Clinical, pathologic, and genomic profiles of exceptional responders to anti−PD1 therapy in renal cell carcinoma.

625 Background: Previous studies have correlated response to PD−1 blockade with PD−L1 over−expression, as well as cell−mediated immune transcripts). However, factors associated with long−term, durable response to nivolumab in patients with RCC have not yet been elucidated. To better understand these factors, we conducted a study to characterize the two extremes of response to therapy – exceptional responders who had durable, complete response and patients who had primary refractory disease. Methods: Patients with durable, complete response (“exceptional responders”) (n=4) and primary refractory disease (n=3) were analyzed. Immunohistochemical staining for PD−L1, CD8 and FOXP3, whole−exome sequencing and quantitative RNA expression profiling was performed and correlated with clinical outcomes. Results: Exceptional responders had trends toward greater CD8+ lymphocyte infiltrate (126.7 vs 28.8 lymphocytes/hpf), higher number of somatic mutations (67 vs 35 somatic mutations/genome), and higher number of predicted mutation associated neoantigens than primary refractory patients (44 vs 8). Expression analysis demonstrated acute phase and immune tolerance signatures in primary refractory patients, while exceptional responders had higher expression of T cell and innate immune signatures. Conclusions: Exceptional responders and primary refectory patients have distinct pathologic, genomic and RNA expression profiles. Larger studies are needed to fully elucidate the basis of response to PD−1 blockade in patients with renal cell carcinoma.