Association of frequent amplification of chromosome 11q13 in esophageal squamous cell cancer with clinical benefit to immune check point blockade.

4036 Background: Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer in South America and East Asian countries and remains an unmet medical need worldwide. Previous studies have shown the efficacy of programmed cell death 1 (PD-1) targeted therapy in a subset of patients with metastatic ESCC. However, robust predictive biomarkers to PD-1 antibody-based immunotherapy remain undefined. Methods: Patients included in this analysis were part of multi-center, phase Ib/II trial (NCT02915432) evaluating the safety and activity of toripalimab, a humanized PD-1 antibody in solid tumors. To identify molecular determinants of response, we performed whole exome sequencing (WES), messenger RNA sequencing and immunohistochemistry on patients’ samples and evaluated genomic and transcriptional biomarkers, PD-L1 expression and tumor mutational burden (TMB) for correlation with clinical efficacy. Results: Sixty advanced chemo-refractory ESCC patients were enrolled and 59 were treated with toripalimab. 94.9% (56/59) patients experienced at least one treatment related adverse event after 16 months; mostly grade 1 or grade 2. Treatment-related grade 3 or higher AEs occurred in 30.5% (18/59) of subjects. By the data cutoff date, 11 (18.6%; 95%CI 9.7 to 30.9) patients achieved an objective response, while the disease control rate was 47.5% (95%CI 34.3 to 60.9). Copy number analysis identified 24 out of 50 (48%) patients with amplifications of chromosome 11q13 region, which was consistent with elevated mRNA expression of amplified genes, including CCND1(Cyclin D1) and fibroblast growth factor family members ( FGF3/4/19). Patients without 11q13 amplification, had significantly better objective response rate (ORR 30.8% versus 4.2%, p= 0.024) and progression free survival (3.7 versus 2.0 months, HR = 0.47 [95%CI 0.24 to 0.91], p= 0.025) when compared with 11q13 amplified individuals. In contrast, patients with high TMB (≥12 Mutations/Mb; 11/47, 23.4%) or positive PD-L1 expression (TC or IC 1%; 19/57, 33.3%) showed no significant advantage in ORR or survival. Conclusions: Toripalimab has demonstrated a manageablesafety profile and promising anti-tumor activity in chemo-refractory ESSC patients. Genomic amplification of 11q13 region may serve as a negative predictive marker for advanced ESSC patients receiving anti-PD-1 based immunotherapy. Further interrogation of putative resistance genes that lie within this region is under study. Clinical trial information: NCT02915432.