Development of leptomeningeal carcinomatosis during a marked response of brain metastases to pembrolizumab in a patient with non-small-cell lung cancer

Pembrolizumab, a monoclonal antibody to the immune-checkpoint protein PD-1 (programmed cell death-1), has been approved for the treatment of several tumor types including non-small-cell lung cancer (NSCLC). On the basis of the results of a randomized phase III trial (KEYNOTE-024) [1.Reck M. Rodriguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (6208) Google Scholar], pembrolizumab is now administered as a standard therapy for patients with advanced NSCLC that expresses the PD-1 ligand (PD-L1) on at least 50% of tumor cells. However, little is known of the efficacy of immune-checkpoint inhibitors (ICIs) for the treatment of central nervous system (CNS) metastasis. We here describe a patient with NSCLC who developed leptomeningeal carcinomatosis despite a marked response of the primary lesion and metastatic brain tumors during pembrolizumab therapy. A 52-year-old man was diagnosed with stage IV lung adenocarcinoma (cT4N2M1b) and multiple brain and bilateral adrenal metastases (Figure 1A and B). The primary tumor tested negative for epidermal growth factor receptor gene (EGFR) mutation and anaplastic lymphoma kinase gene (ALK) rearrangement. Given that the IHC 22C3 pharmDx assay (Dako) detected PD-L1 expression on 100% of tumor cells, pembrolizumab was administered at a dose of 200 mg every 3 weeks as first-line therapy. After two cycles of pembrolizumab treatment, a marked response of both the primary lesion and metastatic tumors in the adrenal glands and brain was apparent. Although this response was sustained after six cycles, at this time the patient developed intermittent headache, and magnetic resonance imaging of the brain and spinal cord revealed enhancement of leptomeningeal disseminations (Figure 1E and F). Cytological analysis of cerebrospinal fluid (CSF) revealed the presence of adenocarcinoma cells. On the basis of these findings, the patient was diagnosed with leptomeningeal carcinomatosis and was treated with whole-brain and craniospinal irradiation for symptom relief. Although the KEYNOTE-024 trial demonstrated the superiority of pembrolizumab over platinum-based combination chemotherapy as a first-line treatment for NSCLC that expresses PD-L1 on at least 50% of tumor cells and which is negative for EGFR mutation and ALK rearrangement [1.Reck M. Rodriguez-Abreu D. Robinson A.G. et al.Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.N Engl J Med. 2016; 375: 1823-1833Crossref PubMed Scopus (6208) Google Scholar], patients with untreated brain metastasis or leptomeningeal carcinomatosis were ineligible for this study. In a recent phase II trial in which pembrolizumab was tested in 18 PD-L1 (clone 22C3)–positive (>1%) NSCLC patients with at least one untreated or progressive asymptomatic brain metastasis, a complete or partial response of brain metastases was achieved in 33% of patients [2.Goldberg S.B. Gettinger S.N. Mahajan A. et al.Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.Lancet Oncol. 2016; 17: 976-983Abstract Full Text Full Text PDF PubMed Scopus (715) Google Scholar]. Disease relapse in the CNS without progression at extracranial sites can occur in some NSCLC patients. ICIs do not directly act on the tumor but rather promote the response of effector T cells to tumor cells [3.Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy.Nat Rev Cancer. 2012; 12: 252-264Crossref PubMed Scopus (8856) Google Scholar], and activated T cells are able to cross the blood–brain barrier to reach metastatic brain tumors even if the barrier is intact. In contrast, the blood–CSF barrier at the choroid plexus, in which epithelial (ependymal) cells are joined together by tight junctions, may be less permissive to the passage of pembrolizumab and activated T cells into the CSF and therefore may limit any effect on tumor cells therein [4.Deeken J.F. Loscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses.Clin Cancer Res. 2007; 13: 1663-1674Crossref PubMed Scopus (550) Google Scholar]. To the best of our knowledge, this is the first report of the development of leptomeningeal carcinomatosis during a pronounced response of the primary tumor and brain metastases to pembrolizumab therapy in a patient with NSCLC. Physicians should thus be aware of the risk for leptomeningeal carcinomatosis during ICI therapy even in the presence of a systemic tumor response. None declared.