Efficacy of pembrolizumab in patients with pituitary carcinoma: report of four cases from a phase II study

Abstract

Pituitary carcinoma is an aggressive tumor characterized by metastatic spread beyond the sellar region. Symptoms can be debilitating due to hormonal excess and survival is poor. Pituitary carcinomas recur despite conventional multimodality treatments. Given the recent advances in the use of immune checkpoint inhibitors (CPIs) to treat various solid cancers, there has been interest in exploring the role of immunotherapy for treating aggressive, refractory pituitary tumors. We treated 4 patients with pituitary carcinoma with pembrolizumab as part of a phase II clinical trial. Two patients (patients 1 and 2) with functioning corticotroph pituitary carcinomas (refractory to surgery, radiotherapy and chemotherapy) had partial radiographic (60% and 32% per Immune-Related Response Evaluation Criteria In Solid Tumors, respectively) and hormonal responses. Patient 1's response continues 42 months after initiation of pembrolizumab and his tumor tissue obtained after treatment with temozolomide demonstrated a hypermutator phenotype with MSH2 and MSH6 gene mutations. Patient 2's tumor after exposure to temozolomide was not sampled, but prior somatic mutational testing was negative. One patient with a non-functioning corticotroph tumor (patient 3) had a best response of stable disease for 4 months. One patient with a prolactin-secreting carcinoma (patient 4) had progressive disease. The latter 2 patients' tumors did not demonstrate a hypermutator phenotype after treatment with temozolomide. Programmed death-ligand 1 staining was negative in all tumors. We report 2 cases of corticotroph pituitary carcinoma responsive to pembrolizumab after prior exposure to alkylating agents. The role of CPIs in treating patients with pituitary carcinoma, the relationship between tumor subtype and response to immunotherapy and mechanisms of hypermutation in this orphan disease require further study.Trial registration number: NCT02721732.

Keywords: biomarkers; clinical trials; immunotherapy; phase II as topic; tumor.

Conflict of interest statement

Competing interests: No, there are no competing interests.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Response to pembrolizumab in patient 1. (A) T1 postcontrast MRI obtained prior to pembrolizumab treatment demonstrates a lobulated enhancing mass within the sphenoid sinus and posterior ethmoid air cells (gray arrow) with extension to the anterior and inferior aspects of the left temporal lobe (white arrow). (B) MRI of the brain after two cycles of pembrolizumab demonstrates significant improvement of the enhancing mass in the cavernous sinus and resolution of the nodule extending to the left temporal lobe. (C) The adrenocorticotropic hormone (ACTH) level became undetectable after treatment with pembrolizumab. (Reference ranges for ACTH are 0–46 pg/mL (before 4/19/18) and 7–63 pg/mL (after 04/19/18); ACTH levels are listed as ‘0’ if the reported value was less than the lower limit of detection for the assay.)

Figure 2

Clinical response in patient 2. (A) Adrenocorticotropic hormone (ACTH) levels became significantly elevated after starting pembrolizumab and then gradually declined but have not yet nadired as of the last evaluation. (B) Overview of the patient’s skin pigmentation changes. (i) Two and a half years before the diagnosis of pituitary carcinoma, the patient had normal skin coloration and an ACTH level of 160 pg/mL. (ii) At diagnosis of pituitary carcinoma, when the ACTH was 84 851 pg/mL, the patient had become remarkably hyperpigmented. Ten months after treatment with pembrolizumab commenced and when the ACTH was 628 pg/mL (iv), her skin pigmentation was noticeably lighter compared with pictures obtained 6 months earlier (iii), after 4 months of therapy, when her ACTH was >11 000 pg/mL. (Reference ranges for ACTH are 0–46 pg/mL (before 4/19/18) and 7–63 pg/mL (after 04/19/18).).