Clinical and molecular correlates of PD-L1 expression in patients with lung adenocarcinomas

Clinical and molecular correlates of PD-L1 expression in patients with lung adenocarcinomas

Programmed death-ligand 1 (PD-L1) expression is the only FDA-approved biomarker for immune checkpoint inhibitors (ICIs) in patients with lung adenocarcinoma, but sensitivity is modest. Understanding the impact of molecular phenotype, clinical characteristics, and tumor features on PD-L1 expression i...

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Bibliographic Details
Published in:Annals of oncology Vol. 31; no. 5; pp. 599 - 608
Main Authors: Schoenfeld, A.J., Rizvi, H., Bandlamudi, C., Sauter, J.L., Travis, W.D., Rekhtman, N., Plodkowski, A.J., Perez-Johnston, R., Sawan, P., Beras, A., Egger, J.V., Ladanyi, M., Arbour, K.C., Rudin, C.M., Riely, G.J., Taylor, B.S., Donoghue, M.T.A., Hellmann, M.D.
Format: Journal Article
Language:English
Published: England Elsevier Ltd 01-05-2020
Subjects:
Adenocarcinoma of Lung - drug therapy
Adenocarcinoma of Lung - genetics
B7-H1 Antigen - genetics
B7-H1 Antigen - metabolism
High-Throughput Nucleotide Sequencing
Humans
immunotherapy
Lung Neoplasms - drug therapy
Lung Neoplasms - genetics
Mutation
NSCLC
PD-1
PD-L1
PD-L1
NSCLC
PD-1
immunotherapy
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Summary:Programmed death-ligand 1 (PD-L1) expression is the only FDA-approved biomarker for immune checkpoint inhibitors (ICIs) in patients with lung adenocarcinoma, but sensitivity is modest. Understanding the impact of molecular phenotype, clinical characteristics, and tumor features on PD-L1 expression is largely unknown and may improve prediction of response to ICI. We evaluated patients with lung adenocarcinoma for whom PD-L1 testing and targeted next-generation sequencing (using MSK-IMPACT) was performed on the same tissue sample. Clinical and molecular features were compared across PD-L1 subgroups to examine how molecular phenotype associated with tumor PD-L1 expression. In patients treated with anti-PD-(L)1 blockade, we assessed how these interactions impacted efficacy. A total of 1586 patients with lung adenocarcinoma had paired PD-L1 testing and targeted next-generation sequencing. PD-L1 negativity was more common in primary compared to metastatic samples (P < 0.001). The distribution of PD-L1 expression (lymph nodes enriched for PD-L1 high; bones predominantly PD-L1 negative) and predictiveness of PD-L1 expression on ICI response varied by organ. Mutations in KRAS, TP53, and MET significantly associated with PD-L1 high expression (each P < 0.001, Q < 0.001) and EGFR and STK11 mutations associated with PD-L1 negativity (P < 0.001, Q = 0.01; P = 0.001, Q < 0.001, respectively). WNT pathway alterations also associated with PD-L1 negativity (P = 0.005). EGFR and STK11 mutants abrogated the predictive value of PD-L1 expression on ICI response. PD-L1 expression and association with ICI response vary across tissue sample sites. Specific molecular features are associated with differential expression of PD-L1 and may impact the predictive capacity of PD-L1 for response to ICIs. •Distinct clinical and molecular features are associated with differential PD-L1 expression and ICI response in patients with lung adenocarcinoma.•The anatomic site sampled for PD-L1 testing may influence its capacity as a biomarker for ICIs.•Molecular alterations in KRAS, TP53, EGFR, STK11, and the WNT pathway are tied to PD-L1 expression and modulate predictiveness of PD-L1.•PD-L1 must be interpreted within the context of these features, which modulate the prediction of response to ICIs.
Bibliography:Contributed equally
ISSN:0923-7534
1569-8041
DOI:10.1016/j.annonc.2020.01.065