Sequential ctDNA whole-exome sequencing in advanced lung adenocarcinoma with initial durable tumor response on immune checkpoint inhibitor and late progression.

Abstract

BACKGROUND:

Despite prolonged tumor response to immune checkpoint inhibitors (ICIs) for a subset of patients with advanced non-small cell lung cancer (NSCLC), a secondary resistance will occur for a majority of these patients. The understanding of late progression mechanisms with ICIs is important to improve future treatment strategies.

METHODS:

We performed whole-exome sequencing (WES) on circulating tumor DNA and compared molecular profiles between the beginning of ICI treatment and tumor progression in patients with advanced NSCLC treated with ICIs and who had initial and prolonged tumor response with secondary progression, after at least 6 months of treatment.

RESULTS:

We identified eight patients who experienced initial and durable tumor response, and secondary tumor progression after 6 months of treatment, with available paired blood samples (diagnosis and progression). All had lung adenocarcinoma, three had programmed-death ligand-1 expression ≥50% in immunohistochemistry and all presented low blood tumor mutational burden (bTMB). Seven patients received nivolumab in second-line or more, and one received pembrolizumab as first-line treatment. WES at progression showed clonal selection with molecular alterations of Wnt pathway-related genes, increase of copy number aberrations in cancer-related genes and loss of tumor-suppressor genes (such as PTEN) or of genes associated with immune response (such as B2M). No difference in term of bTMB was observed at progression.

CONCLUSIONS:

This is the first study describing putative molecular mechanisms associated with late progression under ICI in lung cancer. Studies on treatment strategies adapted to these mechanisms are needed.

• Authors: Etienne Giroux Leprieur, Zofia Hélias-Rodzewicz, Paul Takam Kamga, Adrien Costantini, Catherine Julie, Alexandre Corjon, Coraline Dumenil, Jennifer Dumoulin, Violaine Giraud, Sylvie Labrune, Simon Garinet, Thierry Chinet, Jean-François Emile
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 8 Issue 1 (06 2020) ISSN: 2051-1426 [Electronic] England
• PMID: 32581058 (Publication Type: Journal Article)
• Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Antibodies, Monoclonal, Humanized
• B7-H1 Antigen
• CD274 protein, human
• Circulating Tumor DNA
• Immune Checkpoint Inhibitors
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Nivolumab
• pembrolizumab

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• B7-H1 Antigen (analysis, immunology, metabolism)
• Carcinoma, Non-Small-Cell Lung (blood, drug therapy, genetics, mortality)
• Circulating Tumor DNA (blood, genetics)
• DNA Copy Number Variations
• DNA Mutational Analysis
• Disease Progression
• Drug Monitoring (methods)
• Drug Resistance, Neoplasm (genetics)
• Female
• Humans
• Immune Checkpoint Inhibitors (pharmacology, therapeutic use)
• Lung (immunology, pathology)
• Lung Neoplasms (blood, drug therapy, genetics, mortality)
• Male
• Microsatellite Instability
• Middle Aged
• Mutation
• Neoplasm Staging
• Nivolumab (pharmacology, therapeutic use)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, immunology, metabolism)
• Progression-Free Survival
• Retrospective Studies
• Time Factors
• Exome Sequencing