Successful treatment with an anti-PD-1 antibody for progressing brain metastases in renal cell cancer.

We present the case of a woman age 54 with clear-cell renal cell cancer (ccRCC), who developed metastases in multiple organs including one brain metastasis (gyrus cinguli). She was treated with pazopanib and the solitary brain metastasis was irradiated with 30 Gy in July 2013. In February 2014, after 8-month treatment with pazopanib, this metastasis increased in size and two new brain metastases were detected. Whole brain radiotherapy was performed leading to a cumulative dose of 52.5 Gy at the site of the gyrus cinguli metastasis. The patient was subsequently treated with bevacizumab for progressive cerebral oedema interpreted as radiation-induced brain necrosis. Upon systemic and central nervous system (CNS) progression 5 months later (Figure 1A), treatment with axitinib was started—achieving partial response (PR) (Figure 1B). However, after 4 months, in March 2015, further systemic and CNS progression was documented (Figure 1C). Treatment with pembrolizumab, a novel human programmed death receptor-1 (PD-1)-blocking antibody, was initiated. Pembrolizumab was chosen due to off-label availability at a time when no anti-PD-1 or anti-PD-ligand (L)1 antibody was licensed in Europe. After four infusions, the patient experienced complete resolution of lung metastases, stabilization of other metastases. Importantly, regression of all brain metastases was documented on magnetic resonance imaging (Figure 1D). This excellent response was seen despite continued steroid use of 4 mg dexamethasone/day and is still ongoing after 7 months of treatment (Figure 1E). There are data on the safety and limited efficacy of sunitinib [1] and other vascular endothelial growth factor targeted therapies [2] in ccRCC patients with active brain metastases. New checkpoint inhibitors are currently under investigation for ccRCC and have shown promising results with improvement of overall survival for patients treated with the anti-PD-1 antibody nivolumab compared with everolimus; however, metastasis to the CNS was a key exclusion criterion in the CheckMate 025 study [3]. No data are published on the effect of anti-PD-1 or anti-PD-L1 antibodies on progressing brain metastases requiring systemic steroids. In early clinical trials with new checkpoint blocking agents, only patients with no or treated and stable brain metastases were eligible [4, 5]. In a phase II trial, the anti-cytotoxic T-lymphocyte-associated protein-4 antibody ipilimumab was assessed in melanoma patients with brain metastases. This study also included 21 patients receiving systemic steroids due to symptomatic brain metastases. Out of these, one patient showed a PR at week 12, all other patients progressed.