Immunotherapy for Aggressive and Metastatic Pituitary Neuroendocrine Tumors (PitNETs): State-of-the Art

Simple Summary The treatment of aggressive and metastatic pituitary neuroendocrine tumors (PitNETs) refractory to current therapies, including temozolomide, is challenging and hopes are relying on personalized therapies. Immunotherapy based on immune checkpoint inhibitors (ICIs) is a revolutionary tool in oncology. This study was stimulated by our recent experience with a metastatic Pit1-derived PitNET expressing PDL1 and showing a remarkable response to pembrolizumab. After a detailed review and critical analysis of a total of 13 cases reported so far (12 from the literature), a significant clinical benefit of ICIs was clearly documented in nearly 50% of the cases. Among potential predictors of response, high PDL1 expression appeared to predominate in Pit-1 derived neoplasia, and elevated tumor mutation burden and/or mismatch repair deficiency in T-pit derived tumors, although all were dispensable. Based on encouraging results and generally acceptable safety profiles, the potential role of ICIs in refractory PitNETs and ICIs regimens are discussed. Background: Aggressive and metastatic PitNETs are challenging conditions. Immune checkpoint inhibitors (ICIs) are currently considered in cases resistant to temozolomide (TMZ). However, clinical experience is essentially limited to case reports, with variable outcomes. Material and Methods: The effects of ICIs on 12 aggressive/metastatic PitNETs from the literature were reviewed and analyzed according to tumor characteristics, with the additional description of a silent-Pit1 metastatic tumor responding to pembrolizumab. Results: Most cases were metastatic (10/13: 6 corticotroph, 3 lactotroph, 1 silent Pit1); 3 were aggressive (2 corticotroph, 1 lactotroph). ICIS was used either as monotherapy or in combination. At last follow-up on ICI, a complete response (CR) was present in 3 cases and a partial response (PR) in 2 cases (4/5 metastatic). One sustained stable disease (SD) was reported. Progressive disease (PD) was observed in 7 cases, 3 of them after initial SD (n = 1) or PR (n = 3), with 2 reported deaths. PDL1 expression was studied in 10 cases and was high (>95%) in 2 Pit1-derived metastatic PitNETs (1 CR and 1 remarkable PR) but absent/low (<1%) in the remaining cases (including 1 CP and 2 PR). Elevated tumor mutation burden could be informative in corticotroph PitNETs, especially in mismatch repair-deficient tumors. Conclusion: Significant benefits from ICIs were documented in about half of TMZ-resistant PitNETS. High PDL1 expression was associated with remarkable responses but may be dispensable. Based on their acceptable tolerance and awaiting recognized predictors of response, ICIs may be considered a valuable option for such patients.