Inpp4b Mutation As A Novel Biomarker For Immunotherapy In Patients With Non-Small Cell Lung Cancer

Background: Immune checkpoint inhibitors (ICIs) have shown remarkable antitumor effects in non-small cell lung cancer (NSCLC), however, only a subset of patients show a response. Therefore, more accurate biomarkers are highly needed. The aim of this study was to examine the prevalence of INPP4B and its association with response to ICIs among patients with NSCLC. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor and matched blood samples of 3433 NSCLC patients from OrigiMed were collected for targeted next-generation sequencing (NGS) panel sequencing from December 2017 to January 2019. Genomic alterations (GAs) including single nucleotide variations, short and long insertions/deletions, copy number variations, and gene rearrangements were assessed. PD-L1 expression positive was defined as ≥1% of tumor cells with membranous staining (22C3, DAKO). Genomic data and ICIs treatment outcome of a cohort of 240 NSCLC patients were derived from cBioPortal (MSKCC, J Clin Oncol 2018). Results: INPP4B GAs were found in 1% of patients (33/3433) in the OrigiMed database and 3.75% of patients (9/240) in the MSKCC database. Sites of INPP4B mutations were found scattered throughout the gene, and no significant difference was observed in the frequency of INPP4B GAs between age, stage, and histologic subtype. INPP4B GAs were associated with a significantly higher tumor mutational burden (TMB) compared with wild-type (WT) INPP4B (14.7 vs. 4.6 muts/Mb, respectively, p<0.001). PD-L1 expression was detected in 20.9% of patients (718/3433), including 9 patients with INPP4B GAs. INPP4B GAs were significantly associated with higher PD-L1 expression compared with WT (66.7% vs 29.1%, respectively, p=0.006). Survival analysis from the MSKCC cohort confirmed that patients with INPP4B GAs had a remarkable clinical benefit to ICIs compared to WT patients in both progression free survival (PFS) (13.17 months vs 3.23 months, respectively, p=0.041) and durable clinical benefit (DCB) (50% vs 29.7%, respectively, p=0.25). Furthermore, INPP4B GAs were independent risk factors of PFS (HR: 0.34, 95%CI: 0.134-0.86, p=0.023). Conclusion: This study's findings suggest that the GAs of INPP4B occur in a subgroup of patients with NSCLC and are associated with an increased TMB and response to ICIs, suggesting that GAs of INPP4B may have implications as a biomarker for guiding ICI treatment. Keywords: non-small cell lung cancer, INPP4B, tumor mutational burden, immunotherapy Citation Format: Zhuojian Shen, Hongbiao Wang, Jianjiang Xie, Yuan Su, Shiyue zhang, Jiqiang He, Hui Chen, Shaohua Yuan, Xiaowei Dong. INPP4B mutation as a novel biomarker for immunotherapy in patients with non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4287.