36077631)). ACTH: adrenocorticotropic hormone; ACTH-PitNET: adrenocorticotropic hormone-secreting PitNET; FGFR: fibroblast growth factor receptor; ICI: immune checkpoint inhibitors; MRI: magnetic resonance imaging; NF-PitNET: non-functioning pituitary neuroendocrine tumour; PitNET: pituitary neuroendocrine tumour.