Exceptional response to pembrolizumab in a metastatic, chemotherapy/radiation resistant ovarian cancer patient harboring a CD274/PD-L1-genetic rearrangement

Purpose: Ovarian carcinoma no longer responsive to surgery and chemotherapy remains an incurable disease. Alternative therapeutic options remain desperately needed. Experimental Design: We describe a heavily pretreated ovarian cancer patient with recurrent disease experiencing a remarkable clinical response to treatment with the anti-PD1 immune check-point inhibitor pembrolizumab. The clinical, pathological, and genomic characteristics of this exceptional ovarian cancer responder were carefully investigated using immunohistochemistry (IHC), quantitative multiplex fluorescence methods (ie, automated quantitative analysis, AQUA) and whole exome sequencing (WES) techniques. Results: The patient harbored a recurrent/metastatic radiation and chemotherapy-resistant high grade ovarian carcinoma with clear cell features.  While progressing on any standard treatment modality she demonstrated a remarkable complete response to the anti-PD1 immune check-point inhibitor pembrolizumab. WES results were notable for the presence a relative low number of mutations (Tumor Mutation Load/Mb = 4.31, total mutations = 164) and a peculiar structural variant disrupting the 3' region of the PD-1L gene causing aberrant PD-L1 surface expression as confirmed by immunohistochemistry (IHC) and AQUA technology. Heavy infiltration of the PD-L1-mutated and PD-L1-overexpressing tumor with T cell lymphocytes (ie, CD4+/CD8+ TIL), CD68+ macrophages and CD20+ B cells was detected in the surgical specimen strongly suggesting immune evasion as a key mechanism of tumor growth and survival. Patient's complete clinical responses remain unchanged at the time of the writing of this report with no significant side-effects reported to date. Conclusions: Anti-PD1 inhibitors may represent a novel treatment option for recurrent/metastatic human tumors refractory to salvage treatment harboring PD-L1 gene structural variations causing aberrant PD-L1 expression.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2rkjWVq