Clinicopathological, genomic and immunological features of hyperprogressive disease during PD-1 blockade in gastric cancer patients.

4106 Background: Hyperprogressive disease (HPD) during PD-1 blockade reported in several cancer types is a big hurdle for applying cancer immunotherapy, whereas there is no report in gastric cancer (GC) and the detailed clinicopathological, genomic, and immunological features remain to be determined. Methods: To clarify clinicopathological, genomic, and immunological features of hyperprogressive disease during PD-1 blockade in patients with advanced GC, 36 patients with advanced GC who received nivolumab from October 2017 to December 2017 and underwent at least one imaging evaluation of their clinical responses were enrolled in this study. Tumor DNA/RNA samples and tumor-infiltrating lymphocyte (TIL) were also analyzed using next-generation sequencing and flow-cytometry assay, respectively. Results: Among 36 patients, four patients (11.1%) experienced hyperprogressive disease, and their prognosis was very poor with three of four patients died within very short period after the initial administration of nivolumab (range 20 to 65 days). Three and two among four patients were subjected to genome analyses and TIL analyses, respectively. One patient had an MDM2 gene amplification as was previously reported, whereas the other patients did not have any MDM2 gene family alterations. Immunological analyses in two patients revealed that effector regulatory T (eTreg) cells with proliferative capacity (Ki67+CD45RA-FOXP3highCD4+ T cells) were markedly increased in TILs from pre-treatment to hyperprogressive disease state, whereas those in non-hyperprogressive disease patients showed significant reduction. Especially, one patient without MDM2 gene amplification contained enormously high frequency of Ki67+eTreg cell-infiltration in the tumor at HPD state. Conclusions: HPD during PD-1 blockade is observed in gastric cancer as well as other cancer types and the prognosis is very poor. High regulatory T cell-infiltration and MDM2 family gene alterations might contribute to HPD, which should be taken care during the treatment with anti-PD-1 antibodies.