Abstract 2250: Combinational markers of neoantigen intratumor heterogeneity and neoantigen burden predict progression-free survival for lenvatinib plus PD-1 blockade in patients with intrahepatic cholangiocarcinoma

Abstract

Abstract Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignant neoplasm derived from biliary epithelial cells. Although many targetable gene alterations have been identified, there has no molecular targeted drug available for these patients at present, which may be due to the high intratumor heterogeneity (ITH) of ICC. Previous studies have demonstrated that some ICC patients could be benefited from immune checkpoint inhibitors (ICIs), but the predictive biomarkers are still unknown. We used whole exome sequencing to evaluate the impact of neoantigen ITH and tumor neoantigen burden (TNB) in 45 ICC patients, in which 15 patients were treated by anti-PD1 inhibitor combined with lenvatinib. The median neoantigen and clonal neoantigen load of these patients were 0.65 and 0.29 per Mb, respectively. The median neoantigen ITH index was 0.45, with a range from 0.02 to 1. Survival analysis of those patients who received the combined treatment revealed significantly longer progression-free survival (PFS) in patients with higher TNB and low neoantigen ITH (9.5 vs 3.5 months, p=0.00583). Among the 30 patients without anti-PD1 combined therapy, there were 36.7% (11/30) ICC patients with high TNB and low neoantigen ITH, indicating these patients might be benefited from this combined therapy. One of these 45 patients had the highest TMB and TNB with high MSI and dMMR has the longest PFS (12 months) after the combined treatment. Besides, we found that the clonal KRAS mutation (G12D) occurred exclusively in patients with shorter PFS and OS and lower TMB and TNB, while the FLG mutation occurred only in patients with longer PFS and OS and higher TMB and TNB. These results indicated the potential relationship between mutations in KRAS and FLG and the levels of TMB and TNB, which needs to further investigation. Therefore, these data revealed that the high TNB and lower neoantigen ITH might be a promising marker for predicting the efficacy of the combination therapy of anti-PD1 inhibitor and lenvatinib in ICC patients. Citation Format: Jianzhen Lin, Yiying Liu, Xu Yang, Yi Bai, Junyu Long, Junyu Long, Yongchao Li, Jiaqian Wang, Dongxu Wang, Xiaobo Yang, Mei Guan, Li Huo, Jie Pan, Ke Hu, Zhibo Gao, Haitao Zhao. Combinational markers of neoantigen intratumor heterogeneity and neoantigen burden predict progression-free survival for lenvatinib plus PD-1 blockade in patients with intrahepatic cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2250.