Abstract 5668: Genomic correlates of PD-L1 expression are associated with response to immunotherapy in non-small cell lung cancer
Authors: Spurr Liam F. , Lamberti Giuseppe , Li Yvonne Y. , Ricciuti Biagio , Recondo Gonzalo , Umeton Renato , Sholl Lynette M. , Meyerson Matthew L. , Cherniack Andrew D. , Awad Mark M. 
Published: September 2020

Abstract
PD-L1 expression is the primary clinical biomarker of immune checkpoint blockade (ICB) response in non-small cell lung cancer (NSCLC); patients with tumors that express higher levels of PD-L1 tend to have better responses. However, somatic genomic events correlating with PD-L1 expression are not fully defined. To investigate this, we utilized a DFCI cohort of 909 non-squamous NSCLC samples grouped into 3 categories of PD-L1 expression based on immunohistochemistry (IHC): &lt;1% (negative, n=304), 1-49% (low, n=326), and ≥50% (high, n=279) expression. All samples were sequenced by hybrid capture for over 300 cancer-associated genes (OncoPanel), and we assessed somatic mutations and copy number (CN) variations for correlation with PD-L1 expression.
Compared to PD-L1 high tumors, PD-L1 neg. cases were more likely to have mutations in STK11 (Permutation test, q=7e-4), EGFR (q=7e-4), CTNNB1 (q=0.04), APC (q=0.17), and SMARCA4 (q=0.2). CN losses that more significantly occurred in PD-L1 neg. tumors included deletions of PD-L1, PD-L2, and JAK2 (Fisher exact test, q&lt;1e-3) as well as 9p chromosomal arm loss (q=0.04) and homozygous deletions in CDKN2A/B (q=0.05).
We assessed the association of these somatic alterations with PD-L1 mRNA expression in an independent cohort of 529 TCGA primary lung tumors. STK11 mutation (Mann-Whitney test, q&lt;1e-3), CN loss of PD-L1, PD-L2, and/or JAK2 (q&lt;1e-3), and CN loss of chromosome arm 9p (q&lt;1e-3) were all associated with decreased PD-L1 mRNA expression. Conversely, CN gain of PD-L1, PD-L2, and/or JAK2 and 9p were significantly (q&lt;1e-3) associated with increased PD-L1 expression.
Next, we examined if somatic alterations associated with PD-L1 expression were also correlated with progression free (PFS) or overall survival (OS) using a partially-overlapping DFCI cohort of 468 advanced stage NSCLCs. STK11 mutation (Log-rank test, q=0.1), EGFR mutation (q&lt;1e-3), and CN loss of PD-L1, PD-L2, and/or JAK2 (q=0.02) were all significantly associated with worse PFS after ICB. EGFR mutation was significantly associated with worse OS after ICB (q=0.19).
We observed the previously identified (Schabath, et al 2016) mutual exclusivity between EGFR and STK11 mutations. We further show that they may indicate distinct subtypes of PD-L1 neg. tumors with STK11 mutant tumors exhibiting strikingly worse prognosis after ICB (med. PFS 52 vs 64 days, p&lt;1e-3; med. OS 212 vs 299 days, p=5e-3).
In summary, we confirm the findings that STK11 and EGFR mutations are associated with reduced PD-L1 expression and worse prognosis after ICB (Rizvi, et al 2018) and identify CN loss of the PD-L1 locus as a potential novel biomarker of lower PD-L1 expression and worse ICB outcomes. In addition, we show a novel anticorrelation between Wnt pathway alterations and PD-L1 expression by IHC. Taken together, this work suggests a role of specific mutations and CNVs in affecting PD-L1 expression and response to ICB.
Citation Format: Liam F. Spurr, Giuseppe Lamberti, Yvonne Y. Li, Biagio Ricciuti, Gonzalo Recondo, Renato Umeton, Lynette M. Sholl, Matthew L. Meyerson, Andrew D. Cherniack, Mark M. Awad. Genomic correlates of PD-L1 expression are associated with response to immunotherapy in 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 5668.