Abstract 5886: Different subtypes of EGFR mutations exhibit distinct patterns of TMB and PD-L1 in patients with non-small cell lung cancer
Authors: Shang Yanhong , Tian Ziqiang , Wen Shiwang , Yang Jie , Guo Jian , Li Mingjiang , Liu Dan , Zhang Shiyue , Wang Kai 
Published: September 2020

Background: Immune checkpoint inhibitors (ICIs) have provided remarkable antitumor effects in non-small cell lung cancer (NSCLC), and 5 PD-1 inhibitors have been approved in China. Several studies showed that NSCLC patients with oncogenic driver mutations may have poor responses to ICIs. However, the role of immunotherapy in oncogene-addicted NSCLC remains unclear and the relationship between PD-L1 expression, TMB, and driver gene mutations is not fully understood.

Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor tissue and matched blood samples of 1111 NSCLC patients from OrigiMed were collected for targeted 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).

Results: We found EGFR GAs in 59.4% of patients (660/1111) in the OrigiMed database, including 249 ex19del, 291 L858R, 31 ex20ins, 33 G719X, 30 T790M, 11 L861Q, and 15 other uncommon mutations. The frequency of EGFR mutations was significantly higher in female patients (p&lt;0.001) and non-smoker patients (p&lt;0.001). EGFR mutations were associated with a significantly lower TMB compared with wild-type (3.7 vs. 6.9 muts/Mb, respectively, p&lt;0.001). However, EGFR G719X was correlated with a significantly higher TMB and TMB-H/PD-L1-positive proportion than EGFR ex19del (p&lt;0.001) and L858R (p&lt;0.001). In addition, the frequency of concurrent TERT GAs with EGFR ex19del and L858R was higher than that with EGFR G719X (p=0.017), while the frequency of concurrent LRP1B and MED12 GAs with EGFR G719X was higher than that with EGFR ex19del and L858R (p=0.009 and p=0.008, respectively). Furthermore, the frequency of concurrent gene copy number amplification with EGFR ex19del and L858R was higher than that with EGFR G719X (p=0.086 and p=0.037, respectively).

Conclusion: This study's findings reveal that different EGFR mutation subtypes display heterogeneous immunotherapeutic features, and EGFR G719X was associated with an increased TMB, a higher proportion of TMB-H/PD-L1 positive patients, and fewer concurrent copy number amplification GAs. This suggests that GAs of G719X may have implications as a biomarker for guiding ICI treatment in EGFR-mutated NSCLC.

Citation Format: Yanhong Shang, Ziqiang Tian, Shiwang Wen, Jie Yang, Jian Guo, Mingjiang Li, Dan Liu, Shiyue Zhang, Kai Wang. Different subtypes of EGFR mutations exhibit distinct patterns of TMB and PD-L1 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 5886.