Abstract 2021: Mutational landscape of STK11, PD-L1 expression, and TMB in patients with non-small cell lung cancer
Authors: Jiang Youhua , Tao Kaiyi , Wang Liang , Hu Yuqian , Zhang Shiyue , Zhang Lin , Yao Ming 
Published: September 2020

Abstract
Background: Cancer immunotherapy, especially immune checkpoint inhibitors (ICIs), has a remarkable antitumor response in non-small cell lung cancer (NSCLC), but only a limited number of patients can derive durable benefits from it. Therefore, more accurate biomarkers are highly needed. STK11 is a well-known negative regulator for response to ICIs, but the mutation frequency of STK11 and its correlation with recognized immune biomarkers in Chinese patients with NSCLC remains unclear.
Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor and matched blood samples of 637 NSCLC patients from the OrigiMed were collected for targeted next-generation (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. Tumor mutational burden high (TMB-H) was defined as ≥10 muts/Mb. PD-L1 expression positivity was defined as ≥1% of tumor cells with membranous staining (22C3, DAKO). Genomic data and ICIs treatment outcome of one cohort of NSCLC patients were derived from cBioPortal database.
Results: STK11 GAs were found in 6.9% (44/637) of patients in the OrigiMed database. No significant difference was observed in the frequency of STK11 GAs within the histologic subtypes. Sites of the STK11 mutations were found scattered throughout the gene. STK11 GAs were associated with a significantly higher TMB compared with wild-type (WT) STK11 (11.95 vs. 4.6 muts/Mb, respectively, p&lt;0.001) while patients with STK11 mutations were significantly enriched in the PD-L1-neg/TMB-H subgroup (p&lt;0.001). Among 44 STK11 mutated NSCLC patients, 19 (43.2%) were co-mutated with KRAS and had a lower TMB than the STK11-MUT/KRAS-WT subgroup (7.7 vs. 14.7 muts/Mb, respectively, p=0.015), and 12 (27.3%) patients were co-mutated with KEAP1 and had a lower TMB than the KEAP1-MUT/STK11-WT subgroup (7.7 vs. 17.4 muts/Mb, respectively, p=0.006). Survival analysis from the cohort confirmed that patients with STK11 GAs had a worse clinical response to ICIs compared to WT in overall survival (OS) (6 months vs 12 months; p=0.12). Furthermore, patients with STK11/KEAP1 co-mutations had significantly worse clinical response to ICIs compared to co-WT in OS (4 months vs 12 months, respectively, p=0.011).
Conclusion: The results showed that in our cohort, Chinese NSCLC patients with STK11 GAs were enriched in PD-L1-neg/TMB-H subgroup and associated with a poor response to ICIs in Chinese NSCLC patients. We also found that co-mutations of STK11 and KEAP1 may have implications as a negative biomarker for guiding ICI treatment.
Keywords: non-small cell lung cancer, FGFR4, tumor mutational burden, immunotherapy
Citation Format: Youhua Jiang, Kaiyi Tao, Liang Wang, Yuqian Hu, Shiyue Zhang, Lin Zhang, Ming Yao. Mutational landscape of STK11, PD-L1 expression, and TMB 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 2021.